OSD211 - Systems 5 Midterm

What is the Origin of The Effector cells of the Innate and Adaptive Immune System?

- NK cells normally around 5-10%, if above then an infection may be occuring - Patients without NK cells often have cancer - NK cells from peripheral blood can kill cancer, but NK cells from tissues can't because of different function - B cells normally 3-7% in peripheral blood - T cells = *largest* around 60% - Monocytes important in cancer patients (20-25%, while normal is 7-10%)

Limiting Clot Formation to Sites of Injury

- Protein C are vitamin K-dependent factors that hydrolyze 5a and 8a breakdown - Thrombomodulin helps activate protein C - Antithrombin (natural anticoagulant) inactivates Thrombin (2) and factor 10a Natural anticoagulants: Protein C, Protein S, antithrombin - *Heparin* enhances activation of antithrombin (as a cofactor) to degrade factor 2 and 10

What are the Laboratory Tests for Allergies?

Laboratory Tests for Allergies 1. IgE antibody tests - In vivo - skin tests a) Skin patch test - patches applied to the surface b) Skin prick test - epidermis pricked and allergen applied c) Intradermal - allergen injected subcutaneously - In vitro - RAST (radioallergosorbent test) = indirect antibody testing with fluorescent tagging 2. Provocation tests - food challenges 3. CXR & pulmonary fxn test - asthma 4. CT - sinusitis

What are the Reactions to Innate Immunity?

Reactions to Innate Immunity 1. Inflammation: Cytokines, complement activation products, other mediators produced to produce cellular, vascular changes. 2. Antiviral defense: Type I interferons are produced in response to viruses to inhibit viral replication as well as degrade viral nucleic acids. 3. Link to stimulate the more powerful adaptive immune response. - Innate Immunity does not have memory or fine antigen specificity - 100 receptors for 1000 molecular patterns -Adaptive immunity: 2 receptors, each with millions of variations, to recognize millions of antigens.

What are the Characteristics of Red Blood Cell Maturation?

Red Blood Cell Maturation 1. Proerythroblast (oval 2 nuclei/open chromatin) 2. Basophilic erythroblast (dense nuclei) 3. Polychromatophilic erythroblast (nuclei) 4. Normoblast (nuclei) 5. Red cells (biconcave disk, no nuclei) Red Cell maturation - As cells mature they lose their nucleus and become hemoglobinized (pink), and enter the circulation - Acute blood loss in presence of a normal bone marrow can result in hyperplasia of red cell precursors and lead to increased immature red cells (reticulocytes) int he circulation

What are the Characteristics of Red Blood Cells and Reticulocytes?

Red Blood cells 1. RBCs transport oxygen to peripheral tissues 2. Normal life span is 120 days and senescent red cells are removed from circulation by spleen and liver 3. Under electron microscopy red cells are biconcave discs with avg diameter of 7.2 µm 4. Red cell plasma membrane is composed of lipid bilayer under which is protein cytoskeleton the main being *spectrin* Reticulocytes 1. Reticulocyte = immature erythrocyte with residual ribosomal RNA (*bluish color* - 2/3 of reticulocytes mature in marrow - 1/3 of reticulocytes mature in circulation within 24 hr 2. Normal range of reticulocytes in blood is 0.5-1.5% 3. If patient is anemic and marrow response is healthy, reticulocytes % can be up to 10x higher 4. If patient is anemic, and the reticulocyte % is "normal" that indicates the marrow is not appropriately responding to anemia

What are the Characteristics of Red Cell Disorders: Anemia?

Red Cell Disorders 1. Anemia - Reduced oxygen carrying capacity of blood, which stems from reduction in total circulating red cell mass below normal - This results in lower hemoglobin (Hb) and hematocrit (HCT) Classification of Anemias 1. Pathology - Decreased red cell production - Increased red cell destruction (hemolysis) - Blood loss, acute or chronic 2. Morphology - Microcytic (iron deficiency, thalassemia) - Macrocytic (folate or B12 deficiency) - Normocytic but with abnormal shapes (hereditary spherocytosis, sickle cell disease) Anemia due to Decreased Production 1. Nutritional deficiency - Iron defiency - B12/Folic Acid deficiency (megaloblastic anemia) 2. Bone marrow failure - Aplastic anemia 3. Erythropoetin deficiency - Renal failure 4. Disorders of globin synthesis - Thalassemia

What are the Characteristics of Erythropoiesis?

Red Cell Production 1. Erythropoiesis is regulated by erythropoietin (a hormone that is synthesized in the kidney) 2. Nutrients required for red cell production include Iron, B-12, Folate 3. Erythropoiesis depends on normal bone marrow function

What are the Characteristics of Secondary Hemostasis - Formation of Blood Clot?

Requirements of Blood Clotting 1. Rapid and efficient 2. No clotting under normal conditions 3. Self-limiting 4. Removal of clots as healing occurs *Fibrinogen monomers are cleaved by Thrombin (catalyst) into Fibrin fibrils* 1. Fibrin crosslinking performed by factor XIII* (13) - Fibrin monomers not linked = Soft Clot - Fibrin monomers crosslinked = Hard Clot (insoluble) Other roles of Thrombin 1. Cleaves a thrombin receptor on platelets causing PLT activation 2. Cleaves Factor V (5) and VIII (8) to form active Va (5a) and VIIIa (8a) 3. Limits clot formation by eventually cleaving Va (5a) and VIIIa (8a)

What are the Risk factors and Treatment for Oral Cancer?

Risk Factors for Oral Cancer 1. Tobacco 2. HPV infection: oropharyngeal cancers 3. Chewing quid of betel 4. Alcohol 5. Radiation exposure 6. Long-term irritation caused by ill-fitting dentures Treatment for Oral Cancer 1. Surgery 2. Radiation therapy 3. Chemotherapy - cisplatin - 5-Fluorouracil - carboplatin - paclitaxel 4. Tumor growth factors: targeting EGFR Implication for Dentistry 1. Oral complication of cancer therapy a) Direct toxicities: - Oral mucositis - Salivary gland dysfunction - Neurotoxicity: taste bud defects and dysfunction, dentinal hypersensitivity - Temporomandibular dysfunction - Dental and skeletal growth and developmental anomalies (pediatric patient)

What are the Classifications of Antineoplastic Drugs?

*By Target of Action* 1. Cell cycle specific drugs (DNA & Mitosis) - Only proliferating cells killed - Schedule dependent rather than dose Ex: alkaloids and antimetabolites 2. Cell cycle non-specific drugs - Both proliferating and non-proliferating cells - Dose dependent rather than schedule Ex: alkylating agents *By Mode of Action* 1. Cytotoxic antineoplastics - Nonselective - Proliferating cells 2. Targeted antineoplastics - Specific molecular targets - Cytostatic (suppress the cell) Cytotoxic Antineoplastics 1. Antimetabolites (DNA) 2. Taxanes (Mitosis) 3. Vinca alkaloids (Mitosis) 4. Alkylating agents (Mitosis) Targeted Antineoplastics 1. Monoclonal antibodies 2. Tyrosine kinase inhibitors

What are the Characteristics of Cancer?

*Central Premise: Cancer is a genetic disease* Central Dogma - DNA sequence changes can lead to altered protein function which leads to phenotypic differences or disease - Proteins regulate normal development, cell division, homeostasis Gene sequencing - Idea of cancer and genetics has been around for decades - A full accounting of the extent of these genetic abberations is only now coming to light - This has been made possibly by technologic advances in DNA sequencing and other methods that permit genome-wide analysis of cancer cells Factors that influence cancer development 1. Environmental: Dominant risk factor for most cancers 2. Hereditary: 5% of cancer cases attributed to genes that you inherit Environmental Factors that influence Cancer development 1. Infectious agents: 15% of all cancers caused directly or indirectly by infectious agents (ex: HPV causes cervical and head & neck cancer) 2. Smoking: implicated in cancers of mouth, pharynx, larynx, esophagus, pancreas, bladder and in 90% of lung cancer deaths 3. Alcohol consumption: increase risk of cancers in oropharynx, esophagus, and hepatocellular carcinomas 4. Diet: thought to influence colon and prostate cancers 5. Obesity; overweight individuals have over a 15-50% higher death rate from cancer 6. Reproductive history: estrogen exposure without progesterone 7. Environmental carcinogens: UV ray, asbestos, arsenic, grilled meat, medications, etc Does that mean genetics is not important? - No, lack of family history does not preclude an inherited component - There is definitely an interplay between genetics and the environment - Ex: Breast cancer risk increased 3x for women who inherit mutated copies of BRCA1 or BRCA2 born after 1940 thna before that year - Polymorphism: Ex: P-450 polymorphism in 1 loci + smoking = inherited susceptibility to lung cancer

What are the Three Hereditary Blood Clotting Diseases?

1. *Hemophilia A* - X-linked recessive deficiency of factor VIII (8) - Incidence: 1/10,000 - Prevalent in European royal families - Affected patients have <5% of normal factor VIII activity - Symptoms include: ease of bruising, intramuscular hematoma, hemorrhage of joints (hemarthrosis), prolonged bleeding 2. *Hemophilia B (Christmas disease)* - X-linked recessive deficiency of factor IX (9) 3. *von Willebrand disease* - Deficiency of von Willebrand factor (*most common type*

What are the Characteristics of Red Cell Membrane Disorders?

*Membrane proteins: Ankyrin, Spectrin, Protein 4.1, and Band 3* Red Cell Membrane Disorders 1. Hereditary Spherocytosis 2. Hereditary Elliptocytosis 3. South Asian Ovalocytosis 4. Acanthocytosis and related disorders 5. Rh deficiency syndrome Hereditary Spherocytosis - Deficiency of one of the cytoskeleton proteins (most commonly Ankyrin) that keep the lipid bilayer intact - This destabilizes the lipid bilayer leading to release of tiny portions of cell membrane as microvesicles - This reduces the overall surface area of the red cell rendering it more rigid - RBCs become non-deformable, and easily trapped within the splenic cords and hence easily phagocytosed - Autosomal dominant inheritance in most patients (70%). most prevalence in Northern Europeans - Presents as hemolytic anemia with variable severity - Favorable response to splenectomy - Diagnosis: anemia, jaundice, splenomegaly - Lab: low hemoglobin, low-normal MCV, high RDW, hemolysis (LDH, reticulocytosis, bilirubin), osmotic fragility test (gold standard) Hereditary Elliptocytosis - Common in African/Mediterranean decent - Majority of cases due to spectrin defect - Confers resistance to malaria Stomatocytosis - Cell membrane leaks sodium and bursts forming cusp Acanthocytosis - Thorny spikes found in cirrhosis alcoholism

Hodgkin's Lymphoma Case

- A 23 year old woman comes into your clinic after a recent diagnosis of Hodgkins Lymphoma. She has just started chemotherapy. On evaluation, she has some dental caries and gingival lesions. There are no dental abscesses. You: *A) Contact her oncologist and coordinate care of her teeth.* B) Prescribe antibiotics and proceed with her dental care. C) Postpone treatment of her teeth until after chemotherapy is complete. D) Inform her that with a diagnosis of cancer, her dental care is not urgent. - This patient also notes that she has been having recurrent high fevers and night sweats, for about a month prior to her diagnosis. A) The symptoms are likely related to an underlying systemic infection B) These symptoms are likely related to her dental carries *C) The symptoms are likely related to her lymphoma* D) The symptoms are related to early menopause

Summary Slide for Allergy

1. Allergic diseases are usually of type I or type IV classes 2. Most common type I responses are urticaria and angioedema 3. Anaphylaxis is the most sever type of type I response 4. Allergic dermatitis is the most common type of type IV response 5. Atopic dermatitis commonly occurs in childhood 6. Drug reactions may involve any of the 4 classic types of allergic reactions 7. Allergic reactions may be self-limited or require the use of agents that either suppress the allergic/immune response or reverse the cardiac and pulmonary manifestations

What are the Characteristics of Cancer and Mutations?

1. Cancer cells have defects in regulatory circuits that govern normal cell proliferation and homeostasis. - Uncontrolled proliferation of cells - Loss of normal growth control - Loss of checkpoint regulation -> fail to correct errors and repair damages -> accumulation of mutations 2. Occurs due to an imbalance between cellular proliferation and cellular death Mutations and Cancer 1. Points of alterations - Receptors - Secondary Messengers - Transcription regulators - DNA replication - Epigenetic regulators 2. Could be primary targets of therapy

How do T cells and B cells respond against pathogens?

1. T cells control intracellular pathogens and activate B cell responses against pathogens 2. B cell antibodies target the extracellular pathogens and their toxin - Neutralization (binds and removes) - Opsonization (mark the cell for phagocytes) - Activation of complement - Need antibodies to activate NK cells to kill tumor via antibody-dependent-cellular-cytotoxicity

Hematopoietic Stem Cell Differentiation Chart

ALL = Acute Lymphocytic Leukemia AML = Acute Myeloid Leukemia CLL = Chronic Lymphocytic Leukemia MM = Multiple Myeloma

B-Cell Development & Disease Diagram

ALL = Acute Lymphocytic Leukemia AML = Acute Myeloid Leukemia CLL = Chronic Lymphocytic Leukemia MM = Multiple Myeloma DLBCL = Diffused Large B Cell Lymphoma FL = Follicular Lymphoma HL = Hodgkin's Lymphoma

What are the Characteristics of Antineoplastic Agents?

Antineoplastic agents - Contributing to the goal of eliminating and destroying neoplastic cells. 1. Goals of Pharmacologic Therapy - Cure - Cure in adjuvant setting - Palliation - Create a chronic disease? (chemo can make cancer become a chronic disease, most cancer develop acutely) 2. Targets of antineoplastic drugs - Rapid cell growth - Cell surface markers - Lack of immune system responses - Defective genes - Angiogenesis 3. Tissues affected by drugs targeting rapid cell growth (lack of specificity): - Bone marrow - Skin - Fetus - GI mucosa - Hair follicles - Cancer cells 4. General toxicities - Nausea, vomiting, fatigue, anemia - Immunosuppression - Leukopenia (blood loss), alopecia (hair loss) - Oral mucositis

What are the Characteristics and Components of Blood?

Blood Components 1. Plasma 2. WBCs & platelets 3. RBCs The "Liquid" Component of Blood 1. Plasma - Fluid left after blood cells are removed, can clot 2. Serum - Fluid left after blood cells and blood clots are removed, cannot clot Source of Plasma Proteins 1. Protein = Liver 2. Globulins (α and β) = Liver 3. Clotting proteins = Liver - Prothrombin, fibrinogen 4. Complement proteins = Liver 5. Plasma lipoproteins Chylomicrones = Intestinal epithelial cells - VLDL = Liver - LDL = Liver

What are the Characteristics of CD8 T-Cell mediated Cytotoxicity?

CD8 T-Cell mediated Cytotoxicity 1. Some type IV hypersensitivity diseases are CD8 mediated. 2. Examples of CD8 mediated disease are type 1 diabetes or graft rejection. 3. In these diseases, CD8+ cytotoxic T lymphocytes specific for an antigen recognize cells expressing them. - End result: cell death. - CTLs Kill by: perforins and granzymes, which are preformed mediators found in its lysosome like granules -> These 2 proteins work to induce apoptosis of the target cell.

What are the Characteristics of Contact Dermatitis?

Contact Dermatitis (type IV) 1. Seen in individuals previously sensitized, mostly women 2. Requires several hours to complete the cascade of cellular immunity - Rxn resembles a burn - Occurs due to exposure to poison ivy, metals, medications, chemicals - *Contact stomatitis* is rare but may occur with exposure to oral hygiene or topical agents and dental materials Contact Stomatitis 1. The oral mucosa is relatively resistant to irritants and allergens due to the following anatomical and physiological factors: - High vascularization that favors absorption and prevents prolonged contact with allergens - Low density of Langerhans cells and T lymphocytes - Dilution of irritants and allergens by saliva that also buffers alkaline compounds 2. Irritant reactions appear to be more common than allergic reactions

What are the Characteristics of Lymphomas?

Conceptualizing Lymphoma 1. Neoplasms of lymphoid origin, typically causing lymphadenopathy 2. Leukemia vs Lymphoma 3. Lymphomas are clonal expansions of cells at certain developmental stages - Clonal Expansion (due to protooncogenes) - Arrest of differentiation - Loss of apoptotic pathways/responses

What are the List of Antineoplastic drugs that Will be Covered?

Cytotoxic Antineoplastics 1. Drugs that interrupt DNA replication 2. Disrupt DNA - Crosslinking - Intercalating - Strand breaking 3. Interrupt mitosis Targeted Antineoplastics *Remember this slide for exam*

What are the Characteristics of Drugs that Interrupt Mitosis?

Drugs that Interrupt Mitosis 1. *Vinca Alkaloids* - The vinca alkaloids binds to the vinca domain at the microtubule leading to *depolymerization.* - Arrest cell division in metaphase = *cell cycle specific* Examples: - *Vinblastine: with methyl group* - *Vincristine: with formyl group* - For treatment of several types of cancer including leukemia, lymphoma, melanoma and breast cancers. 2. *Taxanes* - Bind to the interior surface of the microtubule at the taxane-binding site. - Disrupt equilibrium between free tubulin and microtubules causing *stabilization* of cytoplasmic microtubules and *inhibits depolymerization.* - Disrupts the normal dynamic reorganization of the microtubule network required for mitosis. Ex: paclitaxel (taxol) & docetaxel - For the treatment of breast, ovarian and prostate cancers Combination Therapy 1. Development of drug resistance 2. Use agent with different cell cycle specificity, mechanisms of actions, toxicities, and potential combination for synergy. 3. Administer the drugs intermittent courses and at maximal tolerated doses to maximize cell kill, allow for host recovery, and avoid prolonged drug-free intervals. - Example: the use of alternating non-cross-resistant regimen for the treatment of advanced Hodgkin's disease: --> ABVD: A, adriamycin (doxorubicin); B, bleomycin; V, vinblastine; and D, dacarbazine - Alternating the two regimens monthly or - Combining the two regimens into a monthly cycle

What are the Dysregulation of Cancer Associated Genes Mechanisms?

Dysregulation of Cancer Associated Genes Mechanisms 1. Chromosomal changes - Mutations, deletion 2. Epigenetic changes - Factors that regulate gene expression (and thereby, cellular phenotype) 3. Noncoding RNAs

What are the Characteristics of Epigenetic Changes?

Epigenetic CHanges 1. Visualized more than 100 years ago as chromatin clumping or chromatin clearing 2. Refers to heritable changes in gene expression without an alteration in DNA sequence 3. *Two* primary and interconnected epigenetic mechanisms: - *DNA methylation and covalent modification of histones* Gene Silencing by Hypermethylation 1. DNA methylation-addition of methyl group, no change in DNA sequence 2. DNA methylation at CpG dinucleotides (cytosine base pair immediately followed by a guanine, separated by a phosphate) and most CpG sequences in the genome are methylated - Methylation is catalyzed by a family of DNA methyltransferase enzyme (DNMTs) 3. Occurs in almost all neoplasms Histones 1. Post-translation modifications of histones regulate their ability to interact with chromatin structures (methylation, acetylation) - Methylation = Closed, repressed - Demethylation = Open, active 2. Acetylation: targets Lys residues in the amino terminal tail of core histone proteins - Acetylated = Open and active - Deacetylated = Closed and repressed 3. Regulated by: - Histone acetyltransferases (HATs) - Histone deacetylaces (HDACs) Examples of Epigenomic Regulatory Genes Mutated in Cancer 1. DNA methyltransferase (DNMT3A) gene functions as DNA methylation - Important in Acute myeloid leukemia (20%)

What are the Characteristics of the Epigenetic Regulation in Cancer?

Epigenetic Regulation in Cancer 1. DNA methylation 2. Histone methylation 3. Histone acetylation 4. miRNA and noncoding RNAs Epigenetic Therapy - Epigenetic activation of stemness and dedifferentiation -> CIC (cancer initiating cell population) -> cancer 1. ↑ Tumor supressor genes - Decrease of tumor growth - Induction of apoptosis - Suppression of invasion of metastasis 2. ↑ Tumor suppressor genes/Drug response genes - Resensitization to chemotherapy 3. ↓ Stem cell genes or miRNAs regulating stem cell genes in CICs - Decrease in self-renewal or survival of CICs - Differentiation of CICs - If genes are increased in cancer, then inhibition of tumor suppressor has occurred Cancer Initiation and Progression - DNMT = DNA methyltransfer - HDAC = Histone deacetylase - PAD4 = Peptidylarginine deiminase 4 - Drugs that target these over activating genes like DNMT < HDAC < PAD4 can revert cancer back to normal cells Epigenetic Drugs 1. Azacitidine (Vidaza) 2. Decitabine (Dacogen) 3. Vorinostat (Zolinza) 4. Romidepsin (Istodax)

What are the Characteristics of Hemostasis?

Hemostasis = Process that minimizes: 1. Hemorrhage when a blood vessel wall is damaged 2. Formation of untimely clots (thrombi) in undamaged vessels Response to Blood Vessel Damage 1. Primary Hemostasis a) Vasoconstriction of damaged vessels - Calcium is important mediator of vasoconstriction b) Formation of a temporary seal by platelets 2. Secondary Hemostasis - Formation of a blood clot = fibrin clot (coagulation)

What are the Characteristics of Neutrophils?

Neutrophils/Polymorphonuclear leukocytes (PMN) - Life span in peripheral blood ~5 days - Neutrohpils play an important role as first line of defense in bacterial infections Neutrophils 1. Primary granules contain *Myeloperoxidase (MPO)*, elastase, defensins, cathepsins - MPO is most abundant 2. Secondary granules contain lactoferrin 3. Tertiary granules contain cathepsin, gelatinase Neutrophils are Primary Defense Against Infections - Phagocytosis - Secrete anti-microbial agents - Release *neutrophil extracellular trap (NET)*, a fiber-like material that forms a web around microorganisms and kills them

Summary of Type I Hypersensitivity

Summary of Type I Hypersensitivity *Immune mechanisms* 1. Allergen cross-links IgE antibody to activate mast cells and Basophils - Immediate response (5 to 30 minutes) 2. Release of vasoactive amines & other mediators from basophils and mast cells - Late-phase reaction (2 to 8 hours & lasts for days) 3. Recruitment of other inflammatory cells 4. These cells amplify and sustain the inflammatory response with additional exposure to the triggering antigen. -Eosinophils

What are the Characteristics of Type IV Hypersensitivity?

Type IV Hypersensitivity - Also called T cell mediated hypersensitivity. Mechanism of Injury: 1. CD4+ T cell express cytokines that induce inflammation that be may chronic and destructive. 2. Cell killing by CD8+ cells Mechanism of T-cell Mediated Hypersensitivity a) Naïve T cells recognize antigen displayed on the APC. They will secrete IL-2 which will induce proliferation. - Upon reintroduction to that antigen, T cell will differentiate into Th1 or Th17 cells. - CD4+ TH1 or TH17 respond to tissue antigens by secreting cytokines (INF-y) that stimulate inflammation and activate phagocytes, leading to tissue injury. b) In some diseases, CD8+ cytotoxic T lymphocytes (CTLs) directly kill tissue cells.

What are the Characteristics of Urticaria and Angioedema?

Urticaria and Angioedema 1. Lay terminology for *urticaria* is *"hives"* - pruritic (itchy), erythematous (red) & blanching (loose color with pressure) skin papules (slightly raised bumps!) - Itching is caused by immediate release of histamine, leukotrienes & PGs from mast cells (vasodilitation, leakage of plasma from venules) - *Shape*: round or oval with pale raised centers (wheals) - *Size*: varies from several millimeters to a few centimeters 2. *Angioedema* involves non-pitting edema of lips, tongue, eyelids, hands, feet or genitalia - May involve the oropharynx & larynx - No report of itching but may feel burning or pressure - Swelling involves a delayed reaction caused by inflammatory cytokines released in subcutaneous or submucosal tissues - Ex: See Oropharyngeal presentations of Urticaria and Angioedema from medication exposure in the oral cavity (very rare) Clinical Aspects 1. *Chronic* recurrent hives or angioedema over 6 weeks or longer; a few common triggers include: - *Food* - requires chronic exposure (i.e., wheat) - *Physical* - triggered by scratching, exercise, exposure of skin to heat, ice, vibration, pressure, UV radiation, chronic infections (sinusitis, dental abscess, H. pylori) - *Immune-mediated* - during flares of autoimmune diseases such as rheumatoid arthritis, Hashimoto's thyroiditis - *Complement-mediated* - Hereditary Angioneurotic Edema 2. *Acute* hypersensitivity reactions 5-30 minutes after ingesting a drug or food or insect bite, but may also be idiopathic a) Treatment - Acute cases are self-limited; antihistamines can prevent recurrent attacks - Antileukotriene medications or corticosteroids may become necessary for severe or chronic cases Hereditary Angioneurotic Edema 1. Inherited disorder of chronic recurrent angioedema - An autosomal dominant trait - Involves a deficiency of *C1 esterase inhibitor* - a regulatory protein that controls and limits complement activation, fibrinolysis & bradykinin production - it is this latter process that causes capillary leakage and edema 2. Clinical features - Mild attacks may begin in infancy but become severe at puberty - Swelling is spontaneous or precipitated by pressure, trauma, stress 3. No direct tx is available - Epinephrine is only modestly effective - Other approaches may include antihistamines, attenuated androgens, transfusion with FFP - Acute attacks may require nasotracheal intubation

What are the Principals of the Innate and Adaptive Immunity (How do they work together)?

- Terms of immunity and inflammation is used interchangeably (process is similar) 1. Inflammatory responses are initiated by activating the immune effectors and factors - Phagocytes (macrophage/dendritic cell) - Complement system 2. Cardinal signs of Inflammation: Calor, Dolor, Rubor, Tumor - Increased permeability - Increased adhesion - Extravasation of PMNs and Monocyte-Macrophages 3. Once phagocytes get to the site of danger they will take up the antigen, process it, and they will present the antigen to the effectors of adaptive immune system 4. Therefore, activation of Antigen Presenting Cells (APCs) is the necessary first step for induction of adaptive immunity - Dendritic Cells (most common) - Monocyte-Macrophages - B cells How do APCs activate effectors of Adaptive Immune System? 1. Binding and signaling of APCs through surface receptors on naïve T cells will deliver three important effects: - *Activation, survival and differentiation of T cells* 2. Receptors involved in the interaction between APCs and T cells are *3 signals*: a) Binding of antigen specific T cell receptors to antigen in the context of MHC class I or II b) Co-stimulation by the co-stimulatory molecules c) Activation through the function of secreted cytokines. - *Cytokine INF-y most important for function*

What two signals are required for Lymphocyte Activation?

- Two signals needed for activation: antigen receptor binding and co-stimulation - If either signal is absent, T cell undergoes anergy (tolerance) and commit suicide - Self-checking mechanism to not be self-reactive - Cancers has antigen expression via MHC1/MHc2 but no costimulatory signals, so T cells will die and not kill cancer

What are the Characteristics of APCs and the associated Costimulatory molecules for T cell activation?

1. B7 family glycoproteins = best characterized co-stimulatory molecules. - The best known ones are B7.1 (CD80) and B7.2 (CD86). 2. B7 binds to CD28 receptor on the surface of CD4+ T cells and co-stimulate in the presence of antigen receptor. - Allows for additional pairing of costimulatory molecules a) For CD4+ we get CD40/CD40L pair b) For CD8+ we get 41-BB/41-BBL pair 3. Upregulation of additional co-stimulatory ligands on activated APCs will amplify the function of helper and cytotoxic T cells. 4. Activated T cells upregulate CTLA4 which is similar in structure to CD28 which limits their activation by binding to B7 family co-stimulatory molecules. - Thus, activation and proliferation of T cells are limited. - CTLA4 binds with higher affinity to B7 than CD28

Dr. Tan's Study Guide

1. Erythropoesis is regulated by erythropoietin, synthesized in kidney 2. nutrients required for RBC production include: iron, B12, folate etc. 3. Reticulocyte: immature erythrocyte with residual ribosomal RNA 4. Definitions of microcytic, macrocytic, and hypochromic anemia 5. Understand iron deficiency anemia and megaloblastic anemia 6. Intrinsic factor in pernicious anemia 7.Anemia of chronic disease: low reticulocyte count 8. Aplastic anemia, bone marrow cellularity < 10% adult globin chains 9. Sick cell disease: 3 types crisis 10. Adult hematopoiesis site: bone marrow 11. Neutrophils: primary granule MPO, neutrophil 12. Extracellular trap 13. Lymphocytes: CD4, CD8 14. Multiple myeloma, clinical features: CRAB 15. Hormone responsible for platelets: thrombopoetin

What are the Characteristics of MHC Presentations?

1. T cells recognize self and non-self antigens as peptide fragments bound to Major Histocompatibility Complex antigens (MHC-Class I and MHC-Class II) - *MHC1* presents a smaller 9 AA to activate killer cells, *usually viral antigens* presented to CD8+ T cells to kill - *MHC2* activate with help of helper T cells, presenting larger antigen of 13 AA/ 17 AA, *usually bacterial fragments* broken up by lysosomes and presented to CD4+ T cells Two different types of T cells 1. CD8+ T cells - Cytotoxic - Recognizes MHC1 and kills infected cells with preformed granules (granzyme B and perforin)and can make more after activated - Tumor cells can resist granzyme B or perforin-mediated cell death 2. CD4+ T cells, helps produce cytokines a) *TH1* cell recognizes complex of bacterial peptide with MHC2 and activates macrophage - TH1 releases Il-2 and INF-y important for T cells and NK cell activation and increase MHC production b) Helper T cell (*TH2*) recognizes complex of antigenic peptide with MHC2 and activate B cell - TH2 releases IL-4, IL-5, IL-6, IL-10 that can be inhibitory (adipose tissue = sanctuary for IL-6 production)

What are the Characteristics of the Immune Response?

1. Innate Immunity - All animals and plants have some form of innate defense. - Rapid response to an infectious agent. - Includes phagocytic white blood cells - These cells ingest and kill microbes by producing a variety of toxic chemical and powerful degradative enzymes. - Inflammation (phagocytic leukocytes are recruited and activated to kill microbes) - Anti-viral defense (mediated by dendritic cells and NK cells) 2. Adaptive Immunity - Takes days (not hours) to develop. - Present only in vertebrates - Depends on specific recognition functions of lymphocytes - More efficient elimination of pathogens Innate Immunity: "sensing enemy within" 1. Recognize certain microbial components that are shared among related microbes and are often essential for infectivity. 2. These structures are called PAMPS: pathogen-associated molecular patterns. 3. The receptors that recognize these molecules called pattern recognition receptors. 4. These receptors are located in all cells and cellular compartments where microbes may be present (so you find them on epithelial cells, dendritic cells, phagocytes, etc). 5. Leukocytes also recognize molecules from injured or necrotic cells: damage-associated molecules (DAMPS) like dsRNA or dsDNA floating around

What are the Key Facts about the Two Legs of the Clotting Cascade?

1. Intrinsic pathway is so-named because all factors are present in blood; it is activated in vitro by interaction of factor XII, kininogen and kallikrein with the damaged surface of container 2. This activation process is not important in vivo because factor XII, kininogen and kallikrein are not required, ex: deficiencies of any of these proteins does not cause bleeding problems 3. Extrinsic pathway requires TF, which is present in fibroblast membranes assuring that blood is exposed to TF at a damaged blood vessel site 4. Pathways are distinct in vitro (an artifact, albeit a useful one), but not distinct in vivo as there is crosstalk, ex: factor VIIa can activate factor IX in vivo 5. The two pathways converge to form the final common pathway 6. The main role of the extrinsic pathway is to initiate clotting, but this action is transient because inhibitors present in blood become active and inhibit factor VIIa 7. The main role of the latter steps of the intrinsic pathway is to prolong the clotting process until it is complete 8. Platelets are not required for clotting in vitro (only need plasma)

What are the Characteristics of the White Blood Cells in Peripheral Blood?

1. Neutrophil (55-65%) 2. Lymphocyte (25-35%) 3. Monocyte (4-6%) 4. Eosinophil (1-3%) - Has two lobes 5. Basophil (0.5-1%) - Granular

Conclusions of Clotting

1. Platelets and the coagulation cascade are essential components of hemostasis 2. Drugs have been developed to prevent clotting, and their effects can often be easily measured in the clinical lab 3. Important to understand different clinical scenarios in which abnormal clotting (and bleeding) can occur

What are the Classes of Factors?

1. Serine proteases: - IIa (2a), VIIa (7a), IXa (9a), Xa (10a), XIa (11a), XIIa (12a), kallikrein 2. Nonprotease activators/accelerators - Va (5a), VIIIa (8a), tissue factor (3), high molecular weight kininogen 3. Stabilizer of factor VIII (8) - von Willebrand factor (vWF) 4. Transamidase that crosslinks fibrin - Factor XIIIa (8a) 5. Nonprotein factors - Ca2+, membrane phospholipids The Coagulation cascade allows for amplification: a low concentration of clotting factors involved early in the cascade activate a greater concentration of down-stream factors - Ex: Factor ------- Concentration VII --------------> 0.015 (dont need high conc) V ---------------> 0.9 II ---------------> 12 I (fibrinogen) -> 30

What are the Characteristics of Heparin and Warfarin?

1. Standard Heparin - Route of Administration: Injection (IV or SC) - Effect after one dose: Immediate (a cofactor) - Cofactor of antithrombin to degrade 2a and 10a 2. Warfarin - Route of Administration: Oral - Effect after one dose: Delayed (an antagonist) - Antagonist of Vitamin K enzyme Question #1: Which of the above would act as an anti-coagulant when placed in a test tube with blood freshly drawn from a normal, untreated individual? - Heparin since Warfarin is in vivo Question #2: How could you tell which drug has been given to a patient bleeding from a medication overdose? - Warfarin, since its orally given Heparin exists as a heterogenous collection of polysaccharides of variable molecular weight (UFH-unfractionated heparin) - Low molecular weight heparin (LMWH): 1. Less non-specific binding to plasma proteins and thus better control of true dosage 2. Fewer adverse side effects (Ex: inhibition of platelets) 3. Has a longer half-life, and once or twice daily subcutaneous dosing can be used for outpatients

What are the Dental Implications of Anemia?

1. The dentist, faced with any of the pathological signs, should recognize the underlying gravity of the situation and actively ensure that the patient receives proper medical evaluation. 2. Anemia is a sign of an underlying hematopoietic disorder, which is frequently the earliest biologic indicators of diseases such as cancer, malnutrition, or conditions of drug toxicity. 3. Patients may have oral mucositis, intraoral or circumoral viral outbreaks, fungal infections, and serious bacterial infections of odontogenic origin.

How does Antigen Recognition Work?

1. The effector functions of B cells depend upon secreted antibodies whose different heavy-chain isotypes trigger distinct effector mechanisms. 2. The effector functions of T cells, in contrast, depend upon cell-cell contact and are not mediated directly by the T-cell receptor, which serves only for antigen recognition - Helper lymphocytes: stimulate B lymphocytes to make antibodies and activate other leukocytes. - Cytotoxic T cells: kill infected cells - Regulatory T cells limit immune response and prevent reactions against self-antigens. Clonal Expansion 1. When an antigen-specific cell is activated by an antigen 2. The sequence of the gene producing the antibody becomes more strongly represented in the population T Cell Diversity - After antigenic exposure, rather than having structural diversity, cells undergo functional changes. - Proliferation or Cytokine secretion or Cytotoxicity - Ex: APC recognition of a spectrum of pathogens through various pathogen-associated molecular pattern receptors results in cytokine release from the APC. - Large diversity of T cell differentiation

What are the Characteristics of the Immune System?

1. The immune system protects the individuals against infections and malignancies through the functions of a) Innate immunity b) Adaptive immunity 2. Immunity is generated through the function of immune cells (Effectors) and factors that they produce Main Differences Between Innate and Adaptive 1. Innate - Non-specific - No memory - Fast acting (neutrophils) - Granulocytes-Monocytes - Invariant receptors (TOLL receptors) - Non-MHC restricted 2. Adaptive - Specific - Memory - Delayed - Lymphocytes (T cells, B cells, NK cells ~ 4 hrs for fast killing or slow via producing cytokines - 24 hrs) - Variant receptors (T and B cells adapt) - MHC restricted *Cells without MHC1 activate our NK cells, such as RBCs that dont have MHC1, undifferentiated tumors/cancer stem cells* *Differentiated cells express MHC1 and are targeted by T cells)

What are the Types of Immune Mediated Injury?

1. Type 1 - Immediate or anaphylactic sensitivity - Equated with allergies - Mediated often by IgE Ab 2. Type 2 - Mediated by IgG antibodies which can engage complement-mediated and phagocytic effector mechanisms - Directed against cell or matrix associated proteins 3. Type 3 - Similar to Type 2 except response is against soluble antigen 4. Type 4 - T-cell mediated - Includes contact dermatitis, chronic asthma, graft rejection

What are the Characteristics of Adaptive Immunity?

Adaptive Immunity 1. Consists of lymphocytes and their products - Ex: antibodies, cytokines, etc. 2. Specific response. 3. Two types of adaptive immunity a). Humoral immunity (B cells) - Protection against extracellular microbes and their toxins b) Cell-mediated (or cellular) immunity (T cells) - Protection from intracellular microbes 4. T and B lymphocytes constantly circulate among lymphoid and other tissues via the blood and lymphatics. 5. Allows cells to home to any site of infection. 6. T and B lymphocytes and their subsets appear morphologically quite similar, *BUT* 7. Function is remarkably heterogeneous and specialized.

What are the Allergic Diseases?

Allergic Diseases 1. *Atopy*: the genetic tendency to develop a hypersensitivity reaction to common environmental substances (allergens) 2. High degree of heritability & concordance among twins 3. Risk increases with a + FHx (esp if both parents are atopic) 4. Common types include: - Allergic rhinitis, urticaria / angioedema, allergic asthma, allergy to food, insect stings and drugs 5. It is estimated that 40% of the population is atopic - Allergic rhinitis > urticaria > asthma

What are the Characteristics of Oncogenes and Tumor Suppressor Genes?

Activation of Proto-Oncogenes - Conversion of proto-oncogenes to an oncogene typically involves a gain of function - *Point mutation is most common* - Localized reduplication (amplification) of a DNA segment that includes proto-oncogene, leads to overexpression - Chromosomal translocation brings the growth regulatory gene under control of a different promoter leading to inappropriate expression of the gene Silencing of Tumor Suppressors - Interplay between chromosomal and epigenetic changes - 80% of mutations are point mutations or small deletions that disrupt the function of the protein that is encoded by the gene - Inactivation: 1. 1st hit - Germline mutation + somatic mutation (familial) - Somatic mutation + somatic mutation (sporadic) - Altered methylation 2. 2nd hit - *Loss of heterozygosity*: gross chromosomal event that results in loss of the entire gene and surrounding chromosomal region -> *Most common method* to lose 2nd tumor suppressor gene allele (during somatic recombination, normal gene is replaced by a mutant or deleted, then loss of heterozygosity turns off the remaining gene) - Loss of function mutation - Epigenetic silencing of normal allele p53 in Barrett's Esophagus: Loss of Heterozygosity - ~100% show LOH in p53 in primary esophageal cancers (92% have a mutation in the other allele) - 70% show LOH in oral squamous cell carcinoma Summary: 1. Genetic damage that activates oncogenes or inactivates genes may be subtle (ex: point mutations) or involve large changes in chromosomal segments detected through a karyotype 2. Changes involve "hallmark of cancer" genes Oral Cancer 1. Deletions - Deletion of chromosome 9p21-22 = 2/3 of all head and neck cancer 2. Oncogenes - ErbB = oral cancer (EGFR growth factor) - Ras = 50% of OSCC have H-ras mutation (promotes cell proliferaiton) - Cyclin D1 = amplified in 30-50% head/neck cancers (regulate G1 to S transition) 3. Tumor suppressor - p53 = 50% of all cancers, blocks G1 to S transition, stimulates repair and/or apoptosis

What are the Characteristics of Acute Leukemias - AML?

Acute Leukemias 1. Cause is unknown 2. Toxins (increase risk) - Radiation, chemotherapy 3. Viruses (EBV) 4. Immunodeficiency (can cause Oral Candidiasis) 5. Genetic disorders (trisomy 21) Acute Myeloid Leukemia (AML) 1. More common in adults 2. Symptoms - Fatigue, fever, infections, bleeding, leukemic infiltration of tissue: *GUMS* 3. Physical Exam - Fever, pallor, *petechia*, +/- HSM (hematosplenomegaly) 4. Blood Smear/Histology - Blood Smear: see myeloid/lymphoid cell bigger than red blood cell 5. Epidemiology - Incidence of AML increases with age, older patient has less tolerance to therapy 6. Prognostic Factors - *Frequency of Cytogenetic Risk Groups* = one of the most important prognostic factors in predicting remission rate, remission duration, and overall survival AML Treatment 1. Survival 3-6 months if untreated 2. 30-60% long term survival with chemo/transplant - Induction (chemo) -> Remission -> Chemotherapy (if low risk) or Transplant (if high risk)

What are the Oral Complications of Acute Leukemias?

Acute Leukemias: Oral Complications *1. Leukemic infiltration of the gums* 2. Mucositis - Chemotherapy, radiation, aphthous ulcers 3. Infections - HSV, *candida* 4. Bleeding - Gingival, petechea 5. *Graft versus host disease* - Very dry mouth, lack of saliva production 6. *Secondary malignancies after transplant* - Squamous Cell Carcinoma *If you see gingival hyperplasia, be suspicious of AML* Monocytic Leukemias - AML Gum infiltration with bleeding Conclusions 1. Leukemias are classified by disease course and cell of origin 2. Treated based on biology of the disease with targeted agents used when available 3. Oral Complications - Gingival hyperplasia - Infection - GVHD - Secondary malignancy

What are the Characteristics of Acute Lymphoblastic Leukemia (ALL)

Acute Lymphoblastic Leukemia (ALL) 1. *Most common neoplasm of children* - Peak age 3-4 years - Bimodal age distribution 2. Symptoms - Anemia: pallor, fatigue, dyspnea on exertion (due to low oxygen stores) - Thrombocytopenia: bleeding, bruising - Neutropenia: infections, fever 3. Physical exam - Bone pain, headache, lymphadenopathy, hepatosplenomegaly - ALL Organ involvement: Mediastinal mass, hepatosplenomegaly, testicular enlargement Childhood vs Adult Disease Outcomes 1. Both adults and children achieve high initial remission rates 2. However, most children are cured while most adults relapse ALL Morphology Classification - FAB - L1, L2, and L3 (Burkitt's) - We treat L1 and L2 similarly Prognostic Factors in ALL - Always look at chromosome and cytogenetics - Age, Gender (female favorable), WBC (<50,000 favorable), CNS (negative favorable) - Immunophenotype (Pre-B cell favorable while B-cell > T cell is unfavorable, Chromosome (>50 favorable) - Cytogenetics: Trisome 4, 10 and t(12;21) favorable - Cytogenetics: t (9;22) philadelphia chromosome unfavorable (not single driver of disease tho) - *Cytogenetics single most important factor at predicting risk of treatment failure* Phases of Treatment 1. Induction - Vincristine, corticosteroids, anthracycline 2. Post-Remission Consolidation - Various regimens: induction, consolidation, stem cell transplant 3. Maintenance Therapy - Historically includes 6-mercaptopurine, methotrexate 4. CNS Prophylaxis Treatment - Various regimens including systemic chemo/radiotherapy CAR-T Structure - Take antigen specificity of B cell and combine with intracellular killing machine of T cell - B cell will be able to attack tumor cell, get chimeric antigen receptor

What are the Characteristics of Acute Promyelocytic Leukemia (APL)?

Acute Promyelocytic Leukemia (APL) 1. Distinct AML variant with different biology and treatmetn 2. 5-20% of AML patients 3. t (15;17) PML-RARA - Causes a differentiation block = stuck at promyelitic phase APL 1. Differentiation block leads to increase promyelocytes 2. Disseminated intravascular coagulation (DIC) 3. Favorable prognosis if treated with *all-trans retinoic acid (ATRA)* and *arsenic trioxide* 4. Most deaths occur within the first week of diagnosis

What are the Characteristics of Rhinitis and Sinusitis?

Allergic Rhinitis and Sinusitis 1. Inflammatory hypersensitivity reaction to *aeroallergens* - Seasonal pollens (pollens, grass, ragweed) - Outdoor molds (airborne fungi) - Indoor allergens (indoor fungi, animal dander, dust mites, insects) 2. Seen in 9-24% of adults, 42% of children Clinical Aspects 1. Lay terminology *"hay fever"* - a collection of flu-like symptoms - although fever is not common! - Sneezing, rhinorrhea (clear secretions), nasal congestion, itching in the nose & palate - Less common signs: conjunctivitis (allergen must be blown into the eyes), fatigue, arthralgia, myalgia, cognitive changes (esp in children) - these are mostly cytokine-mediated effects - Other: obstruction of sinus ostia causing acute (bacterial) sinusitis 2. Management - Avoidance of the allergen is the best intervention - *First-line therapy*: antihistamines - first generation formulas reduce motor skills, second generation compounds are better - *Immune therapy*: anti-IgE (omalizumab) - effective but $$ Allergic Rhinitis: - Nasal mucosa may be pale, cyanotic & swollen with clear secretions

What are the Classifications of Allergies?

Allergy Classification 1. Type I - *IgE-mediated hypersensitivity* - Ex: allergic rhinitis, urticaria / angioedema, anaphylaxis 2. Type II - *IgM or IgG mediated hypersensitivity* - Ex: immune hemolytic anemia where Abs may be exogenous (blood transfusion or fetus with blood type different from the mother's), or autogenous (rxn to medications) 3. Type III - *Immune-complex mediated* - Ex: serum sickness seen as rxn to antiserum (for tetanus and rabies tx), blood products or drugs 4. Type IV - *Cell-mediated hypersensitivity* - Ex: contact dermatitis, atopic dermatitis (eczema) *Type I and Type IV most commonly encountered in practice*

What are the Qualitative Abnormalities in RBCs?

Anemia 1. *Microcytic* - Red cells smaller than normal (MCV decreased) - <80 2. *Macrocytic* - Red cells larger than normal (MCV increased) - >100 3. *Hypochromic* - Less Hb than normal (HCT decreased) 4. *Anisocytosis* - Increased variation in size of red cells (RDW increased) 5. *Poikilocytosis* - Increased variation in shape of red cells (RDW increased) Values: - Hemoglobin (Hb) - Hematocrit (HCT) = packed cell volume - Mean Cell Volume (MCV): normal = 76-100 - Red Cell distribution Width (RDW)

What are the Characteristics of Anticoagulants?

Anticoagulants 1. *Aspirin* - Irreversibly inhibits platelet COX (t1/2 for PLTS is ~10 days) 2. *Clopidogrel* (Plavix), Tricagrelor 3a. *Unfractionated Heparin* 3b. *LMW Heparin* (ex: enoxaparin = Lovenox) 3c. *Fondaparinux* (synthetic pentasaccharide) - Factor Xa (10a) inhibitor 4. *Warfarin (Coumadin)* - Requires regular monitoring of patient's clotting activity (INR, protime) 5. *Direct oral anticoagulants (DOACs)* - Protease inhibitors that do not require monitoring of patient's clotting activity during therapy a) *Dabigatran (Pradaxa)* - specific inhibitor of thrombin (IIa); also argatroban (intravenous) b) *Rivaroxaban (Xarelto)*, Apixaban (Eliquis) and Edoxaban (Savaysa) are specific factor Xa inhibitors Advantages and Disadvantages of DOACs 1. Are administered orally and required no monitoring of patient's clotting activity 2. FDA approved for non-valvular atrial fibrillation, acute treatment for VTE, prophylaxis after knee and hip replacement surgery (generally inferior to warfarin in patients with mechanical heart valves, antiphospholipid antibody syndrome) 3. Have short half-lives (8-12 hrs) and thus require good patient compliance 4. Must be cautious in patient's with kidney failure - dose may need to be reduced or drug omitted altogether 5. Hemorrhage is a potential adverse side effect (as with all antiocoagulants) and only recently were (expensive) antidotes FDA approved Question: What is the antidote for Coumadin? How fast would it work? Why? - Vitamin K is antidote if there is overdose or levels are too high, generally acts slowly due to need to outcompete Coumadin for enzyme and increase levels of factor 2, 7, 9, 10

What are the Characteristics of PolyCythemia?

Polycythemia 1. Increased in RBC count 2. Can be seen in dehydration, but this is not persistent polycythemia 3. Can be due to excess erythropoietin synthesis - Reactive: high altitude, lung, or heart disease - Pathologic: tumors that secrete erythropoietin, or in the presence of a myeloproliferative process

What are the Characteristics of Antigen Presentation via MHC/HLA?

Antigen Presentation via MHC/HLA 1. Major histocompatibility complex: MHC - In mice, identified as products of genes that evoke rejection of transplanted organs. 2. Human leukocyte antigen: (HLA) 3. Genes encoding HLA molecules clustered on chr. 6. 4. HLA system is highly polymorphic, meaning that there are many alleles of MHC genes (in the thousands) in humans. Each individual's HLA alleles differ from those inherited by most other individuals in the populations. HLA antigen presentation 1. *MHC Class I* - Expressed on all nucleated cells and encoded by 3 genes. - Heterodimers consisting of a polymophic a chain noncovalently linked to the nonmorphic β2 microglobulin. - Displays peptides derived from proteins located in the cytoplasm to CD8+ cells. 2. *MHC Class II* - Heterodimeric protein consisting of an α and β chain encoded on a region called HLA-D. - Presents antigens that are internalized into vesicles and are derived from extracellular microbes and soluble proteins. - Class II peptide complex recognized by CD4+ cells.

What are the Characteristics of Aplastic Anemia?

Aplastic Anemia 1. Trilineage bone marrow hypoplasia due to stem-cell and acquired causes leading to hypocellular bone marrow 2. Presentation - Pancytopenia (peripheral blood counts for all three lineages is decreased) - Bone marrow hypoplasia (cellularity <10%) 3. Clinical signs: - Anemia, bleeding, infections Causes of Aplastic Anemia 1. Idiopathic: most common 2. Infections: Parvovirus, Hepatitis, HIV1, Infleunza, EBV 3. Drugs; Chloramphenicol, chemotherapy, sulfonamides, anticonvulsants 4. Genetic: Fanconi's anemia, Familial aplastic anemia, dyskeratosis congenita 5. Others: Paroxysmal nocturnal hemoglobinuria, pregnancy, immune disorders Normal Bone Marrow ratio to Fat: *40:60%*

What are the Characteristics of Atopic Asthma?

Atopic Asthma (Hay Fever) -Type 1 Hypersensitivity 1. Classic example of type I IgE mediated hypersensitivity. 2. Term atophy refers to the predisposition to develop localized immediate hypersensitivity reactions to a variety of inhaled and ingested allergens. Atopic individuals tend to have higher serum IgE levels, more IL-4 producing TH2 cells, compared with the general population. 3. Triggered by environmental allergens and food. - Family history common. 4. Initial airway sensitization to the antigen that binds to mucosal mast cells) - 2nd exposure of IgE-coated mast cells to the same antigen releases mediators that open mucosal intercellular junctions > more antigen reaches mast cells - Get: Bronchoconstriction, Edema (vascular permeability), Mucus secretion Over Time, the result is "Airway Remodeling" 1. Thickening of the basement membrane of the bronchial epithelium 2. Edema and an inflammatory infiltrate in the bronchial walls, with a prominence of eosinophils and mast cells 3. An increase in the size of the submucosal glands 4. Hypertrophy of the bronchial muscle walls Clinical Course 1. Asthmatic attack lasts up to several hours and causes recurrent episodes - Chest tightness, breathlessness, wheezing - Cough without sputum - Difficulty exhaling (air is trapped distal to bronchi) 2. Asthma attack due to - Intermittent and reversible airway obstruction - Chronic bronchial inflammation with eosinophils - Bronchial smooth muscle cell hypertrophy and hyper-reactivity (bronchoconstriction)

What are the Characteristics of Atopic Dermatitis?

Atopic Dermatitis 1. Often referred to as eczema, a chronic inflammatory skin disorder involving: - Genetic susceptibility - mutation in the gene encoding for the filaggrin protein, a component of keratinocytes' envelope - Epidermal barrier dysfunction - decreased antimicrobial peptides - Immunologic factors - Th2 T cell cytokines (IL-4, IL-5, IL-13) predominate the acute type and Th1 T cell cytokines (IFN-gamma, IL-12) are present in chronic forms - Environmental triggers - foods (eg, milk, eggs, soy, wheat, peanuts, fish), airborne allergens (eg, dust mites, molds, dander), staphylococcus aureus colonization on skin, topical products (eg, cosmetics, fragrances, harsh soaps), sweating, rough fabrics Clinical Aspects 1. It primarily affects children (mostly before age 5) in urban areas or developed countries - Hygiene hypothesis may explain why up to 20% of children and 1 to 3% of adults in developed countries are affected 2. In the *acute phase*, lesions are red, swollen, scaly patches that may become vesicular 3. In the *chronic phase*, scratching and rubbing create red and dry skin lesions 4. *Diagnosis*: by history and clinical exam 5. *Treatment*: childhood Dz resolves with age; also use moisturizers, avoid triggers, topical corticosteroids or immune modulators

What are the Characteristics of Blood Counts and Leukocytosis?

Blood Counts 1. Decreased (Cytopenia) - Decreased or ineffective production - Peripheral destruction or abnormal loss 2. Increased (Cythemias/Cytoses) - Appropriate marrow response to external stimuli (inflammation, infection) - Primary marrow abnormality (neoplastic or preneoplastic) Leukocytosis 1. Which cell line is increased? - PMN, lymph, mono, eosinohpil, basophil 2. What is the stage of maturation of the cell 3. Is it primary or secondary - Primary: Bone marrow/neoplastic - Secondary: Response

What are the Characteristics of Burkitt's Lymphoma?

Burkitt's Lymphoma 1. African variety: jaw tumor, strongly linked to Epstein-Barr Virus infection. 2. In U.S., about 50% EBV infection. 3. May present as abdominal mass. 4. Most rapidly growing human tumor. 5. Typical chromosome abnormality: - *c-myc oncogene* linked to one of the immunoglobulin genes. Treatment - Treated with multidrug regimen similar to pediatric leukemia/lymphoma regimens. - Sensitive to chemotherapy (highly curable) Case: - John is 22 years old. He is a student at UCLA, and is on the wrestling team. He had an injury to his teeth last month while wrestling. He comes in to the UCLA dental clinic for evaluation. He has had a numb lower lip on his left side. He had no pain, but the tooth was notably darker than its neighboring teeth. - He also notes that he has had severe itching throughout his body. In the past few weeks, he has been having fevers, and drenching night sweats.

What is the Molecular Mechanism of Cancer?

Cancer is a Genetic Disease: Common Theme 1. Nonlethal genetic damage lies at the heart of carcinogenesis 2. A tumor is formed by clonal expansion of a single precursor cell that has incurred genetic damage DNA Sequence Variations 1. Polymorphism - DNA sequence variation is common in population - SNPS: single nucleotide polymorphism are most common (occur once every avg 3000 nucleotides) - Often are neutral, can be responsible for individual variability - Can play a more direct role if within a gene or in a regulatory region near a gene 2. Mutation - Change in DNA sequence away from normal - Implies there is a normal allele - Frequency < 1% - Rare in population. Disease causes reduced fitness Germline vs Somatic 1. Germline - Gametes (sperm, ova) - Mutations transmitted to every cell in organism 2. Somatic - Cells forming body of an organism (internal organs, skin, bones, blood, connective tissue) - Mutations transmitted to clonal descendants only Common Themes Continued - Development of cancer through stepwise accumulation of complementary mutations - Often takes years - Tumors evolve in 3 broad phases 1. Breakthrough phase: cell acquire a driver gene mutation and begin to proliferate abnormally, takes years to develop something that could be visualized 2. Expansion phase: driven by a 2nd mutation that allows cell to thrive in local environment (grow under low nutrient, oxygen conditions), changes number and shapes of cells 3. Subsequence mutations allow cells to evolve and invade

What are the Characteristics of Chronic Anemia?

Causes of Anemia of Chronic Disease 1. Chronic infections - TB, osteomyelitis 2. Chronic immune disorders - Rheumatoid arthritis, regional enteritis 3. Neoplasms - Lymphoma, carcinoma Pathogenesis of Anemia of Chronic Disease 1. In response to inflammatory cytokines and interleukins, liver produces Hepcidin which suppresses ferroportin from releasing iron from the enterocytes and macrophages 2. Inflammatory cytokines also blunts bone marrow response to erythropoetin 3. Serum Ferritin levels are high, TIBC is low 4. Reticulocyte count is low

What are the Characteristics of Chromosomal Changes?

Chromosomal Changes *A. Mutations* 1. Point Mutations - Missense: change in one DNA base pair resulting in substitution of one AA for another in the protein - Nonsense: change in one DNA base pair causing premature signal stop signal = shortened protein 2. Insertions - Frameshift 3. Microdeletions - Frameshifts Ex: Proto-oncogenes *RAS Gene* - Greatest impact on malignant phenotype - Immediately downstream of receptor tyrosine kinases = cellular functions including cellular proliferation and differentiation - Associated with guanine nucleotide binding protein (Resting: Ras bound to GDP, exchange for GTP in active) - Has 2 signaling arms: MAPK and PI3K/AKT pathway - Most (and possible all) human cancers have molecular defects that affect one or more components of these pathways - Encoded by 3 genes: KRAS, N-RAS, HRAS *B. Deletions* - Changes number of DNA bases by removing a piece of DNA. Small deletions may remove 1 or a few base pairs within a gene, larger deletions can remove an entire gene or several neighboring genes -> may alter function of resulting protein *Ex: Retinoblastoma* (first tumor suppressor gene) - Deletion of RB gene on Chr 13 = neoplastic proliferation of retinal cells -> blindness if both copies mutated -Familial form: Autosomal dominant, meaning 1 RB gene defect can result in unilateral/bilateral retinoblastoma - Sporadic form: both RB mutations are required to get disease * In protooncogene, just need one change but in tumor suppressor genes you need to inactivate TWO* *C. Chromosomal Translocations* - Chromosomal rearrangemetn 1. Regulatory elements gets swapped with another gene, typically one that is highly expressed 2. Formation of a fusion gene in which coding sequence of 2 genes are fused in part or in whole leading to expression of a novel chimeric protein with oncogenic properties * Ex: BCR-ABL protooncogene* - t9:22 (BCR-ABL) oncogene causes CML, ALL, and occasionally AML *D. Gene amplification* - Instead of one copy of the gene, now have more (good for tumor suppressor, but bad if oncogene) 1. Growth Factor Receptors - Large number of oncogenes encode growth factor receptors - Most important are the receptor tyrosine kinases - These are transmembrane proteins with an extracellular ligand-binding domain and a cytoplasmic tyrosine kinase domain 2. Amplification *Ex: ERBB2 (HER2, HER2/neu)* - Amplified in 20-30% of breast cancers: associated with aggressive biology, decreased survival - Constitutive activation of the receptor and constitutive tyrosine kinase activity - HER2 forms dimers and activates tyrosine kinase activity -> *enhanced cancer motility, increased/uncontrolled cell proliferation, angiogenesis, decreased apoptosis* *E. Chromothyrpsis* 1. Chromosomal scattering/shattering - Tens to hundreds of locally clustered rearrangements affecting one or a few chromosome(s) in cancer cells

What are the Characteristics of Noncoding RNAs?

Chromosomal Changes 1. Changes in the genome that lack protein-coding capacity, yet contain other type of genes that exert their function as RNA molecules, the noncoding RNAs, can influence cell proliferation and function 2. Less than 2% of the genome encodes proteins, but at least 75% is actively transcribed into noncoding RNAs Noncoding RNAs and Cancer 1. Short non-coding RNA - Ex: microRNAs: small noncoding, single stranded RNA - 22 nucleotides in length - Mediate sequence-specific inhibition of mRNA translation through the action of the RNA induced silencing complex - Altered miR expression identified in many cancers (ex: amplification, deletions) 2. Long non-coding RNA (IncRNA) - Greater than 200 nt in length - Associated with disease, most notably cancer

What are the Characteristics of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)?

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) 1. Leukemias (cells are in blood/marrow) - Acute Leukemias (*Lymphoblasts*) - Chronic Leukemias (*Intermediate-Mature cells*) 2. Lymphomas (cells primarily in nodes/lymphoid tissue) - High grade Lymphoma (*Immature cells*) - Intermediate-Low grade (indolent) Lymphomas (*Intermediate to Mature cells*) - See overlap between the two and differentiate by their origin Lymphocytosis 1. Absolute lymphocyte > 4000 mcL (normal is 1000-4000) 2. Acute infections - EBV, CMV, hepatitis, pertussis 3. Chronic infections - TB, syphilis, brucellosis 4. Neoplasms - CLL, lymphomas CLL/SLL 1. Symptoms - Malaise, weakness, night sweats, weight loss, enlarged lymph nodes, infections 2. Physical Exam - Hepatosplenomegaly, lymphadenopathy, other masses 3. Laboratory findings - Increased WBC, low hemoglobin and platelets 4. Blood Smear/Histology - Bone marrow: see multiple small round cells (normal lymphocytes, but see too much) Treatment 1. Treat only if there are symptoms (big nodes, abnormal blood count, B symptoms) 2. Targeted agents - *Ibrutinib* (inhibit pathway) - Idelalisib (hits PI3K pathway) - Venetoclax 3. Median survival 15-20 years 4. Rarely use transplant

What are the Characteristics of Chronic Myeloid Leukemia (CML)?

Chronic Myeloid Leukemia - First cancer attributed to genetic abnormality and first cancer to have normal life expectancy with appropriate treatment 1. Chromosome translocation 9 (ABL) and 22 (BCR) into Philadelphia Chromosome BCR-ABL (deformed, larger 9 on Karyotype-metaphase) 2. Constitutively active Tyrosine Kinase leads to intracellular signal transduction and continued cell growth CML 1. Proliferation of myeloid cells 2. Genetic instability, 1.5 case per 100,000 3. All ages, slight male preponderance 4. Symptoms - Fatigue, weight loss, fever, night sweats 5. Physical exam - Splenomegaly, palor, sternal tenderness 6. Laboratory - Leukocytosis: Myeloid stress - Philadelphia chromosome 7. Blood Smear - *See different maturation stages in blood smear* - Don't see stroma in Bone Marrow Treatment: - Stem cell transplant used to be standard - Tyrosine kinase inhibitors: *Imatinib*, Dasatinib (2nd gen), Ponatinib (3rd gen) - 98% of patients have normal life expectancy

What are the Different Classifications of Lymphomas?

Classifications of Lymphomas 1. Non-Hodgkins Lymphoma (collection of 55) 2. Hodgkins Lymphoma (ONE type) - Very sensitive to radiation, curable Frequency of NHL Subtypes in ADults - Diffuse Large B-cell = 31%, most common - Follicular = 22% Lymphoma Classification: Clinical Behavior 1. Low grade Lymphomas: Indolent Disease - Life expectancy in years, untreated - 85-90% present in Stage III or IV - *Incurable* 2. Intermediate grade Lymphomas: Aggressive Disease - Life expectancy in weeks to months, untreated - Potentially curable 3. High grade Lymphoma: Very Aggressive Disease - Life expectancy in weeks, untreated - Potentially curable Note: Intermediate and High grade are constantly undergoing mitosis, more sensitive to cytotoxic chemotherapy so more curable B-Cell Neoplasms: WHO Modification of REAL Classification 1. Indolent - Chronic Lymphocytic Leukemia (CLL) - Follicular Lymphoma (grade I, II) (FL) 2. Intermediate/Aggressive - Follicular Lymphoma (grade III) (FL) - Diffuse Large B-cell Lymphoma (DLBCL) - Multiple Myeloma (MM) 3. Very Aggressive - Burkitt's Lymphoma

What are the Clinical Features, Diagnosis, and Treatment for Non-Hodgkins Lymphoma?

Clinical Features 1. Lymphadenopathy (lymph node enlargement) - May fluctuate or spontaneously remit, especially in *low-grade lymphomas* 2. Cytopenias (low RBC/WBC) 3. Systemic symptoms (*B symptoms*) - Fever - Night sweats - Weight loss (>10% of patient's body weight) *Recurrent symptoms* - B symptoms more common in *high-grade lymphomas* 4. Hepatosplenomegaly (large liver/spleen) - Hematogenous spread of disease, with no predictable pattern Clinical Feature X2 1. Classic lymphoma: arises in lymph node or bone marrow. 2. Waldeyer's ring involvement frequent in GI lymphomas. Diagnosis of NHL 1. Excisional biopsy is preferred to show nodal architecture (*EXCISE WHOLE LYMPHOID*) - Evaluate Morphology - Evaluate Nodal Architecture 2. Immunohistochemistry to confirm cells are lymphoid 3. Flow cytometry 4. Chromosome changes a) 14;18 translocation in follicular lymphoma - bcl-2 oncogene (apoptosis) b) t(8;14), t(2;8), t(8;22) in Burkitt's lymphoma - c-myc oncogene (protooncogene) c) (11;14) in mantle cell lymphoma - cyclin D1 gene (protooncogene) Staging Workup 1. CBC, chemistries, urinalysis 2. CT scans of chest, abdomen and pelvis 3. Positron Emission Tomomgraphy (PET) 4. Bone marrow biopsy and aspirate 5. Lumbar puncture - AIDS lymphoma - T cell lymphoblastic lymphoma - High grade lymphoma with positive marrow *Different stages of lymphoma/leukemia doesn't mean anything, stage 4 does not mean they would die or its incurable* Treatment Options 1. Indolent Lymphomas - 10-15% in Stage I or II -> Local Radiotherapy - 85-90% Stage III or IV -> incurable, improve PFS, OS - Reasons to Treat Indolent Lymphomas: constitutional symptoms, anatomic obstruction, organ dysfunction, painful lymph nodes, cytopenias, autoimmune, immunodeficiency

What are the Clinical Laboratory Testes of Clotting Function?

Clinical Laboratory Testes of Clotting Function 1. Bleeding Time - Simplate device + BP cuff should be at 40 mmHg 2. Prothrombin Time (PT) - Clotting time in presence of added tissue factor - *INR* = international normalization ratio is used to standardize results - *For Extrinsic Pathway* - *Used to assess Warfarin Levels* 3. Activated Partial Thromboplastin Time (aPTT) - Partial Thromboplastin Time (PTT): clotting time in presence of added clay, kaolin, etc - *For Intrinsic Pathway* - *Used to assess Heparin Levels* 4. Others - Anyone on Coumadin gets their INR tested every 2-3 weeks - Both PT and PTT tests meet if there is high levels enough - Ex: Factor 5 deficiency will lead to prolongation of both PT and PTT Most Common Uses of Clotting Tests 1. Although in theory the PT and aPTT should both be affected by warfarin (Coumadin) and heparin, it has been found that: - The PT is much more sensitive to changes in warfarin levels than is the PTT - The aPTT is much more sensitive to changes in heparin levels than is the PT 2. Low molecular weight heparins are used without assessing their levels by clotting testes. However, in some cases it is desirable to do so. The aPTT is not sensitive to LMWH, so an anti-Xa test is used (activity of Xa in the patient's blood)

What are the Characteristics of Failure of Host Defense Mechanisms?

Completion of Immune Response and Immunological Memory 1. Majority of effector lymphocytes induced by an infectious pathogen undergo apoptosis after microbe is eliminated. 2. Immune system returns to basal state (homeostasis) 3. Initial activation generates long-lived memory cells (which can survive for years after infection) Failure of Host Defense Mechanism 1. Pathogen Dependent - Grow without activating too rigorous an immune response - Prevent host death Evasion and subversion of immune defenses 1. Persistent viruses or bacteria - Persist by ceasing to replicate until immunity wanes (e.g. herpes simplex virus) - Resist destruction or exploit host defenses (e.g. Mycobacterium tuberculosis, Listeria monocytogenes) -> escape death from phagosome/macrophage - Inappropriate immune response can contribute to persistent disease (e.g. toxic shock, M. Leprae) Inappropriate immune responses 1. Gene defects 2. Hypersensitivity disorders: abnormally active immune system (e.g. graft rejection, allergies) - Allergies = immune response directed at non-infectious antigens. Antigen is an innocuous foreign substance - Graft rejection: antigen is borne by a transplanted foreign cell. 3. Immunodeficiency diseases: defective immune system. - Autoimmune disease: response is to a self-antigen. Hypersensitivity 1. Reaction against a noninfectious antigen to produce an acute or chronic reaction. 2. Immunological response involving specific T cells or antibodies (IgG or IgE). 3. Development of hypersensitivity diseases (both allergic and autoimmune) are associated with the inheritance of particular susceptibility genes. Immunodeficiency 1. One or more components of the immune system are defective. 2. Characterized as primary or secondary. - Primary: caused by mutation in a large number of genes that are involved in or control immune responses. - Secondary consequence of other diseases or are secondary to environmental factors (e.g. starvation, medication)

What is the Definition of an Allergy?

Definition 1. Reaction of immune system to an external antigen - Prevalence of allergic disorders are increasing in Western societies - the hygiene hypothesis 2. Most common classification is based on immunological mechanisms (types I through IV) 3. In general, allergic reactions involve: - Aberrant activation of TH2 lymphocytes and cytokines (IL4, 5, 13) that activate B-cells to produce IgE antibodies - Interaction of an allergen with allergen-reactive IgE on mast cells a) Release of granule-associated mediators (histamine), lipid mediators (leukotrienes), cytokines (several, including TNF-α) and adhesion molecules b) Attraction of CD4 T lymphocytes, eosinophils and basophils c) *Smooth muscle contraction, vascular dilation and endothelial leakage* (explain the way allergies present clinically) *IL-4 plays important role of the switch from TH1 to TH2 response*

What are the Characteristics of Delayed Hypersensitivity (DTH)?

Delayed Hypersensitivity (DTH) *Mantoux Test* for M. tuberculosis 1. Injection of tuberculin in sensitized individual 2. Local T cell inflammatory reaction - If positive, get a small, hard raised lesion (2-3 days later) = *Perivascular cuffing* - Get accumulation of mononuclear cells, CD4 T cells, which produce a cuffing. 3. Peaks at 24-72 hrs - Driven by T-cell secreted cytokines: IFN-y, IL-12, IL-2, TNFα & lymphotoxin Granuloma = Special form of DTH - With certain persistent or nondegradable antigens (such as tubercle bacilli in the lungs), the perivascular infiltrate is dominated by macrophages over a period of 2-3 weeks. - The activated macrophages change appearance (epithelioid cells) and are surrounded by a collar of lymphocytes. - This pattern of inflammation is called a granulomatous inflammation and is associated with strong T cell activation with cytokine production.

What is the Developmental Pathway of T cells?

Developmental Pathway of T cells 1. CD3-CD4-CD8- (triple negative) will develop to CD3+CD4+CD8+ (Triple positive) at the early stages. - Obtained in the thymus 2. 95% of triple positive thymocytes will be eliminated by apoptosis, therefore, only 5% of T cells will become either CD3+CD4+ or CD3+CD8+ T cells. - If see triple positive in peripheral blood, then patient has malignancy of the thymus 3. Once antigen receptors are formed the receptor is tested for its antigen recognition properties against molecules present in Thymus (stroma) 4. The specificity and affinity of the receptors for the self ligands will determine the fate of the T cells. 5. When receptors interact weakly with self antigens in developing T cells, a survival signal is transmitted and the cells are selected positively. 6. When receptors bind strongly to self antigen receive a death signal, thus they are eliminated. This is called negative selection.

What are the Characteristics of Diffuse Large B Cell Lymphoma (DLBCL)

Diffuse Large B-Cell Lymphoma 1. Most common type of "aggressive" lymphoma 2. Usually symptomatic 3. Extranodal involvement is common 4. Cell of origin: Germinal center B-cell 5. Treatment should be offered (curable 60-75%) Clinical Presentation 1. Present with a rapidly enlarging symptomatic mass, most usually nodal enlargement in the neck or abdomen. 2. Systemic "B" symptoms (fever, weight loss, drenching night sweats) are observed in approximately 30% of patients - Don't need all 3 to be B symptom 3. Serum LDH is elevated in over one-half Three Different Subtypes based on Gene Expression Profiling 1. Activated B Cell-like DLBCL (ABC) 2. Germinal Center B Cell-like DLBCL (GCB) 3. Primary Mediastinal B Cell Lymphoma *Staging does not define need for therapy or prognosis, only to convey burden of disease* - Internal Prognostic Index (IPI for DLBCL) is still a poor way of predicting Treatment Options Overview A) Curative Intent 1. Chemoimmunotherapy - R-CHOP B) Palliative Intent 1. Chemoimmunotherapy - RCVP, EFND, etc 2. Immunotherapy - Rituximab, other antiCD20 mAb 3. Radioimmunotherapy - Bexxar, Zevalin R-CHOP Chemotherapy (combined therapy) - Rituximab (Rituxan) - Cyclophosphamide (Cytoxan) - Hydroxydaunorubicin (Adriamycin) - Oncovin (vincristine) - Prednisone Shown that Ibrutinib (blockade of BTK) is effective

Type II Hypersensitivity Disease Examples

Diseases Examples 1. Autoimmune hemolytic anemia - Red cell membrane proteins 2. Pemphigus vulgaris - Proteins intracellular junctions (cadherin) - Blistering disorder caused by IgG antibodies directed against epidermal cadherin - Antibody mediated activation of proteases which disrupts intracellular junctions. - Superficial blisters that rupture easily. Lesions are first seen in oral and genital mucosa. 3. Myasthenia gravis (muscle weakness) - Antibodies to acetylcholine receptors block neuromuscular transmission, causing muscle weakness 4. Graves disease - Hyperthyroidism - Antibody mediated stimulation of TSH receptor 5. Insulin resistant diabetes - Insulin receptor 6. Goodpasture syndrome - Noncollagenous protein in basement membrane of kidney glomeruli and lung alveoli - Autoimmune disease in which kidney and lung injury is caused by circulating autoantibodies against the basement membrane type IV collagen. - Initiate inflammatory destruction of the basement membrane in renal glomeruli and pulmonary alveoli. - It causes nephritis and lung hemorrhage. 7. Acute rheumatic fever - Streptococcal cell wall antigen

What are the the Characteristics of Drug Allergy?

Drug Allergy 1. *Type A*: reactions are predictable and dose dependent - most common type 2. *Type B*: reactions are unpredictable and not dose dependent - 10-15% 3. 5% of hospitalized pts experience a drug adverse reaction; 10% of US population has PCN allergy - Risk factors include: drug frequency & dose, route of administration, patient's ethnicity 4. Responses may involve any of 4 allergy types - Large MW drugs are very likely to cause a *hypersensitivity rxn* - Low MW drugs can bind larger proteins in plasma to induce *an allergic rxn* (hapten-carrier complex) - e.g., penicillin Clinical Aspects 1. There is often a *dermatologic* manifestation - 80-90% of drug allergies cause urticaria or angioedema or both - Also, contact dermatitis, erythema multiforme, photosensitivity 2. There may be *other organ involvements* - Pulmonary infiltration, eosinophilia, hematopoietic abnormalities (hemolytic anemia, thrombocytopenia), hepatic damage, nephrotic syndrome and infectious mono-like symptoms 3. Rxns may lead to anaphylactic shock 4. Consider timing of the drug - If no prior exposure to the drug, allergic symptoms rarely occur before 1 week of continuous therapy; drugs used with no reactions for several months are rarely responsible 5. *Treatment*: skin lesions usually resolve spontaneously; immunosuppressive agents for other manifestations Erythema Multiforme (EM) - Response to medication or exposure int he mouth like mouthwaste/toostpaste/bleaching tray never used before - Skin lesions called target lesions - Have ulcerations in mouth and ocular ejection - *Lead to Toxic Epidermal Necrolysis (TEN)* = severe exfoliation of the skin

What are the Characteristics of Drugs that Disrupt DNA?

Drugs that Disrupt DNA 1. Crosslink DNA (alkylating agents) 2. Intercalate or forms adducts with DNA 3. Cause strand breaks *Crosslinking Agents* 1. Alkylating agents, mitomycin C and platins 2. Forming alkyl radicals, which form covalent linkages with nucleophilic moieties such as the phosphate, sulfhydryl, hydroxyl, carboxyl, amino, and imidazole groups. 3. Interact with DNA causing substitution reactions, cross-linking reactions or strand breaks. 4.*Cell cycle non-specific* - Ex: cisplatin, dacarbazine, mitomycin C - Example-cisplatin: it reacts directly with sulfur groups (such as glutathion), cross-links in DNA *Crosslinking of DNA* *Miscoding of DNA (G-T pairing)* *DNA strand breakage (depurination)* *Intercalating agents* 1. *Some antitumor antibiotics:* Microbial metabolites produced by Streptomyces species. Antineoplastic activity because of their cytotoxic properties - chromomycins and anthracyclines. 2. Bind with DNA to produce irreversible complexes that inhibit cell division. 3. *Cell cycle non-specific*, but maximal toxicity in S phase - Examples: a) *Dactinomycin (actinomycin D)*: - Intercalates into DNA between adjacent guanine-cytosine base pairs and inhibits transcription. b) *Doxorubicine (adriamycin)*: - Combines with DNA in an intercalative mode. Inhibit biosynthesis and replication of DNA. **Also inhibits the progression of topoisomerase to unwind DNA for transcription. **For treatment of wide spectrum of solid tumors. *DNA strand breaks* 1. *Bleomycin* - Antitumor antibiotics. - DNA scission and fragmentation with inhibition of DNA repair mechanisms - Bleomycin is *cell phase specific*: major effects on G2 and M phases of the cell cycle 2. *Etoposide* - Topoisomerase II inhibitor -> DNA double strand breaks and inhibition of repair - *Cell cycle specific* (S and G2 phases)

What are the Characteristics of Drugs that Interrupt DNA Replication?

Drugs that Interrupt DNA Replication *Antimetabolites* 1. Similarity in structure or function to naturally occurring metabolites involved in nucleic acid synthesis - either inhibit enzymes involved in nucleic acid synthesis or produce incorrect codes. - Examples: a) *methotrexate*:dihydrofolate reductase inhibitor b) *purine analogues*: mercaptopurine c) *pyrimidine analogues*: 5-fluoruracil (metabolites inhibit thymidylate synthetase) 2. *Cell cycle specific*: - They exert their major effects during the *S phase* of the cell cycle Methotrexate 1. Tetrahydrofolate is an important cofactor in the production of purines. 2. Methotrexate substitutes as folic Acid and inhibits the metabolism of folic acid 3. Interferes with the production of Tetrahydrofolate 4. Interferes with the de novo synthesis of purines 5. Affects cells that rapidly turn over and slow down the growth

What are the Examples of Targeted Antineoplastics?

Examples of Targeted Antineoplastics 1. Hormone therapies: hormone sensitive tumors (ER+ or PR+) - Ex: tamoxifen for breast cancer 2. Signal transducer inhibitors - Ex: protein kinase inhibitors 3. Gene expression modulators - Ex: mTOR inhibitors 4. Apoptosis inducers: induce cancer cell death - Ex: curcumin for lung cancer via inhibition of PI3K/Akt/mTOR 5. Angiogenesis inhibitors - Ex: anti-VEGF 6. Immunotherapies - Ex: Mab against cancer cell surface marker 7. MAbs to deliver toxic molecules - Ex: toxic molecule linked to Mab targeting cancer cells 8. Cancer vaccines and gene therapy - Ex: HPV vaccine, viral delivery of TSG, etc. Activation of the Epidermal Growth Factor (EGFR) receptor - EGFR overexpression or activation in many human cancers including HNSCC and NSCLC - Dimerization of EGFR receptor and activation by autophosphorylation causes downstream phosphorylation signaling -> overexpression is very frequent in many cancers *Blocking Agents* 1. Anti-receptor antibodies - Anti-EGFR Mab: Cetuximab, Panitumumab - Binds to receptor and prevents dimerization a) *Ramucirumab* - Antagonist of VEGF receptor 2 (angiogenesis pathway) - There are 3 different VEGF receptors, so can have monoclonal antibody target VEGF and stop binding of ligand to receptor 2. Tyrosine kinase inhibitors a) Iressa (gefitinib) - Non-small cell lung cancer(NSCLC) - Binds to ATP-binding site b) Tarceva (erlotinib) - Metastatic unresectable NSCLC and pancreatic cancer - JAK2 inhibitor (blocks ligand binding domain) c) Gleevec (imatinib mesylate) (expensive) - Chronic myelogenous leukemia (Bcr-Abl) - KIT+ GIST (gastrointestinal stromal tumors)

Examples of Type III Hypersensitivity Diseases

Examples of Type III Hypersensitivity Diseases 1. Single large exposure to antigen - usually resolves a) *Acute serum sickness* (foreign serum protein) - Prototype of a systemic immune complex. It was once frequent when large amount of foreign serum (e.g. serum from immunized horses were used for protection against diphtheria or scarlet fever). It is now less frequent. - The introduction of a protein antigen triggers an immune response that results in the formation of antibodies (typically a week). These antibodies are secreted into the blood where they react with the antigen still present in circulation and form the antigen-antigen complex. - Causes fever, vasculitis, arthritis, nephritis b) *Streptococcal glomerulonephritis* (streptococcal cell wall protein) - Most common in children 6-10 years old after a streptococcal infection - Antibody to streptococcal antigen form complexes that deposit in glomeruli. - Not as common now due to use of antibiotics - Get necrosis of vessel wall and intense neutrophilic infiltration 2. Local exposure to the antigen a) *Arthus Reaction* (various foreign proteins) - Localize area of tissue necrosis resulting from acute immune complex vasculitis in the skin - The reaction can be produced experimentally by intracutaneous injection of antigen in a previously immunized animal that contains circulating antibodies against an antigen. - As the antigen diffuses into the vascular wall, it binds the preformed antibody, and large immune complexes are formed locally. These complexes precipitate in the vessel walls and cause fibrinoid necrosis, and superimposed thrombosis worsens the ischemic injury. 3. Chronic exposure to antigen a) *Systemic lupus erythematosus* (nuclear antigens) - Persistent antibody responses to autoantigens b) *Polyarteritis nodosa* (Hepatitis B virus antigens)

What are the Characteristics of Follicular Lymphoma?

Follicular Lymphoma 1. Most common type of "indolent" lymphoma 2. Often asymptomatic (not curable, except certain cases) - FL has variable clinical behavior (staging doesn't really make sense) 3. Associated with BCL-2 gene rearrangement of chromosome (t 14:18) - BCL-2 > 80% expressed - Apoptotic evasion: BCL-2 accumulation (BCL-2 normally stops apoptosis, overexpression is bad) 4. Cell of origin: germinal center B-cell Histopathology of FL - Similar in architecture to normal germinal centers - Can resemble reactive follicular hyperplasia (rfh) - Low proliferation rate in comaprison to RFH - BCL-2 staining absent in RFH - Residual benign mantle zones not seen Treatment 1. Difficult to Asses Value of Various Treatments - Very Long survival times and multiple treatment options for relapsed disease preclude easy analysis of OS as an endpoint - Heterogeneity of outcomes depending on risk - Most trials demonstrate differences in RR but not OS Treatment Options Overview 1. Watch and Wait (no therapy, same survival as with therapy) 2. Immunotherapy - Rituximab (and other *antiCD20 Ab*) are cell-specific to cause recruitment of macrophages to kill the cell, activate the complement, or cause apoptosis of the malignant B cells 3. Radioimmunotherapy - Bexxar, Zevalin - Targeted delivery of radiation, greater exposure of tumors vs surrounding organs by virtue of selectivity of carrier antibody (Rituximab has radioisotope to bind to cells we want to see) 4. Chemoimmunotherapy - R-CHOP 5. Immunomodulators - Lenalidomide 6. BCR inhibitors (blocks B cell growth) - Ibrutinib (Btk- Bruton's tryosine kinase) - Idelalisib (PI3K - phosphatidylinositol 3-kinase) - Venetoclax = BCL-2 inhibitor (causes apoptosis) 7. Rituximab Maintenance

What are the Characteristics of Primary Hemostasis?

Formation of platelet seal at the site of blood vessel damage - *PG2, a specific prostacyclin* released by endothelial cells, inhibits platelet aggregation (binding to endothelium) when the vessel wall is not damaged - When platelets bind to an area of damage, they undergo shape change and release *ADP* and *Thromboxane A2* = vasoactive to bring other platelets in Platelet adherence to damaged vessel endothelium "activates" platelets by triggering: 1. Platelet shape change resulting in interaction with other platelets and adherence to vessel endothelium 2. Platelet release of ADP and thromboxane A2, which bind to specific receptors on other platelets causing further platelet activation Activated Platelets 1. The protein *von Willebrand factor (vWf)* bind platelets to collagen and other proteins in vessel endothelium - *vWf synthesized in endothelial cells 2. Platelets bind to each other via the protein *fibrinogen* 3. Glycoproteins *Ib* and *IIb/IIIa* are the receptor proteins for von Willebrand factor and fibrinogen, respectively PLT Shear and Chemical Release 1. Shear induces PLT shape change, adhesion to endothelium, and activation 2. This enhances granule secretion, PLT recruitment, and clot propagation - Aspirin affects platelet by inhibiting platelet cyclooxygenase (COX) enzyme (required for prostaglandins and thromboxanes production) PLT Plug Formation: Putting it all Together 1. Activated - PLT shear induces adhesion (via vWf and GPIb-IX) and activation (shape change & granule release) 2. Aggregated - Aggregation occurs via fibrinogen-GPIIb/IIIa interaction; clot propagation by additional PLT activation

What are the Characteristics of Red Cell Enzyme Disorders?

Glucose-6-phosphate Dehydrogenase (G6PD) 1. G6PD is a housekeeping gene essential for basic cellular functions 2. G6PD generates NADPH which is utilized for glutathione reduction - Reduction in glutathione restores hemoglobin in soluble state and prevents oxidative damage due to release of O- G6PD Deficiency Leads to... 1. Hemolysis in presence of oxidant stress 2. Morphologic consequence of oxidative damage to hemoglobin is Heinz bodies (precipitated globin chains) 3. Bite cells and blister cells are also rarely seen 4. G6PD deficiency confers protection against malaria G6PD - Gene for G6PD is encoded on X chromosome - Laboratory diagnosis: spectrometic analysis - Treatment: avoidance of oxidant stressors medications like antimalarials, fava beans, infections Pyrimidine 5' Nucleotidase - Inherited in autosomal recessive fashion - Participates in degradation of RNA in the reticulocytes - Is the only red cell enzyme deficiency that has a specific consistent morphological abnormality- basophilic stippling Basophilic Stippling - Ribosomal RNA is precipitated during staining - Causes: heavy metal poisoning, sideroblastic anemias, thalassemia

What are the Characteristics of Graft vs Host Disease?

Graft Versus Host Disease 1. Affects preferentially skin, mouth, GI tract, liver 2. Secondary Malignancy: Squamous Cell Carcinoma - Increased risk of cancer due to immunosuppression Autologous Stem Cell Transplant (ASCT) - Need chemo-sensitive disease for this to work, patient given high dose of chemo before being given stem cells - Patient is their own donor (give growth factor after chemo) 1. Hodgkin and non-Hodgkin lymphoma 2. Multiple myeloma 3. Sarcoma 4. Germ cell tumors 5. CNS tumors

What are the Characteristics of Hematopoietic Stem Cell Transplantation?

Hematopoietic Stem Cell Transplantation 1. Used to replace deficient or defective hematopoietic cells 2. Used as a rescue to allow for the administration of high doses of chemotherapy 3. Adoptive immunotherapy effective in allogeneic (graft versus tumor effect) - Don't need to be same blood type, just same MHC (HLA typing) - Sibling receives 50% from parent, so 25% they ll be a match for you Allogeneic Stem Cell Transplant: Indications 1. Acute leukemias 2. Chronic leukemias 3. Myelodysplasia 4. Aplastic Anemia 5. Lymphomas 6. Congenital metabolic disorders 7. Congenital immunologic disorders 8. Hemoglobinopathies CD34+ Stem Cells 1. About 1% of mononuclear cells in the bone marrow are CD34+ 2. Very small numbers in the blood - Immature enough to potentially differentiate into all the blood cells the body need 3. Can use bone marrow or peripheral blood stem cell after injections to increase circulating CD34+ count Stem Cell Source 1. Bone marrow - Harvest 2. Peripheral blood (preferred method now) - Growth factor (G-CSF, CXCR4 antagonist) 3. Umbilical cord blood 4. Haploidentical

What are the Characteristics of Hemoglobinopathies?

Heme + Globin = Hemoglobin 1. Each Hb molecule is composed of 4 globin chains and 4 heme molecules 2. Globin genes - Each Chr 16 encodes 2 α chains genes -> 4 α alleles in each cell - Each Chr 11 encodes 1 β gene and 1 γ gene -> 2 β and 2 γ alleles in each cell Normal Physiologic Hb - Hemoglobin A: α2β2 globin chains in adults - Hemoglobin F: α2γ2 globin chains in fetus Two Types of Hemoglobinopathies Exist 1. Production of normal quantities of qualitatively defective globin chains - Ex: HbS, HbC, HbE 2. Decreased production in qualitively normal globin chains - Ex: Thalassemia syndromes Hemoglobinopathies - Synthesis of abnormal globins - More than 90% of Hb variants are due to single-point mutations in one of the globin chains - Hemoglobin variants are inherited as co-dominant trait according to Mendelian genetics Sickle Cell Disease - Generic term used to describe group of disorders characterized by abnormal synthesis of HbS - Spleen enlarges in SCD, then hypoxia, and eventually "auto-splenectomy" from fibrosis - HbS = 6th codon of β chain *glutamic acid* is replaced by *Valine* (HbA to HbS) - In presence of decreased oxygen tension, the HbS polymerizes and deform to form sickle cells - *Three types of crisis* 1. Aplastic crisis 2. Hemolytic crisis 3. Painful (vaso occlusive) Crisis Thalassemia - Quantitative defect, primary defect lies in amount of globin chains produced - Leads to iron overload (secondary hemochromatosis) = increase iron in liver and heart, get skeletal abnormalities in skull and bone marrow expansion - Most α thalassemia are result of *deletion* in α gene located on Chr 16 - Most β thalassemia due to *point mutation* of β gene on Chr 11 1. Normal adults: - HbA (95-97%), HbA2 (2-3%), HbF (1%) 2. α Thalassemia has reduced alpha chain leading to increased amount of its partners - Excess γ chains - Hb Barts (γ4) - Excess β chains - Hb H (β4) 3. β Thalassemia has reduced β chains lead to increased amounts of its partner, α - Excess α chains cause red cell lysis SCD and Thalassemia leads to increased hematopoiesis displacing bone stimulating remodeling - Prominent cheekbones and changes in skull that resemble a crew-cut

What are the Characteristics of Hemolytic Anemia?

Hemolytic Anemia is Destruction 1. Intrinsic destruction of the cell - RBC membrane defects - Red cell enzyme deficiency - Defects in hemoglobin synthesis 2. Extrinsic Destruction out of the cell - Trauma to red cells - Antibody mediated - Mechanical trauma - prosthetic valves - Infections (ex: malaria) Lab Evaluation of Hemolysis - Reticulocytosis, sometimes nucleated RBC - Polychromatophilia of erythrocytes - Increased indirect bilirubin - Increased urinary and fecal urobilinogen - Erythroid hyperplasia of boen marrow Causes Include - Incompatible transfusion, IgM Abs, complement fixation - Results in free serum hemoglobin -> bilitubin (yellow/red serum) -> get jaundice - Results in free urine hemoglobin -> red urine Intravascular Hemolysis - Fragmented RBC - Howell-Jolly inclusion (nucleoid remannt) - Nucleated RBC Autoagglutination 1. Clumping of RBCs (Rouleaux FOrmation) - Stack of Coins 2. May be due to cold agglutins - IgM antibodies - Patients with Mycoplasma, infectious mononculeosis, etc 3. CBC incorrect values - ↓ RBC count - ↑ MCV 4. Treat by warming

What are the Characteristics of Hodkin's Disease?

Hodgkin's Disease 1. One-seventh as common as non-Hodgkin's lymphoma. 2. Highly treatable and curable, even when disseminated. 3. Presence of Reed-Sternberg cell is necessary to make diagnosis. - Two nucleus, owl-eye, malignant, minor population, unknown cell origin Subtypes of Hodgkin's Disease - Lymphocyte predominant - Nodular sclerosis - Mixed cellularity - Lymphocyte depleted *Unlike non-Hodgkin's lymphoma, in Hodgkin's Disease the histologic subtype does not determine how the disease is treated.* Signs and Symptoms 1. Lymph node enlargement, usually cervical or mediastinal. 2. Systemic "B" symptoms common. 3. Pel-Ebstein fever. - Relapsing, high-grade fever that can reach 105-106°F, periodicity of 7-10 days. Fever spikes abrupt in onset and resolution 4. Pain on drinking alcohol. Clinical Features 1. Predictable contiguous spread of disease: - Cervical nodes to mediastinum or axilla - Mediastinum to periaortic nodes or spleen, etc. 2. Basis for staging and treatment decisions. Diagnosis - Excisional biopsy of a lymph node (fine needle aspirate is not sufficient) Chemotherapy Regimens 1. ABVD - *Adriamycin, Bleomycin, Vinblastine, Dacarbazine* 2. BEACOPP Late Complications of Hodgkin's Disease 1. High incidence of second malignancies - Leukemia first 10 years, solid tumors over time. 2. Leukemia in patients receiving alkylating agents or combined chemo/XRT. 3. Lung cancer and breast cancer in patients receiving XRT to chest. Lung cancer especially high in smokers. 4. Hypothyroidism after irradiation of the neck. 5. Constrictive pericarditis after radiotherapy to the mediastinum. 6. Infertility after use of alkylating agents. 7. Heart failure after Adriamycin treatment

How much Genetic Damage to do you need and the characteristics of Cancer?

How Much Genetic do you Need? 1. Mutations that contribute to the development of the malignant phenotype are called "driver" mutations. - 1st mutation: initiating mutation, maintained in all of the cells of the tumor, rarely is this fully transforming 2. Most often development of cancer requires that the initiated cell acquire a number of additional driver mutations 3. Loss of function mutations that increase genomic instability but by themselves produce no phenotypic consequence = passenger mutations (more frequent than driver mutations) Once established, tumors... 1. Evolve genetically during their outgrowth and progression under Darwinian selection pressure - Early on, all cells identical - By the time its detected (usually as a mass of about 1 gm), it has gone through a min of 30 cell doublings - During this time, the cells have "evolved" - Metastatic lesions and primary tumor will often be different (both have same mutations as in founding cell but have mutations unique to tumor site) Acquired Characteristics of Cancer Cells - All cancers display 10 fundamental changes in cell physiology called "hallmarks of cancer" 1. Evading growth suppressor - Insensitivity to anti-growth signals - Tumor suppressor genes 2. Enabling replicative immortality - Self-sufficiency in growth signals - Oncogenes 3. Tumor-promoting inflammation 4. Activating invasion and metastasis 5. Genomic instability (mutator phenotype0 6. Inducing angiogenesis 7. Resisting cell death 8. Deregulating cellular energetics 9. Sustaining proliferative signaling 10. Avoiding immune destruction

What are the Characteristics of B Cell Activation?

Humoral immunity: 1. B cells ingest protein antigens into vesicles, degrade them and display peptides bound to MHC molecules for recognition by helper T cells. 2. The helper T cells express CD40L, secrete cytokines, which work together to activate the B cells. 3. Plasma cells: secrete antibodies that have the same antigen binding site. - Polysaccharides and lipids stimulate secretion of IgM antibodies. - Protein antigens stimulate different classes or induce isotype switching (IgG, IgA, IgE) 5 Classes of Immunoglobulins a) IgM: Occur early as it is the first Ig to reach site of infection. Looks like the IgG but repeated 5 times. So most efficient in agglutination, and complement fixation as it has 10 antigen binding sites.. b) IgG = most abundant c) IgA: Main Ig in secretions such as colostrum, saliva, tears, GI secretions. Prevents attachment of microbes to mucous membrane. Does not fix complement. d) IgD: Not much known but present at low levels e) IgE: important for fighting parasites (worm infections). Does not cross placenta or fix complement. At very low levels in serum.

What are the Characteristics of the Hypercoagulable States (Thrombophilia)?

Hypercoagulable States (Thrombophilia) 1. Defintion - Untimely venous clot formation due to an imbalance between the anticoagulant and prothrombotic activities of plasma 2. Hereditary causes - Factor V mutation (Leiden variant): resistance to activated protein C - Prothrombin G20210A variant: elevated levels of prothrombin factor (2) - Deficiency in protein C, S, or antithrombin - Note:Clotting often manifests only when other risk factors are present: drugs (hormones/oral contraceptives), immobilization, surgery/hospitalization* 3. Acquired Thrombophilia a) Central venous catheters b) Cancer c) Pregnancy d) Antiphospholipid antibody syndrome - Production of antibodies causing arterial, ex: stroke, or venous clots, inhibition of coagulation in vitro (prolonged PT or PTT in absence of drugs), fetal loss/other pregnancy complications e) Myeloproliferative disorders (bone marrow) - Polycythemia vera, essential thrombocytosis Acquired Thrombophilia: Possible causes 1. Inflammation or cancer-induced expression of tissue factor - Certain chemicals can induce tissue factor expression by normal endothelial cells and by normal monocytes - Tissue factor exists in blood in an inactive state on particles derived from dead WBC; activation can occur by some unknown mechanism (ex: lipid reorganization) 2. Reduced levels of antithrombin, protein C and protein S due to ongoing coagulation and inflammation 3. If widespread activation of clotting occurs (sepsis, trauma, pregnancy complication, active cancer), it is called *Disseminated Intravascular Coagulation (DIC)* - Both thrombosis and bleeding can occur - *Systemic activation of coagulation:* a) Intravascular deposition of fibrin - Thrombosis of small and midsize vessels, and organ dysfunction - Increased D-dimer b) Depletion of platelets and coagulation factors - Bleeding - Low fibrinogen, elevated PT and aPTT, low PLTs 4. DIC Treatment: - Platelets, plasma, cryoprecipitate - Anticoagulation (occasionally) - Treat underlying condition (infection, malignancy)

What are the Characteristics of Hypersensitivity?

Hypersensitivity 1. Refers to excessive, undesirable (damaging, sometime fatal) reactions produced by the normal immune system. 2. Adaptive immune response sometimes against an inherently harmless antigen such as pollen, food, or drugs. 3. Aberrant adaptive immune response. Players in hypersensitivity responses: T & B cells Four general features of hypersensitivity disorders: 1. Hypersensitivity reactions can be elicited by exogenous environmental antigens (microbial and nonmicrobials) or endogenous self antigens. 2. Hypersensitivity results from an imbalance between the effector and control mechanisms that limit the immune responses. 3. There are susceptibility genes associated with the development of disease. 4. Mechanism of tissue injury in hypersensitivity is the same as which occur to an infectious pathogen. 5. It requires a pre-sensitized (immune) state of the host 6. Hypersensitivity reactions can be divided into 4 types based on the mechanisms involved and the time it takes to develop a reaction. In many clinical disease, more than one type of reaction may be present.

What are the Characteristics of Leukemia

Leukemias - A *neoplastic* disorder of the hematopoietic system characterized by an unregulated accumulation or proliferation usually of members of the leukocyte series in the bone marrow. The abnormal cells eventually invade the blood, frequently in large numbers, hence the name "leukemia" (white blood) - Acute leukemia = immature blood cells - Patients with leukemia blood sample has a large white buffy coat Classifications of Leukemias 1. Disease course - Acute vs Chronic 2. Cell lineage - Myeloid vs lymphoid 3. Chronic myeloid leukemia (CML) 4. Acute myeloid leukemia (AML) 5. Chronic lymphocytic leukemia (CLL) 6. Acute lymphoblastic leukemia (ALL) Chronic Leukemias 1. Chronic myeloid leukemia (CML) 2. Chronic lymphocytic leukemia (CLL) 3. Indolent, incurable, very treatable 4. Largely treated without chemotherapy

How is Diversity generated in B and T cells?

Lymphocyte Diversity 1. Lymphocytes specific to a large number of antigens exist before exposure to an antigen. They are naïve before they encounter an antigen. 2. When an antigen enters, it selectively activates the antigen-specific cells. - *CLONAL EXPANSION* 3. Once they encounter an antigen, they differentiate into effector T cells. How was Diversity Generated? 1. Generated by somatic recombination of genes that encode the receptor. 2. Turns out that all cells of the body, including lymphocyte progenitors, contain antigen receptor genes in the germline (inherited) configuration. 3. Genes encoding these receptors consist of spatially separated segments that cannot be expressed as proteins. 4. During lymphocyte maturation, these gene segments recombine in random sets and variations are introduced at sites of recombination, forming many different genes that can be transcribed and translated. Somatic Recombination - Only occurs in T and B cells - Mediated by enzyme called RAG (recombination activity genes) - VDJ = variable, diversity, joining - Inherit some ability to respond to pathogens from our family - T cells can't go through somatic hypermutation What about T cells? 1. TCR is a heterodimeric proteins comprised of an α and β chain. 2. Thymic selection: more than 5x10^15 possible TCRs can be selected.

What are the Characteristics of Lymphocytes, Monocytes, Basophils, and Eosinophils?

Lymphocytes are Mononuclear Cells 1. T-cells derived from the thymus, participate in cellular immunity - T-helper cells: CD4 - T-effector/cytotoxic cells: CD8 2. B-cells are derived from bone marrow, participate in humoral (antibody) immunity 3. Natural Killer cells are T-cell like and participate in innate immunity Increase/Decrease in Lymphocytes 1. Decreased: Lymphopenia - Ex: HIV infection, shows reduced CD4 T-cells 2. Increased: Lymphocytosis - Ex: Leukemia or lymphoma Monocytes 1. Morphology - Mononuclear cells with a kidney shaped nucleus and pale blue cytoplasm with vacuoles 2. Function - Replenish the macrophage dendritic system (circulating form is a monocyte, tissue form is a macrophage or dendritic cell) - Participate in cellular and humoral immunity (phagocytose, antigen presentation, complement activation, cytokine production) Basophils 1. Morphology - Contains numerous basophilic granules which overlap the bilobed nucleus 2. Function - Least common in blood - Participates in active inflammation and allergy - Granules contain/release histamine, leukotrienes, heparin, cytokines Eosinophils 1. Morphology - Contains eosinophilic (red) course granules that do not overlap the bilobed nucleus 2. Function - Life span 8-12 hours in circulation - Participates in allergy and parasitic infections - Granules contain/secrete numerous cytokines and other inflammatory enzymes

What are the Characteristics of Mast Cell Mediators?

Mast Cell mediators 1. Primary Mediators (preformed granules) - Granules: Histamines, Proteases, Chemotactic Factors (CF) a) Histamine (vasoactive amine, 4 diff receptors): - ↑ Vascular permeability (edema) - ↑ Vasodilation of smooth muscle - ↑ Bronchoconstriction - ↑ Mucus production b) Proteases - Tryptase: generate kinins & cleave complement components to activate complement c) Chemotactic Factors (CF) - for necrosis - Eosinophil CF - Neutrophil CF 2. Secondary mediators (cytokines made) - In about 50% of patients with an early-phase response, a late-phase reaction occurs. - Caused by arachidonic induced synthesis and release of prostaglandins, leukotrienes, chemokines, and cytokines. These cells then recruit other leukocytes (eosinophils and TH2 lymphocytes) to the site of inflammation. - Late phase cytokines: Leukocyte infiltration, epithelial damage, damage bronchospasm - All mammalian cells, except RBC's, produce prostaglandins and their related compounds, the prostacyclins, thromboxanes and leukotrienes (known collectively as eicosanoids) a) Cytokines - TNF-alpha, IL-1, *IL-4, IL-5, IL-6 - Recruit and activate many types inflammatory cells b) Leukotrienes (hypersensitivity) - C4 & D4 = most potent vasoactive spasmogenic agents known (similar to histamine) - B4 = chemotactic eosinophils, neutrophils, monocytes, and leukocyte adhesion c) Prostaglandin D2 - Vasodilation - Mucous secretion d) Platelet-activating factor (PAF) - Causes platelet aggregation and release of heparin and other vasoactive amines - Chemotactic for Eosinophil & Neutrophils

What are the Mechanisms of Action of Antineoplastic Drugs?

Mechanisms of Action of Antineoplastic Drugs 1. Cell proliferation = DNA synthesis 2. Prevent DNA synthesis 3. Disrupt DNA structure, induce DNA damage and prevent DNA repair and/or prevent RNA synthesis 4. Interrupt mitosis 5. Interfere with protein or hormone synthesis 6. Immunotherapy on receptors 7. Prevent angiogenesis and/or formation of metastases The Mechanism and Site of Action 1. Synthesis of Nucleic Acid precursors - Inhibit purine and pyramidine biosynthesis 2. DNA synthesis and replication - Inhibit DNA synthesis, induce DNA damage, prevent DNA damage repair 3. RNA synthesis and transcription - Intercalate with DNA, induce DNA adduct formation, prevent RNA synthesis 4. Protein synthesis and translation - Inhibit amino acid biosynthesis and protein synthesis 5. Protein function - Inhibit biofunction of enzymes and microtubules, inhibit cell division

What is the Mechanism of Lymphomagenesis?

Mechanisms of Lymphomagenesis 1. Genetic alterations 2. Infection - Can treat infection and lymphoma will go away 3. Antigen Stimulation 4. Immunosuppression 1. Chronic inflammation and antigenic stimulation - Helicobacter pylori inflammation, stomach - Chlamydia psittaci inflammation, ocular adnexal tissues - Sjögren's syndrome (autoimmune disorder against lacrimal gland, salivary gland) 2. Viral causes - EBV and Burkitt's lymphoma - HTLV-I and T cell leukemia-lymphoma - HTLV-V and cutaneous T cell lymphoma - Hepatitis C 3. Immune Suppresion - Congenital (Wiskott-Aldrich) - Organ transplant - AIDS - Increasing age 4. DNA repair defects - Ataxia telangiectasia - Xeroderma pigmentosum

What are the Characteristics of Megaloblastic Anemia?

Megaloblastic Anemia 1. Both B12 (cobalamin) and Folic Acid are vitamisn that are required for DNA synthesis 2. Deficiency in B12 or Folic Acid leads to impairment in DNA synthesis which results in delay in nuclear maturation and cell division in comparison to cytoplasmic elements 3. This results in nuclear to cytoplasmic asynchrony affecting all cell lineages (not just red cells) 4. Pathologic hallmark is the presence of abnormally enlarged erythroid precursors (megaloblasts), which give rise to abnormally large red cells (macrocytes) Clinical Presentation 1. Vitamin B 12 deficiency - Neurologic manifestation: accumulation of homocysteine, myelin synthesis disruption, neuropathy - Pallor anemia - Fatigue, glossitis 2. Folic Acid Deficiency - No neurologic manifestation - Pallor, anemia - Fatigue, glossitis Findings in Megaloblastic Anemia 1. Peripheral smear shows macrocytic anemia (MCV >100) and hypersegmented (5+) neutrophils 2. Normal bone marrow cellularity in adults 40-60% 3. Bone marrow in megaloblastic anemia is hypercellular with increased megaloblasts 4. Hematopoetic lineages show nuclear to cytplasmic asynchrony and abnormal morphology (dysplasia)

What are the Coagulation Factors?

Most Synthesized in the Liver - Calcium: people whoa re hypocalcemic have increased risk of bleeding - Factor 7 activated can get hemostasis - Factor 8 = Hemophilia A - Factor 9 = Hemphilia B (Christmas Factor) - Factor 12 = Non-essentially, deficiency can still clot - Factor 13 = cross-links fibrin and makes insoluble clot

What are the Characteristics of Multiple Myeloma?

Multiple Myeloma 1. Second most common hematologic malignancy 2. 15th most common cancer, median age 69 3. Male predominance 4. Cancer of plasma cells - Myeloma cells (B cells) produce monoclonal M proteins (antibody-like) 5. Serum electrophoresis - Get M spike Multiple Myeloma 1. "Crowding out" of the normal marrow cells 2. Bone lesions - Increased bone resorption - Signal increase osteoclast and decrease osteoblasts - Osteolytic lesions (not masses) 3. Increased cell turn over - Uric acid, calcium phosphate deposits Defining Symptom: *CRAB* Criteria - Calcium - Kidney dysfunction (renal) - Anemia - Bone lesions - Biomarker Kidney Dysfunction - Plasma Cell causes osteoclast = Increase Ca2+ (tubular injury) - Increase light chain kappa/lambda = clog kidney (tubular injury) - Leads to dehydration and decreased GFR - Decreased GFR = hallmark of Multiple Myeloma Multiple Myeloma 1. Elevated serum protein (protein M Ab secreted) 2. Hyperglobulinemia 3. Monoclonal spike on SPEP 4. *Rouleaux formation* of the RBCs on the peripheral smear - Extra protein cause red cells to crowd together Phase of Treatment 1. Induction - Combination with a novel agent 2. Autologous Stem Cell Transplant - High dose melphalan 3. Consolidation/Maintenance *Want to make sure patient is off bisphosphonate drugs (Zometa - Zoledronic acid) because its potential to cause osteonecrosis of the jaw*

What are the Characteristics of Non-Hodgkin's Lymphoma?

Non-Hodgkin's Lymphoma - 6th most common cancer death Case: - Gary is a 40 year old man. He has been homeless and has not had insurance. He comes to your office complaining of severe tooth pain for a few days. He has tried pain medications but the pain has worsened more recently. - On exam, he has extensive decay, multiple carries. He has a palpable tender left submandibular lymph node. He feels unwell and has been having fevers, chills. He is unable to eat, and has lost weight. - Does he have lymphoma? * No, he's homeless, probably lymph node swollen due to infection -> treat the tooth, give antibiotics, settle infection, have him come back* Case: - Marianne W. is 55 year old woman with hypothyroidism. She comes into the office for evaluation of pain in #4 tooth. She noted some sensitivity and pain about a week or two ago. About a week ago, she noticed fracture involving the mesial and buccal aspects. - She has been feeling unwell, in general. Feels fatigued all the time. Also having recurrent fevers, night-sweats. She thinks it may be related to dental abscess. - On evaluation, there is no evidence of dental abscess but there is Posterior-auricular Lymph Node bulging out, what do you recommend? * Can be infection we can't see, hypothyroidism, or lymphoma depressing immune system -> Give antibiotic and see patient back in a week* Case: - A 21 year old young woman comes into your office for evaluation of a tooth that has been bothering her for months. She also has been running a low grade fever for the past few days. On exam, you find evidence of dental carries and a possible abscess, as well as some lymph node enlargement on the side of the abscess. You should: A) Reassure her that the lymph node enlargement is likely reactive to the infection. B) Proceed with appropriate care of the tooth and antibiotics, for management of the dental abscess. C) See her back in 1-2 weeks for further evaluation. *D) All of the above* Case: - Alex is 70 years old and has been diagnosed with Non-Hodgkins Lymphoma. - What do you think his Oncologist may recommend? - What evaluations would you consider before he starts treatment? During his treatments? - What potential complications can you anticipate? * Lymphoid disorders are not treatable by surgery, require systemic therapy (chemo/immuno), disease not just at neck, could be entire body* Case: - A 55 year old woman come to clinic for her routine dental check up. She had a liver transplant six years ago, and has been on immuno- suppression since then. Her liver has been functioning well. More recently, she has noted some increasing fatigue, and painful glands in the neck. Enlarged lymph nodes are palpable on exam. Her dental practitioner should: A) Reassure her that she probably has had an infection, especially since she is on immuno-suppression. She should come back in 6 months. B) Inform her that you are quite suspicious that she has a lymphoma because of her transplant and recently enlarged lymph nodes, and that she should see an oncologist and start treatment as soon as possible. *C) Refer the patient to a head and neck specialist for biopsy.* D) Reassure her that she probably has a low grade lymphoma and that she will not require therapy. Case - A 22 year old man comes into your office for evaluation for dental whitening, before he goes for a photography session for his job as an actor. On exam, you note an enlarged lymph node in the left supraclavicular area. The patient tells you the node has been there for months and has gotten a little bigger, but does not bother him much. You should: *A) Refer the patient for a biopsy and evaluation.* *B) Reassure the patient that this is likely to resolve on its own, and see him back in 6 months for his routine dental care.* *C) The lymph node is likely reactive in etiology, and should be monitored closely.* D) Prescribe a course of antibiotics.

What is the Normal Development of Blood Cells?

Normal Development of Blood Cells 1. 3 Week - Yolk Sac - Primitive stem cells differentiates into hematopoietic stem cells (HSC) 2. 3 Month - HSC migrate to the liver, which is the chief site of blood cell formation until birth 3. 4 Month - HSC migrate to bone marrow as a secondary site of blood cell formation 4. 9 Month - Birth - After birth, bone marrow is the sole source of hematopoiesis Bone Marrow (10kg) - Provides the microenvironment for the orderly proliferation, differentiation, and release of blood cells - In a normal adult the marrow cavity includes the ends of long bones - Has a lot of blood supply for hematopoiesis Bone Marrow Histology - Normal cellularity to fat is 40:60%

What are the Normal Sequence of Events in Response to Iron Deficiency?

Normal Sequence of Events in Response to Iron Deficiency 1. Decreased serum ferritin is (first response) 2. Decreased % saturation of transferrin 3. Decreased serum iron 4. Decreased hemoglobin 5. Microcytic red cells (MCV <80) 6. Hypochromic red cells Lab Findings in Iron Deficiency Anemia - Serum Iron ↓ - TIBC ↑ (total iron binding capacity) - Bone marrow stores ↓ - Ferritin ↓ Signs of Iron Deficiency - Seen more in women than men - Paler hands (less red) - Foggy sclera - Anemia Oral Lesions (sore tongue, angular cheilitis, aphthous ulcerations, atrophic mucositis of upper aero-digestiv tract) Clinical Presentation of Iron Deficiency 1. Fatigue, breathelessness 2. Pica: persistent compulsive desire to ingest certain food or non-edible items like icy, clay, plaster 3. Sore mouth, angular stomatitis, pallor (pale appearance)

Where do Antigen-Specific T cells come from?

Origin of Antigen-Specific T Cells 1. Lymphocytes mature in Bone Marrow and Thymus and gain the ability to express antigen specific receptors. - T cells go to thymus to gain specific receptors (95% are self-reactive and die) - B cells go to bone marrow for their receptors 2. Unique antigen receptors are generated by gene rearrangement 3. Lymphocytes activated by antigen give rise to clones of antigen specific cells which mediated adaptive immunity. 4. Clonal selection is the central principal of adaptive immunity 5. Signals received through antigen receptors determine the development and survival of lymphocytes - Receptors not functional in cancer 6. Binding of antigen and the activation of the cells result in the generation of effector cells and the establishment of immunological memory

What are the Characteristics of Pattern Recognition Receptors?

Pattern Recognition Receptors - 4 Classes of Innate Immune Receptors 1. TLRs: Toll Like Receptors - 22 TLRs in mammals - Each recognizes a different set of microbial molecules. - Present in the plasma membrane and endosomal vesicles. - All signal downstream to activate 2 pathways: a) NF-kB transcription factor: turns on synthesis & secretion of cytokines. b)Activates interferon regulatory factors (IRFs) which turns on type I interferons (anti-viral cytokines) - What happens if you have loss of function mutation in your TLRs? Not enough immune response 2. NLRs: (Nod Like Receptors) - NOD = Nucleotide Oligomerization Domain - Inflammasome is a cytosolic multiprotein complex - Recognize a wide variety of substances, including products of: a) Necrotic cells (e.g. uric acid and released ATP) b) Ion disturbances (e.g. loss of K+) c) Some microbial products - Inflammasome consists of: a) Sensor protein called NLRP3 b) Adapter c) Enzyme caspase-1 - If system went out of whack -> too much = inflammation, too little = not enough response *Disruption in NLRs* 1. Gain of function mutations - Periodic fever syndromes called "autoinflammatory syndromes" -> NOTE: this is NOT an autoimmune disease 2. NLR inflammasome pathway thought to play a role in: - Recognition of urate crystals that underlies the inflammation associated with gout. - Detecting lipids and cholesterol crystals that result in inflammation that contributes to obesity associated type 2 diabetes and atherosclerosis 3. C-type lectin receptors - Expressed on the plasma membrane of dendritic cells and macrophages. - Detect fungal glycans and elicit inflammatory reactions to fungi. 4. RLRs (RIG-like receptors for viral nucleic acids) - Found in the cytosol of most cells and detect nucleic acids of viruses replicating in the cytoplasm. - Stimulate production of antiviral cytokines. 5. Others (there's more than 4) - G protein-coupled receptors on neutrophils, macrophages recognizes N-formylmethionine residues (of bacteria) - Mannose receptors recognize microbial sugars

What are the Pharmaceutical Inhibitors of Platelet Activation?

Pharmaceutical Inhibitors of Platelet Activation 1. *Clopidogrel* (Plavix) - Blocks binding of ADP to its receptor on platelets 2. *Aspirin* - Irreversibly inhibits synthesis of thromboxane A2 - Interaction with other platelets occurs via the plasma protein fibrinogen that acts as a crossbridge by binding to a specific receptor (glycoprotein IIb/IIIa) - GP IIb/IIIa inhibitors are used clinically to decrease the risk of platelet aggregation - Among them are: 1. The monoclonal antibody *abciximab* 2. *Eptifibatide* (Integrillin) and *tirofiban* (Aggrastat) which are synthetic analogs of snake venom toxins

What are the Characteristics of Plasma Cells?

Plasma cells 1. Terminally differentiated B-cells that originate in the bone marrow - Accentrically located nuclei located on one side 2. Normal plasma cells do not circulate in peripheral blood 3. Plasma cells secrete antibodies (immunoglobulin), and are important in humoral immunity Multiple Myeloma 1. Disease of malignant plasma cells 2. Affects bone marrow replacing normal hematopoetic elements with malignant plasma cells -> peripheral cytopenia - *Lead to lytic lesions in bone* 3. Malignant plasma cells secrete abundant abnormal immunoglobulin (paraprotein) - Inhibits normal antibody secretion by normal plasma cells (immuneparesis) - Deposits in kidneys causing renal failure 4. Clinical features - *CRAB* - *Calcemia* - *Renal failure* - *Anemia* - *Bone lesions* Diagnosis of Multiple Myeloma 1. Symptomatic Myeloma - M-protein (paraprotein) in serum or urine - Bone marrow showing monotypical plasma cells or bone lesion showing plasmacytoma - Organ or tissue impairment (CRAB): hypercalcemia, renal dysfunction, anemia, lytic bone lesions 2. Rouleaux Formation in Blood: Stack of Coins - Secretes lots of abnormal proteins

What are the Characteristics of Platelet Disorders?

Platelet Disorders 1. Normal platelet count = 150,000 to 350,000 2. Thrombocytopenia: less than normal numbers 3. Thrombocythemia/Thrombocytosis: more than normal numbers Causes 1. Thrombocytopenia - DIC = Disseminated intravascular coagulation - TTP = thrombotic thrombocytopenia purpura - ITP = immune thrombocytopenia - Primary bone marrow failure (aplastic anemia) - Alcoholism *Risk of bleeding with lower numbers* 2. Thrombocythemia - Primary (ex: Myeloproliferative neoplasm) - Secondary (ex: Acute blood loss, post splenectomy, steroid therapy) Clinical Findings of Platelet Defects 1. History of easy or spontaneous bruising 2. Skin findings: bleeding underneath the skin - Petechia < 0.3 cm - Purpura 0.1 - 1cm - Ecchymoses/bruises > 1 cm 3. Mild to moderate mucosal membrane bleeding - Gingival bleeding, menorrhagia, epistaxis Thrombocythemia/Thrombocytosis 1. Increased numbers of platelets can lead to increased clot formation leading to stroke, myocardial infarction and pulmonary embolism 2. Reactive thrombocythemia usually resolved once the primary cause is removed Platelet Dysfunction without Decreased Quantity - Renal failure: Uremia, abnormal platelets - Liver disease - Prosthetic valves - Aspirin or NSAIDs or other drugs (many) - Congenital (intrinsic platelet defects): Bernard Soullier syndrome, Glaznmann's thrombasthenia

What are the Characteristics of Platelets?

Platelets 1. Platelets are cytoplasmic blebs arising from megakaryocytes 2. Normal life span is 7-10 days 3. Hormone responsible for platelet production is *thrombopoetin* produced by the *liver and kidney* 4. Most common "cellular" components in blood 5. Normal platelet count 150,000 to 350,000 ul 6. One megakaryocyte gives rise to 1000 platelets 7. Most important function is to prevent bleeding when there is damage to the endothelium (inner lining) of the blood vessel by formation of a platelet plug Formation of a Platelet Plug 1. Platelet granules which secrete substance that promote blood vessel constriction and facilitate platelet plug formation preventing further bleed 2. Platelet membrane glycoproteins (GF), vWF and factor VIII all interact to form the plug, and initiate clotting at the site of the plug (scaffold)

What are the Characteristics of Anaphylaxis?

Systemic Analphylaxis 1. Systemic vasodilation and smooth muscle contraction leading to severe bronchiole constriction, edema and shock. 2. It may occur in sensitized individuals in the hospital after administration of foreign proteins (e.g. antisera, hormones, penicillin) or in the community (e.g. peanuts) 3. Can occur within minutes of exposure to minute quantities of the allergen Localized Anaphylaxis 1. About 10-20% of the populations suffers from allergies involving localized reactions to environmental allergens. 2. Target organ responds to direct contact with the allergen. - Digestive tract contact results in vomiting, cramping, diarrhea - Skin sensitivity: reddened inflamed area resulting in itching - Airway sensitivity results in sneezing and rhinitis OR wheezing and asthma

What are the Characteristics of Anaphylaxis here?

Systemic Anaphylaxis 1. Immediate and life-threatening hypersensitivity reaction 2. Allergy mediators are found in multiple organs - Skin: urticaria, angioedema, flushing - Respiratory: laryngeal edema, bronchospasm - CV: hypotension, arrhythmia, - GI: nausea, vomiting, gastrointestinal spasms 3. Most common allergens are drugs, insect venoms, foods, radiocontrast media & latex - Allergen exposure must lead to sensitization before an immediate hypersensitivity can occur Epidemiology 1. Food allergies - Children: egg, peanut, cow's milk, wheat, soy - Adult: peanut, tree nuts, seafood 2. Latex allergy 3. Venom allergy: bites from bees, hornets, fire ants 4. Drug allergies: common with parenterally administered drugs than oral formulations Clinical Aspects 1. Must be distinguished from other conditions - Ex: vasovagal syncope - sweating, nausea, hypotension, bradycardia *but no urticaria* 2. Fatal outcomes are due to airway obstruction and hypotension - Acute treatment involves ensuring airway patency (intubation or tracheostomy) and blood pressure (volume expansion and vasopressors) - IM epinephrine is critical; may also require administration of oxygen, inhaled bronchodilators and parenteral antihistamines

What are the Characteristics of T cell receptors?

T Cells 1. Each T cell receptor consists of a and b polypeptide chains (most common) 2. A second class of T cell receptor called gd T cell receptor consists of g and d polypeptide chains 3. Because it has a *short cytoplasmic tail* region, it cannot do signaling by itself (which is good since we don't want it to be self-activating) - T cell receptor associates with accessory T cell receptor chains called CD3 complex which aid in signaling. There are *γ, δ and 2 ε* T cell accessory chains (each with 1 ITAM) - T cell receptor is also associated with the *2 ζ-zeta* chain which is an important signaling component of T cell receptor chain -> For each chain there are 3 ITAMs (immunotyrosine activation motifs) 4. T cell has a total of *10 ITAMS*, larger than the 2 we get from B cells or 1 from NK cells - Tumor cell antigen bombardment or CD3 complex down-regulation leads to T cell dysfunction = chronic inflammation

What are the T-Cell mediated Diseases in Type IV Hypersensitivity?

T-Cell mediated Diseases in Type IV Hypersensitivity 1. Rheumatoid arthritis (collagen?) 2. Multiple sclerosis (protein antigens in myelin) 3. Inflammatory bowel disease (enteric bacteria) 4. Psoriasis (unknown) 5. Contact sensitivity (environmental chemicals like poison ivy)

What are the Characteristics in the Dissolution of the Clot?

TPA = Tissue Plasminogen Activator (synthesized by vascular endothelium) - Clot buster - Note: Alteplase is TPA produced by recombinant DNA technology (rhTPA) D-Dimers = breakdown of fibrin of two D domains - Patients with clots, like from DVT, often have elevated D-dimers (use CAT scan to locate clot) Note: Plasma levels of D-dimers are increased in: 1. Venous thrombosis 2. Thromboembolism 3. Infection 4. Neoplasia

What are the Characteristics of Targeted Antineoplastics?

Targeted Antineoplastics - NCI Definition: drugs or other substances that block the growth and spread of cancer by interfering with specific molecules (molecular targets) that are involved in the growth, progression, and spread of cancer. 1. Act on *specific molecular targets* that are associated with cancer, whereas most standard chemotherapies act on all rapidly dividing normal and cancerous cells. 2. *Designed to interact with their target and regulate*, whereas many standard chemotherapies were identified because they kill cells. 3. *Cytostatic* (that is, they block tumor cell proliferation), whereas standard chemotherapy agents are cytotoxic (that is, they kill tumor cells). 4. Could be *patient specific* How are Targeted Therapies Developed? 1. Identification of molecular target- basic science on molecular mechanisms 2. Develop a therapy that affects the target in a way that interferes with its ability to promote cancer cell growth or survival- monoclonal Abs, small-molecular compounds - *Small molecular compounds* by high-throughput screens, chemical modification, test for safety and effectiveness. - *Monoclonal antibodies* are developed by injecting animals (usually mice) with purified target proteins. Abs are tested to find the ones that bind best to the target without binding to nontarget proteins. Humanization to reduce immune problems. 3. Clinical testing and regulatory approval Side Effects of Targeted Antineoplastics 1. Diarrhea and liver problems- hepatitis and elevated liver enzymes. 2. Skin problems- rash, dry skin, nail changes, hair depigmentation 3. Problem with blood clotting and wound healing (since some drugs target immune cells/RBCs) 4. High blood pressure (target angiogenesis of cancer cells, effecting cardiac function) 5. Rare gastrointestinal perforation - Certain side effects of some targeted therapies have been linked to better patient outcomes: patients who develop rash or high blood pressure have bad better outcomes.

What are the Characteristics of Iron Deficiency Anemia?

Terminology Iron Metabolism - Transferrin: Transport protein for iron - Ferritin: storage form of iron, levels reflect iron stores in body - TIBC: amount of iron that the transferrin could bind in a fully saturated state; TIBC is high when serum iron is low Hemoglobin Synthesis 1. You eat iron -> it is absorbed in body and stored in macrophages 2. It is released from macrophages and goes to RBCs 3. in RBC, it goes into mitochondria where it joins *tetrapyrole ring to form heme* 4. Globin chains are also being synthesized 5. Heme and globin combine to make hemoglobin Iron Deficiency Anemia - If you are iron deficient, you are not making iron and do not initiate pathway to make hemoglobin 1. Most common form of nutritional deficiency 2. Results in hypochromic microcytic anemia 3. Iron is absorbed in duodenum 4. Transferrin is transport protein for iron 5. Storage form of iron includes ferritin and hemosiderin found in liver, spleen, bone marrow and skeletal muscle 6. Serum ferritin is best indicator of body iron stores 7. Causes include dietary, malabsorption due to spure and celiac disease, chronic blood loss Iron Metabolism 1. In duodenum, iron is absorbed into epithelial cells Divalent Metal Transporter (DMT) 2. Ferroportin found in epithelial cells and macrophages release iron from enterocytes into hepatic portal system 3. Hepcidin peptide hormone produced by liver plays a major role in iron homeostasis 4. Hepcidin inhibits secretion of ferroportin hence inhibits iron absorption 5. Juvenile Hemochromatosis is caused by Hepcidin mutation or hemojuvelin mutation

What are the Characteristics of Transplantation of Hematopoietic Cells?

Transplantation of Hematopoietic Cells Problems 1. Graft vs Host Disease (GVHD) - When immunologically competent cells are transplanted into immunologically crippled recipient. Donor T cells recognize recipient's HLA antigens as foreign and react. - A complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted donor cells attack the transplant recipient's body. - Bay occur after a bone marrow or stem cell transplant in which someone receives bone marrow tissue or cells from a donor (called an allogeneic transplant). The new, transplanted cells regard the recipient's body as foreign. - The chance of GVHD is: a) Very low when a person receives bone marrow or cells from an identical twin b) Around 30 - 40% when the donor and recipient are related c) Around 60 - 80% when the donor and recipient are not related 2. Immunodeficiency - Frequent complication. Can result from delay in repopulation of host's immune cells.

How do we Test and Treat Type I Hypersensitivty?

Testing for Systemic Type I hypersensitivity - "Wheal"—a raised, blanched, itchy bump and surrounding red "flare"—indicates the presence of the allergy antibody when the person is exposed to specific allergens. - The larger the wheal and flare, the greater the sensitivity. - Wheal and Flare reaction: a skin eruption that may follow injury or injection of an antigen- skin watched for 15 min. It is characterized by swelling and redness caused by a release of histamine. The reaction usually occurs in three stages, beginning with the appearance of an erythematous area at the site of injury, followed by development of a flare surrounding the site; finally a wheal forms at the site as fluid leaks under the skin from surrounding capillaries. Treating Type I hypersensitivity 1. Pharmacotherapy (Drugs) - Non-steroidal anti-inflammatories - Antihistamines block histamine receptors - Steroids - Epinephrine: prolongs or increases cAMP levels in mast cells which inhibits degranulation 2. Immunotherapy - Desensitization (hyposensitization) aka allergy shots - Repeated injections of allergen to reduce the IgE on Mast cells and produces IgG

How do B cells and T cells antigen receptors gain diversity?

The diversity of B cell and T cell antigen receptors is generated by 4 and 3 main mechanisms respectively 1. Somatic recombination (both) 2. Pairing of heavy and light chains (B cells) - Pairing of alpha and beta chains (T cells) 3. Junctional diversity (both) 4. Somatic hypermutation (only B cells) - Point mutations within the receptor that changes affinity

What are the Characteristics of Transplant Rejection?

Transplant Rejection 1. Example of Type IV hypersensitivity 2. Major barrier to transplants is the process of rejection, when the recipient's immune system recognizes the graft as being foreign and attacks it. - Rejection of transplants are differences in HLA alleles 3. Both cell mediated immunity and circulating antibodies play a role (complex process). - Grafts exchanged between individuals of the same species: allografts - Grafts exchanged between different species: xenografts. Mechanism of recognition and rejection of allografts - Recipient's T cells recognize donor antigens from the graft by 2 pathways a) Direct - T cells of the transplant recipient or "host" recognize the graft molecules on the surface of the APCs in the graft. - Donor class 1 and class 2 MHC antigens on APCs in the graft are recognized by host CD8 and CD4 cells. - CD8+ cells respond to graft antigens differentiate into CTLs and kill graft cells. - CD4+ cells proliferate and produce cytokines (IFN-g) which induce tissue damage by a local inflammatory reaction. b) Indirect - The host T cells recognize donor peptides after they are presented by host APCs. The APCs are presenting the donor peptides as "foreign" objects similar to any foreign peptide. - Recipient APCs are able to process the donor antigens and present the resulting foreign peptides to CD4+ T-cells using self-MHC molecules - CD4 helper cells damage the graft by an inflammatory reaction and stimulate b lymphocytes to produce antibodies. ->Postulated that direct pathway is the major pathway in acute cellular rejection, whereas the indirect pathway is more important in chronic rejection. Graft Rejection - Kidney Transplant rejection - Classified on basis of morphology 1. Hyperacute rejection: - Occurs within minutes of transplant and occurs only in well-vascularized grafts. - Preformed antibodies existing in recipient before transplanation 2. Acute or chronic cellular rejection: - Occur within days or months. *Most commonly seen.* - See expression of CD4 and CD8 T lymphocytes. - Recognition is important as in the absence of humoral rejection patients will respond to immunosuppressive therapy. - *T cells are dominant (cellular)* 3. Acute or chronic humoral rejection. - Mediated by anti-donor antibodies. See damage to the blood vessels. - Will also have complement deposits produced during the antibody-dependent classical pathway. - Important again to recognize as there are treatments such as B cell depleting agents. - *B cells are dominant (humoral)*

What are the Characteristics of Triggering an Allergy?

Triggering an Allergy 1. Ex: Dermatophagoides pteronyssinus (dust mite) - Enzyme Der p 1 cleaves occludin at tight junction - Dendritic cells pick up Der p 1 for antigen presentation and TH2 priming - Immune response leading to IgE production is driven by 2 main groups of signals: a) Signals that favor the differentiation of naïve T cells to a TH2 phenotype b) Activation of cytokines and co-stimulatory signals from Th2 cells that stimulate B cells to switch to the production of IgE antibodies. - Resting mast cell contains granules containing histamine and other inflammatory mediators - Activated B mast cells provide contact and secrete signals to B cells to stimulate IgE production - IgE secreted by plasma cells bind to a high affinity Fc receptor (FCεR1) on mast cells and reside there for months - At 2nd exposure: multivalent antigen cross-links bound IgE antibody, causing release of granule contents Mast Cells Immune Mechanism 1. Initial response (5 to 30 minutes) 2. Late-phase reaction (2 to 8 hours & lasts for days)

What are the Characteristics of Type I Hypersensitivity?

Type I Hypersensitivity 1. Person becomes sensitized to an innocuous antigen (food, pollen, house dust)-the allergen- by producing IgE antibodies against it. 2. The reaction may involve the skin (urticaria and eczema), eyes (conjunctivities), nasopharynx (rhinorrhea, rhinitis), bronchopulmonary tissue (asthma) and GI tract (gastoenteritis). - Symptoms may range from minor inconvenience to death. Allergens - Allergens are nonparasitic antigens that can stimulate the response. Characteristics of Allergens - Small 15-40K MW proteins - Specific protein components (often enzymes) - Exposure to low dose of allergen - Mucosal exposure - Most allergens promote a TH2 response (drives B cell response) Cells at Mucosal Surface - The primary cellular component of this type of hypersensitivity is the mast cell or basophil. - Mast cells are common at sites in the body that are exposed to the external environment, such as the skin. - In these locations, they are found in close proximity to blood vessels, where they can regulate vascular permeability and effector-cell recruitment. *Mast cells have FCε receptor for IgE antibody*

What are the Characteristics of Type II Hypersensitivity?

Type II Hypersensitivity - Mediated by IgG antibodies which can engage complement-mediated and phagocytic effector mechanisms. - Can also have antibody mediated cellular dysfunction. - Directed to cell surface or the extracellular matrix or may take the form of an exogenous antigen (drug) that is adsorbed on a cell surface or matrix Mechanism for Antibody Mediated Injury 1. Antibody-Mediated Cellular Dysfunction - Antibodies don't usually bind to a receptor -> can *Activate, Inhibit, or Kill* - Antibodies to cell surface receptor impair or dysregulate the function of the cell without causing injury or inflammation - Ex: *Pemphigus vulgaris, Myasthenia gravis, Graves disease* 2. Complement Dependent Reactions a) *Opsonization and Phagocytosis* - Opsonization of cells by antibodies and complement components and ingestion by phagocytes. - Phagocytosis is responsible for depletion of cells coated with antibodies. - Cells opsonized by IgG antibodies are recognized by Fc receptors, which are specific for the Fc portions of some IgG subclasses. - In addition, when IgM or IgG antibodies are deposited on the surfaces of cells, they may activate the complement cascade by the classical pathway. - C3b is a by-product of complement activation, promoting phagocytosis. - Can occur with transfusions with an incompatible donor - Hemolytic disease of the newborn (erythroblastosis fetalis) in which there is an antigen difference between the mother and fetus, and anti-erythrocyte IgG antibodies from the mother cross the placenta and cause destruction of fetal red cells - Autoimmune hemolytic anemia: individuals produce antibodies to their own blood cells which are then destroyed. b) *Complement and Fc receptor-mediated inflammation * - Inflammation induced by antibody binding to Fc receptors of leukocytes and by complement breakdown products. APCs bears receptors for complement that enhance the uptake of complement coated antigens and the presentation of these antigens to the adaptive immune system. - Ex: *Goodpasture Disease*

What are the Characteristics of Type III Hypersensitivity?

Type III Hypersensitivity - Similar to Type II, except it's against a soluble antigen. Three Phases 1. Introduction of antigen triggers an immune response that produces antibodies. (Takes about a week) - Antibodies are secreted into blood where they react with antigen still present in circulation, forming an antibody-antigen complex. 2. Deposition of immune complex - Antigen-antibody complexes produce tissue damage by eliciting inflammation at site of deposition - Circulating Ab-Ag complexes are deposited in various tissue. - Immune complexes tend to be deposited where blood is filtered at a high pressure (e.g. urine, synovial fluid) so see these complexes often in glomeruli and joints. - Immune complex mediated diseases can be systemic (if immune complexes are formed in the circulation and are deposited in many organs, or localized to a particular organ such as the kidney (glomerulonephritis), joints (arthritis), etc. -> What determines whether complex formation will lead to tissue deposition and disease? a) Complexes that are medium size b) Formed in slight antigen excess 3. Tissue Injury caused by immune complex: Once in tissue, complexes initiate acute inflammatory response. - Complement Activation - Neutrophil Accumulation - Clinical features (10 days): Fever, Rash/Urticaria (hives), Arthritis, glomerulonnephritis Locations 1. Systemic - Vasculitis: small blood vessels - Arthritis: joints - Glomerulonephritis: kidney 2. Localized to organs - No tissue specificity Distinguishing Characteristics 1. Intense neutrophilic infiltration 2. Necrotic tissue will have deposits of immune complexes (called fibrinoid necrosis) 3. Acute necrotizing vascularitis (necrosis of the vessel wall)

What are the Characteristics of Vitamin B12 and Folate Deficiency?

Vitamin B12 (Cobalamin) 1. Dietary Sources - Abundant in all animal products and resistant to cooking and boiling. Dietary deficiency confined to strict vegans 2. Once absorbed, B12 is stored in liver which normally contains reserves for 5-20 years 3. In western world, cause for B12 deficiency is Pernicious Anemia Pernicious Anemia - Vitamin B12 deficiency resulting from inadequate production or defective function of *intrinsic factor (IF)* - Intrinsic factor is secreted from *parietal cells* of stomach forming complex with B12, which attaches to IF receptors present in epithelial cells within distal ileum - Leads to absorption of Vitamin B12 - Absorbed B12 is bound to transport protein *transcobalmin II* which delivers it to the liver and other parts of the body Causes for B12 Deficiency 1. Autoimmune - Antibodies attack parietal cells, IF-B12 complex - Patients have RA, diabetes, Hashimoto thyroiditis 2. Malabsorption - Gastrectomy (decrease IF production) - Small bowel disorders: Whipple disease, Crohn's disease, tropical Sprue Folic Acid (Folate) 1. Sources: uncooked fruits/vegetables 2. Folates are in polyglutamate forms and must be split to monoglutamate for absorption in proximal 1/3 of small intestine 3. Within cells the monoglutamate form is converted into tetrahydrofolate which is involved in synthesis of purines and pyrimidines (DNA synthesis)\ Causes of Folic Acid Deficiencyt - Diet poor in fresh fruits/vegetables - Alcoholism - alcohol interferes with folate metabolism - Increased metabolism needs - pregnancy and lactation - Drugs: anticonvulsants, antimicrobials, methotrexate - Malabsorption: celiac desease and tropical Spure Lab Findings in B12 and Folate Deficiency 1. Peripheral Blood smear - Macrocytic anemia (MCV >110), hypersegmented neutrophils (5+ lobes, normal is 3-4, first sign of deficiency) 2. Bone marrow - Hypercellular bone marrow, megaloblastic changes, erythroid hyperplasia

What is the Role of Vitamin K in Clotting?

Vitamin K Role 1. The following coagulation factors require binding of *Calcium* to be active: - *II, VII, IX, X and protein C & S* (1972) 2. After synthesis, some glutamate residues of these factors have to be modified in order to bind calcium 3. This modification requires vitamin K (fat soluble vitamin), which is a cofactor of the enzyme that catalyzes the modification reaction - GLU to GLA Transformation requires Vitamin K (adding a carboxyl group) - Note: Vitamin K was discovered by a Belgian biochemist, who named it "K' for its role in koagulation Vitamin K and Analogs - Vitamin K antagonist (VKA) decreases factors II, VII, IX, X and Protein C and S - Ex: Warfarin (Coumadin): competitive inhibitors of Vitamin K enzyme

Quiz Question

Which of the following is not correct: A) Burkitt lymphoma is an aggressive lymphoma that requires urgent attention and treatment *B) Follicular lymphoma is typically a low grade lymphoma that is highly curable* C) Diffuse large B cell lymphoma is and aggressive lymphoma, often treated with combination chemotherapy D) Stage IV metastatic diffuse large B cell lymphoma is curable. Which of the following statements regarding Rituximab is not correct: *A) A monoclonal antibody against CD20 antigen* B) Works by directly causing cell cycle arrest *C) Mechanism of action may involve antibody dependent cellular cytotoxicity* D) Can be used for management of T cell lymphoma B is for apoptosis, D is for B cells,

What are the White Blood Cell Disorders?

White Blood Cell Disorders 1. Increased = LeukoCYTOSIS - Reactive (infection) - Neoplastic (leukemia, lymphoma) 2. Decreased = LeukoPENIA - Decreased production - Increased destruction - Splenic sequestration 3. Dysfunction - Congenital - Toxic - Neoplastic Terms to Describe White Blood CElls 1. Increased white cell count: Leukocytosis - Neutrophilia - Lymphocytosis - Monocytosis - Eosinophilia - Basophilia 2. Decreased white cell count: Leukopenia - Neutropenia - Lymphopenia - Monocytopenia Neutropenia 1. Decreased production - Aplastic anemia, bone marrow failure - B12 folate deficiency - Chemicals: arsenic, benzene suppress bone marrow - Congenital neutropenia 2. Increased destruction - Immune mediated, chemotherapy 3. Sequestration - Splenic, hemodialysis 4. Symptoms - Related to infection, typically due to bacterial and/or fungal pathogens hence sepsis - Mild, moderate, severe neutropenia Leukocytosis 1. Neutrophilia - Bacterial infections, myocardial infarction - *Leukemoid Reaction*: increased white cells, usually reactive such as acute bacterial infection 2. Lymphocytosis - Tuberculosis, viral infection, pertussis, infectious mononucleosis a) Acute infection: pertussis, infectious mononucleosis b) Chronic infection: brucellosis, syphilis, TB c) Malignancy: leukemia, lymphoma 3. Monocytosis - Chronic infections, Lupus, Ulcerative colitis, malaria 4. Eosinophilia - Parasitic infections, allergies, lymphoma, carcinoma 5. Basophilia - CML *Infectious Mononucleosis (IM)* - Lymphocytosis 1. Result of Epstein Barr Virus (EBV) infection 2. Pathogenesis - EBV infects pharyngeal epithelium and B-cells, remains dormant after acute infection - Carries shed virus sporadically - Latent infections reactivated in immunocompromised state 3. Clinical presentation - Fever, malaise, skin rash, lymphadenopathy, sore throat, spleen/liver enlarged, recovery 3-4 months - Kissing disease "mono" 4. Diagnosis - Serology, atypical lymphocytes in blood smear

What are the Characteristics of the Hygiene Hypothesis?

Why don't we all have allergies? 1. Studies have shown that 40% of the population in Western industrialized countries show an exaggerated tendency to mount IgE responses to a wide variety of common environmental allergens. 2. Susceptibility loci: - Chr 6 (for MHC1/2) - Chr 20 (polymorphism) "Hygiene Hypothesis" 1. Postulates that exposure to some infectious agents in childhood drives the immune system towards a general state of TH1 responsiveness and non-atopy. 2. Atopy: syndrome where people are "hyperallegic" - A person with atopy typically presents with one or more of the following : eczema (atopic dermatitis), allergic rhinitis (hay fever), or allergic asthma 3. In contrast, children with genetic susceptibility to atopy and who live in a "too clean" environment with low exposure to infectious disease tend to mount TH2 responses, which naturally predominate in the neonatal period of life. Why do Responses Vary in Different Tissue? - Mast cells have different effects on tissues 1. GI tract = increase fluid secretion/ peristalsis 2. Airways = decrease diameter, increase mucus secretion 3. Blood vessels = increase blood flow/permeability