Pharmacology IV: Exam 1

The three kinds of professional antigen-presenting cells (APCs) are shown as follows EXCEPT A: Mast cells B: Dendritic cells C: Macrophages D: B cells

A: Mast cells

Which major cell types are involved in each type of inflammation?

Acute: Neutrophils, basophils, eosinophils, monocytes/MO Chronic: Monocytes/MO, lymphocytes, plasma cells, fibroblasts

What are the causative agents of each type of inflammation?

Acute: Pathogens, injury Chronic: Persistent acute inflammation from non-degradable pathogen, foreign bodies, or autoimmune reactions

Describe the primary mediators involved in each type of inflammatory process.

Acute: Vasoactive amines (histamine, eicosanoids, complement, cytokines (TNF, ILs) Chronic: IFN-gamma, other cytokines, reactive oxygen species, hydrolytic enzymes

Which of these is a stress-related molecule primarily associated with immune suppression? A: Epinephrine B: Cortisol C: INF-alpha D: CRP

B: Cortisol

Which of the following is NOT a function of an antibody? A: Opsonization B: Processing and presentation of a pathogen antigen to a T cell by MHC molecules C: Virus neutralization D: Formation of immune complex with an antigen

B: Processing and presentation of a pathogen antigen to a T cell by MHC molecules

What is the malignant disorder that causes rapid growth of non-functional lymphoid-type cells? A: AML B: CML C: ALL D: CLL

C: ALL

How is the adaptive immune system inducible and develops immunological memory?

Can be activated very rapidly upon reinfection · Lymphocytes can travel through the body in the lymph as well as the blood · ~ 5 millions lymphocytes leave the blood and enter *secondary lymphoid organs* every minute. · While in the LN, naïve lymphocytes can be activated by pathogens in the afferent lymph draining from an infection, dividing and differentiating into effector cells · If not activated, naïve lymphocytes leave the LN in the efferent lymph and go back to the blood · Lymphocytes recirculate all the time, irrespective of infection

IgG and IgA are the first antibodies made in adaptive immunity. T/F

False It is IgM and IgD

What type of cells gives rise to the entire blood system?

Hematopoietic stem cells (HSCs) - Self-renewing - Multipotent

Understand that the innate immunity is always present but does not generate memory.

No memory involved, nonspecific, rapid first immune response

Describe the major types of cytokines and their functions.

Regulate host responses to infection, immune responses, inflammation and trauma · Soluble proteins, peptides or glycoproteins released from immune cells in damaged tissues · Also called lymphokines · Dilate local blood capillaries and increase permeability · Contribute to clinical signs associated with triggering innate immunity and induction of inflammation · Recruit additional immune cells · Activate NK cells 1. Interleukins 2. Interferons 3. Tumor necrosis factor α (TNF-α) 4. Chemokines

Understand what contributes to the secondary response and why it's more powerful and effective than the primary response.

Secondary response - Rapid, strong, more sensitive, and more abundant due to the presence of memory cells - Clones of specific memory B and T cells expanded - Ab switched from IgM to IgG, IgA, IgE isotypes - Often clears infection before symptoms occur

Which of the following is NOT a lymphoid branch (lineage) cell (agranulocyte)? A: Basophils B: T-cells C: Natural killers D: B-cells

A: Basophils

Which of the following is NOT an autoimmune inflammatory disorder? A: Bee sting allergy B: Lupus C: Rheumatoid arthritis D: Chron's disease

A: Bee sting allergy

Which of the following statement is TRUE for Type III hypersensitivity? A: It is caused by soluble immune (antibody-antigen) complexes formed in the circulation and later deposited on the basement membranes in tissues and blood vessels, eliciting inflammatory responses. B: It is mediated by activated T cells. C: It is the type of hypersensitivity responsible for allergic reactions, mediated by allergen cross-linking of cell-bound IgE causing release of vasoactive substances. D: It is antibody-mediated cytotoxic reaction initiated by interaction of antibodies with cell-bound antigens.

A: It is caused by soluble immune (antibody-antigen) complexes formed in the circulation and later deposited on the basement membranes in tissues and blood vessels, eliciting inflammatory responses.

An adult patient's blood sample is analyzed in a laboratory. Assuming it is a normal sample, which type of leukocytes accounts for the highest percentage? A: Neutrophils B: Eosinophils C: Lymphocytes D: Basophils

A: Neutrophils

Which statement is NOT TRUE about the innate immune system? A: Specificity and immunological memory are involved. B: It induces inflammatory response by recruiting inflammatory cells to the site of infection. C: The immune response occurs rapidly, usually within several hours. D: Each time the body is exposed to an infectious agent, the immune response remains the same.

A: Specificity and immunological memory are involved.

What is the lymphoid organ/tissue where T cells are most likely to be activated? A: Spleen B: Thyroid C: Thymus D: Bone marrow

A: Spleen Where lymphocytes are active

Which of the following is an example of type 1 hypersensitivity? A: Systemic anaphylaxis B: Graves disease C: Lupus D: Autoimmune hemolytic anemia

A: Systemic anaphylaxis

Know which regions of an antibody form the antigen-binding sites.

Antigen binding site at the ends of the variable region

General understanding of the causes of leukocytosis (leukophilia)

- High WBC count in the blood due to increased bone marrow activity - Normal protective response to physiologic stressors, e.g. invading microorganisms, strenuous exercise, drugs/toxins - Also caused by malignancies and other disorders - '-cytosis' for agranulocytes; '-philia' for granuloctyes

General understanding of the causes of leukopenia.

- Low WBC count in the blood due to decreased marrow activity - Not normal response, not beneficial - Predispose a patient to infections - Maybe caused by radiation, anaphylactic shock, autoimmune diseases, immune deficiencies, chemo agents - Also caused by disorders that suppress BM function

Know how leukemia is classified; describe the 4 major types of leukemia and major differences between acute and chronic leukemia.

- Predominant cell origin o Myeloid vs. lymphoid - Degree of differentiation before becoming malignant Acute: a rapid growth of immature blood cells Chronic: a slow growth of more differentiated cells 4 types: 1. Acute lymphocytic (ALL) 2. Acute myelogenous (AML) 3. Chronic lymphocytic (CLL) 4. Chronic myelogenous (CML)

List the classic signs of inflammation.

- Redness (erythema), fever, and swelling (edema) caused by increased blood flow into tissue - Pain & tenderness (from release of prostaglandins, histamine and other mediators) - E.g. a pimple results from a very localized inflammatory response, manifesting a whitish pustule in the affected area produced from dead neutrophils

Relate IM pathophysiology to symptoms (e.g. lymphoid tissue swelling, sore throat and fever)

- Virus infects oropharynx, nasopharynx, and salivary epithelial cells => lymphoid tissues & B cells; - B cells => antibodies; cytotoxic T cells (CTLs) activated & multiplied - Increased counts and activation of B and T cells + removal of dead and damaged leukocytes => lymphoid tissue swelling - Inflammation and infection => sore throat and fever

Able to give examples of inflammatory disorders.

1. Autoimmune - Rheumatoid arthritis: inflammation in joints and tissues surrounding joints - Celiac disease: inflammation of the inner lining of small intestine - Crohn's disease: inflammation mostly in small intestine - Graves' disease: neck swelling due to inflammation in the thyroid gland - Lupus: inflammation in the joints, lungs, heart, kidney and skin - Addison's disease: inflammation of the adrenal glands - Vasculitis: inflammation in blood vessels eventually destroying them - Transplant rejection: inflammation in and around the donated organ 2. Allergies - Asthma: inflammation of the airways - Hay fever: inflammation of the nose, ear and throat mucous membranes - Bee stings: may cause life-threatening inflammation affecting the whole body (anaphylaxis)

What are the major cellular players?

1. B cells 2. T cells, dendritic cells 3. mast cells.

What are primary lymphoid organs/tissues? What are their major functions?

1. Bone Marrow · Primary lymphoid organ, confined to the cavities of bone · Site of hematopoiesis after birth (see below); site of B-cell differentiation and maturation 2. Thymus · Site of T-cell differentiation and maturation · Cortex is dense with immature T cells; medulla is pale with mature T cells

List the major hematopoietic organs and tissues in an adult.

1. Bone marrow 2. Thymus 3. Spleen 4. Lymph nodes

Case: A 55-yo woman presents to her primary care physician for a routine physical. She reports an unintentional 30-lb weight loss and chronic fatigue. Abdominal examination reveals an enlarged spleen. The following tests have been done. •Relevant laboratory findings showed very high WBC counts (167, 000/mm3) •Blood smear testing indicated many late granulocytic precursor cells, eosinophils, and basophils •Cytogenetic analysis showed t(9;22), i.e. translocation between chr 9 and chr 22 1.What is the most likely diagnosis? 2.What is this chromosomal abnormality called and what is its product? 3. What is the pathophysiology of this condition? 4. What is the targeted drug treatment for this condition?

1. CML given the 9;22 translocation 2. Philadelphia chromosome leads to Bcr-Abl fusion product, results in constitutively active Abl tyrosine kinase in the Ras/Raf/MEK/MAPK pathway 3. Inhibition of apoptosis and unregulated cell division 4. First-line: Imatinib specific for Bcr-Abl tyrosine kinase inhibitor Second line: Dasatinib Allogenic bone marrow transplant

Describe the specific functions of each type of effector T cells, i.e. CTLs, helper T cells, and regulatory T cells. What toxic substances are contained in the lytic granules in CTLs?

1. CTLs (cytotoxic CD8 T cells) o Respond to intracellular infections o Recognize peptide:MHC class I · Recognize intracellular pathogens - E.g. virus or altered self-cells like cancer - Displayed by MHC class I · Get activated and expanded in secondary lymphoid organs · Release lytic granules that contain cytotoxins - *Perforin & granulysin, granzyme* · After killing one target cell, a CTL can make new granules and get ready to kill another target cell 2. CD4 T-helper cells o Respond to extracellular infections o Recognize peptide:MHC class II o Stimulate B cell to make Ab and activate macrophages · Recognize extracellular pathogen - E.g. bacterial peptides - Displayed by MHC class II · Produce cytokines and activate different immune cells 3. Regulatory T cells (Treg) · A subset of CD4 T cells · Suppress activation of autoreactive Th cells & CTLs that can attack self tissues, i.e. to promote self-tolerance · Produce cytokines that are immunosuppressive & anti-inflammatory · Regulate CTLs and Th cells - By preventing Ag-presentation by APCs - Thru direct contact with effector T cells

1. Pus is a creamy exudate primarily made up of_____ 2. Pus-forming bacteria involve large numbers of ____ 3. A pimple results from a localized inflammatory response, manifesting a whitish pustule produced from ____

1. Dead neutrophils 2. Dead neutrophils 3. Dead neutrophils

Which of the following is NOT an example of innate immunity? A: Phagocytic killing of pathogens by neutrophils B: Antibody production C: Inflammation D: Fever

B: Antibody production

Which of these is least involved in the innate system inflammatory fever response? A: Complement B: Interleukins C: Antibodies D: Interferons

C: Antibodies

What kind of T cell does not express CD4 TCRs? A: Th1 B: Th2 C: CTLs D: Treg

C: CTLs

_________ proteins are a group of 30 proteins sequentially activated during infection, which promotes inflammation and pathogen destruction by phagocytosis. A: Papain B: Lysozyme C: Complement D: Interferon

C: Complement

Which granulocyte is in both parasitic infections and hypersensitivity reactions? A: Monocytes B: Basophils C: Eosinophils D: Mast cells

C: Eosinophils

Which of the following does NOT involve Type III hypersensitive reactions? A: Rheumatoid arthritis B: Systemic Lupus Erythematosus C: Food allergy D: Serum sickness

C: Food allergy

Which of the following is NOT true of the secondary immune response process? A: Adaptive response is faster B: Adaptive response is stronger C: Innate response is reduced D: Memory B cells make better antibodies

C: Innate response is reduced

Which of the following statement is NOT TRUE about Philadelphia chromosome? A: It is present in the majority of chronic myelogenous leukemias (CML). B: It refers to a reciprocal translocation between chromosomes 9 and 22. C: It is present in the majority of acute myelogenous leukemias (AML). D: It contains fusion gene of BCR and ABL, encoding a modified tyrosine kinase and resulting in dysregulated cell growth.

C: It is present in the majority of acute myelogenous leukemias (AML).

Which of these is NOT a pro-inflammatory/fever signaling molecule? A: TNF alpha B: IL6 C: MHC-1 D: CRP

C: MHC-1

Which of the following is a short-lived phagocytic cell? A: Macrophage B: Dendritic cell C: Neutrophil D: NK cell

C: Neutrophil

Which of the following is NOT a characteristic of type IV hypersensitivity reactions? A: Occurs 2-3 days after exposure B: Involves activation of macrophages C: Only occurs in autoimmune responses D: May result in granuloma formation

C: Only occurs in autoimmune responses

Which of the following cell types is most likely present in lymph nodes of people with Hodgkins lymphoma? A: Merkel cell B: Schwann cell C: Reed-Sternberg cell D:

C: Reed-Sternberg cell

Which of the following is NOT a characteristic of type 2 hypersensitivity disorder? A: Involved antibodies like IgC and IgM B: Responsible for penicillin-caused lysis of RBCs C: Takes a minimum of 3-4 days to occur D: Involves phagocytic cell destruction

C: Takes a minimum of 3-4 days to occur

Describe each type of the MHC molecules, its major properties, and the type of T cells it presents antigen peptide to.

1. MHC Class I - Expressed on all nucleated cells (e.g. APCs, leukocytes) o Cells that activate CD8 T cells o Cells to be killed by activated cytotoxic CD8 T cells (CTLs) - Present Ag from INTRACELLULAR pathogens to CD8 T cells - These CD8 T cells are activated to become CTLs 2. MHC Class II - Expressed on APCs and B cells o Cells that activate CD4 T cells o Immune cells that need activation signals from Th cells - Present Ag from EXTRACELLULAR pathogens to CD4 T cells, which are then activated to become Th cells

Briefly describe what humoral immunity is and how resting or naïve B cells are activated and selected to become antibody-producing cells (plasma cells).

1. Mature naïve (resting) B cell expresses BCR of a single antigen (Ag) specificity 2. Upon Ag binding, become activated, then divide & differentiate into effector B cells (plasma cells) 3. Plasma cells secrete antibody (Ab) of the same specificity as BCR

What are the other 3 types of hematopoietic cells in hematopoiesis besides HSCs?

1. Progenitor cells - Myeloid and lymphoid stem cells - High mitotic activity, reduced multipotency 2. Precursor cells (blasts) - Lineage committed - High mitotic activity 3. Mature cells - No mitotic activity

What are the two stages of hematopoiesis? Where does each stage occur?

1. Proliferation, which stops before cells enter peripheral blood 2. Maturation and differentiation, regulated by hematopoietic growth factors/cytokines

Know the role bone marrow plays in hematopoiesis. What are the 2 types of bone marrow and how different are they?

1. Red marrow (active or hematopoietic) o Pelvic bones (34%), vertebrae (28%), cranium and mandible (13%), sternum and ribs (10%), humerus & femur (4-8%) 2. Yellow marrow (inactive)

Describe how chemical barriers work by giving 3 examples.

1. Saliva, tears, ear wax, sweat, and mucus (e.g. lysozyme) 2. Antimicrobial peptides (e.g. defensins) 3. Stomach acid (pH 2-3) and proteases

Describe how physical barriers work by giving 2 examples.

1. Skin 2. Linings of gastrointestinal, genitourinary, and respiratory tracts (coughing, sneezing, vomiting, diarrhea, flushing)

What is the most common type of NHL in children that is often associated with EBV infections? A: Hodgkin lymphoma B: Infectious mononucleosis C: Multiple myeloma D: Burkitt lymphoma

D: Burkitt lymphoma

Acalabrutinib and venetoclax treat with specific kind of leukemia? A: AML B: CML C: ALL D: CLL

D: CLL

CD8 cytotoxic T cells (CTLs) kill infected target cells by releasing cytotoxins from lytic granules. Which of the following is NOT a component of the lytic granules? A: Perforin B: Granulysin C: Granzyme D: Chymotrypsin

D: Chymotrypsin

Which of the following lymphocytes is not part of the innate immune system? A: Natural killer B: Macrophage C: MAST cell D: Cytotoxic T cell

D: Cytotoxic T cell

In response to pathogens, naive CD8 T cells become activated and differentiate into which of the following effector cells? A: Regulatory T cells to suppress auto-reactivity B: Helper T cells to stimulate B cells to make antibodies C: Helper T cells to activate macrophages to produce cytokines D: Cytotoxic T cells to kill infected cells

D: Cytotoxic T cells to kill infected cells

Which type of stem cells gives rise to the entire blood system through the process called hematopoiesis? A: Progenitor cells B: Stromal stem cells C: Embryonic stem cells D: Hematopoietic stem cells

D: Hematopoietic stem cells

Which of the following is TRUE of acute inflammation? A: Associated with abnormal innate immune response B: Often involves plasma cells C: Closely linked to hypersensitivity reactions D: It is a non-specific, protective response

D: It is a non-specific, protective response

A 15-year-old girl presents with splenomegaly, hepatomegaly, and lymph node enlargement. She is diagnosed with infectious mononucleosis. Which of the following is NOT TRUE about this disease? A: It is also called "kissing disease" B: It is an infection with Epstein-Barr virus (EBV) C: It is from acute infection of B cells D: It is from an acute infection of T cells

D: It is from an acute infection of T cells

Which of the following is NOT involved in the regulation of hematopoiesis?? A: EPO B: G-CSF/GM-CSF C: IL-22 D: Leukemia inhibitory factor

D: Leukemia inhibitory factor

Which of the following does describe the innate immune system? A: Improved activity during response B: Has memory C: Slow response rate D: Limited number of specificities

D: Limited number of specificities

Which of the following is NOT a characteristic of adaptive immune response? A: Specialized, targeted responsiveness B: Provides long lasting memory C: Quick response upon reinfection D: Prevents initial infection

D: Prevents initial infection

Which of the following situations could cause newborn hemolytic disease? A: Rh + mother, Rh + fetus B: Rh- mother, Rh- fetus C: Rh + mother, Rh- fetus D: Rh - mother, Rh + fetus

D: Rh - mother, Rh + fetus

Which of the following organs is not involved in non-specific barriers of innate immunity? A: Lungs B: Skin C: Stomach D: Spleen

D: Spleen

Define the terms "phagocyte" and "phagocytosis" and what types of cells are capable of performing this task.

Eat/destroy microbes Monocytes/Macrophages/Neutrophils/Basophils/Eosinophils

Give examples of type III disorders.

Examples: · Serum sickness -Treatment with horse serum used to be common for many diseases (e.g. tetanus, diptheria) · Raynaud's disease · Arthus reaction (local vasculitis) · SLE (Lupus) · Rheumatoid arthritis · Leukocytoclastic vasculitis · Hypersensitivity pneumonitis · Glomerulonephritis (kidney)

Which 3 inflammatory cytokines play a major role in this process? How?

IL-6, TNF-α, IL-1β - Primary function is to increase body temperature (fever), causing systemic effects

Which antibody isotope is most associated with parasitic infections and allergic responses?

IgE

Know the general functions of IgG, e.g. virus neutralization, opsonization, phagocytosis, etc.

IgG · Most abundant class (80-85%) · Made and secreted later in primary response · High affinity Ag binding · Is actively transported from blood to tissues · Activates complement but less efficient than IgM · Excellent at neutralization, opsonization, ADCC, etc. · Accounts for most of the protective activity · Subclasses: IgG1, IgG2, IgG3, IgG4

What are Reed-Sternberg cells?

Large and bi-nucleated, secrete cytokines (e.g. IL-10, TGF-beta)

What are granulocytes and agranulocytes? Give examples of each.

Leukocytes (nucleated white blood cells) 1. Granulocytes (neutrophils, eosinophils, basophils, mast cells) - Contain membrane-bound granules (enzymes, prostaglandins, and inflammatory mediators) capable of destroying microorganisms 2. Agranulocytes (monocytes/macrophages, lymphocytes (T cells, B cells, NK cells))

Know what isotypes of antibody are produced during the secondary response.

Primary: IgM Secondary: IgG, IgA, IgE

Know the concept of degranulation.

Rapidly release granules, rich in histamine, heparin, and chemokines

Which type of cells produces these cytokines?

Tissue resident effector cells in inflammation · Mainly macrophages, dendritic cells, and mast cells · Present in all tissues · Display pattern recognition receptors (PRRs) (e.g. toll-like receptors (TLRs)) that recognize pathogen-associated molecular patterns (PAMPs) shared by many pathogens - PAMPs, glycoproteins and glycolipids with distinctive shapes on the pathogen cell surface - ~100-200 of these PAMPs remained unchanged through evolution · Undergo activation upon infection or injury and release chemical inflammatory mediators responsible for the clinical signs of inflammation

A T-cell receptor (TCR) recognizes antigen only in the form of a peptide:MHC complex, not unprocessed antigen T/F

True

Chronic inflammation is associated with many types of immune disorders. T/F

True

Mast cell is the most important cell type in the release of histamine to promote inflammation. T/F

True

T cell receptors on CD8 T cells recognize processed pathogen antigens presented by MHC I Class? T/F

True

Describe how an individual becomes sensitized to an allergen in type I hypersensitivity reactions, and how IgE, mast cells, and histamine are involved in the development of asthma.

Type I: IgE-mediated response causing mast cell degranulation and release of histamine (e.g. allergic reactions to pollens) · IgE-mediated · Against environmental Ags (or allergens) - Allergic reactions provoked by re-exposure to the same Ag/allergen · Ag presented to specific Th2 cells => stimulate B-cell => Ag-specific IgE · IgE binds to high-affinity Fc receptor (FcεRI) on tissue mast cells and blood basophils, sensitizing these cells · Re-exposure to same Ag/allergens cross-links bound IgE on sensitized mast cells and basophils => causing immediate degranulation and release of vasoactive inflammatory mediators (e.g. histamine) · Either local or systemic reactions, can affect multiple tissues via GI tract, airway, blood vessels Symptoms vary from mild discomfort to sudden death from anaphylactic shock · Treatment - Pharmacological: NSAIDs, corticosteroids, antihistamines, leukotriene inhibitors - Immunological: *desensitization (allergen shots)* by repeated allergen injections to reduce IgE and produce IgG

Where is adult active bone marrow found?

the vertebrae, sternum, and ribs

Know the basic structural components of an antibody and how different it is from a B-cell receptor (BCR).

· Also called immunoglobulin (Ig) · *A secreted form of BCR (membrane-bound Ig)* · Produced by effector B cells (plasma cells) · Circulate in blood & lymph; also present at mucosal surfaces · Recognize all types of antigens (esp. proteins & carbohydrates) with unique specificity · Antibody-bound pathogens are susceptible to killing by other components of the immune system · Y-shaped glycoprotein · 2 identical heavy (H) chains and 2 identical light (L) chains · Variable (V) regions of H and L chains are involved in Ag recognition and binding · Constant (C) regions of H + L chains · Contains flexible hinge regions and disulfide bonds

Understand how Penicillin initiated type II hypersensitivity causes lysis of RBCs.

· An example of type II hypersensitivity reactions · Penicillin covalently modifies a protein(s) on RBCs, creating a new epitope(s) to be recognized as different Ag · B cell proliferation is activated, producing Abs (IgG and IgM) specific to the new Ag (drug modified proteins) · IgG and IgM form complexes with the new Ag and activate the complement cascade or ADCC · Mediators of acute inflammation are generated, causing cell lysis or death · Penicillin can cause all types of hypersensitivity

Describe the role mast cells play in inflammation.

· An important activator of the inflammatory response · Initiates inflammation by releasing mediators via degranulation and synthesizing new mediators - Histamine and chemotactic factors 0 Eicosanoids (prostaglandins and leukotrienes) · Histamine - Major vasoactive amine released from mast cells - Causes dilation of capillaries and retraction of endothelial cells => increases vascular permeability Acts through H1 and H2 receptors

Describe how IgE, mast cells, and histamine are involved in the development of asthma.

· Chronic inflammatory disorder caused by Type I hypersensitivity reactions from IgE-mediated activation of mast cells in lower airways - Characterized by bronchial hyper-reactivity and reversible airflow obstruction due to influx of inflammatory cells into the airways - Chronic inflammation causes persistent infiltration of Th2 lymphocytes, eosinophils, and neutrophils · Clinical manifestations - Cough, shortness of breath, chest tightness, expiratory wheeze, fast breathing, nasal flaring, use of accessory muscles, increase of fluid and mucus in lungs · A variety of "triggers" may initiate or worsen an asthma attack, e.g. respiratory viral infections, exercise, exposure to allergens (air pollution, dust mites, tobacco smoke) · Genetic predisposition plays a significant role in the development of asthma reactions

Describe the major types of antigen-presenting cells and their properties.

· Common features - Express MHC I & MHC II => process and present Ag => activate T cells 1. Dendritic cells (DCs) - far superior to MΦs - Phagocytic and present in all tissues - "sentinels" - Migratory - carry Ag to naïve T cells in secondary lymphoid organs 2. Macrophages (MΦs) - Phagocytic and present in all tissues - Non-migratory - don't move to secondary lymphoid organs, but can move from blood to tissues in response to inflammation as monocytes - Activity can be enhanced by activated Th cells 3. B cells - Populate mainly in LNs and main function is to make Ab with help of CD4 Th cells - Capable of stimulating naïve T cells but not as efficient as DCs or macrophages

Briefly explain the "complement system".

· Composed of ~30 soluble plasma proteins (proteases) (C1-C9) · Made by the liver and found in blood, lymph, and extracellular fluids · Present in inactive forms as proenzymes but sequentially activated upon infection - A biochemical cascade that promotes inflammation and pathogen destruction · Systemic activation can cause anaphylactic shock (anaphylaxis) · Often involved in allergic diseases

What types of cytokines influence the differentiation pathways of naïve CD4 T cells to become either helper T cells or regulatory T cells?

· Different cytokines drive the differentiation of CD4 T cells that make different cytokines and have different effector functions 1. TGF-Beta=> Treg cells 2. IL-12, IFN-gamma=> TH1 cells 3. IL-4=> TH2 cells

Know the functions of natural killer cells.

· Do not directly attack microbes - Killing due to perforin, granzymes, TNF, Fas/FasL, ADCC (antibody-dependent cell-mediated cytotoxicity) · Named "natural killer" because they do not require activation to kill cells that are "missing self" · Destroy compromised host cells (e.g. virus-infected cells) by recognizing a condition called "missing self", where MHC molecules are at abnormally low levels or molecularly altered · Can be activated by IFN-α and IFN-β to kill viruses · Can be stimulated by IL-12 to produce IFN-γ and other cytokines · Overlap with adaptive immune response

Know the basic structural components of a T-cell receptor (TCR) and how similar and different it is from a B-cell receptor (BCR) and an antibody.

· Expressed by effector T cells - CD8 molecule by cytotoxic T cells (CTLs) - CD4 molecule by T helper cells (Th1, Th2) and regulatory T cells (Treg) · Structurally similar to BCR in both V and C regions · Characteristics - Ig-like cell surface receptor with TM region -1 α and 1 β chain - Ag-binding site in V regions of α and β chains

Describe how fever is developed.

· Helps immune system fight infection · Slows replication of bacteria and viruses · Normal cells more resistant to deleterious effects of TNF-α at higher temperature · Adaptive immune response is more active at higher temperature

What is the major function of dendritic cells?

· Highly phagocytic · Main role is to process and present antigen to antigen-presenting cells (APCs) · Function as link between innate and adaptive immune systems · Form branch-like projections (dendrites) during development

What are the functions of IgM, IgG, IgA?

· IgM, IgG & monomeric IgA provide defenses to internal tissues - Via neutralization, complement fixation & opsonization - E.g. prevent blood-borne infection & spread of microorganisms by neutralizing them · Dimeric IgA protects mucosal epithelial surfaces - Produced in lamina propria of mucosal-associated lymphoid tissues (MALT) - Provides defenses to mucosal surfaces vulnerable to infection (e.g. nose, GI, respiratory, and genitourinary tracts)

Describe Philadelphia chromosome and its involvement in CML and ALL.

· In 95% CML, 30% ALL adults • Reciprocal translocation between long arms of chromosome 9 and chromosome 22 • bcr-abl gene created => BCR-ABL fusion protein (a tyrosine kinase) => affect cell cycle control genes => increased cell division & inhibition of DNA repair => dysregulated cell growth -can be caused by ionizing radiation

Briefly describe what cell-mediated immunity is and how resting or naïve T cells are selected and activated to become effector T cells.

· Infinite number of specificities and diversity - Determined by amino sequence in variable region - Generated by gene rearrangement · Clonal selection - Involved in pathogen recognition and selection of particular lymphocytes - Via Ag presentation & complex cellular interactions · Clonal expansion - The process by which selected clones proliferate - Only pathogen-specific B or T cell clones are selected - This primary response takes days to be effective

What are Chemokines?

· Large family (~40) of chemoattractive cytokines · Direct trafficking of leukocytes to sites of inflammation from damage or infection · Via G protein-linked trans-membrane receptors · Synthesized by MΦs, fibroblasts, endothelial cells · Can either be a ligand (e.g. CXCL8) or a receptor (e.g. CCR7)

What is the major function of basophils?

· Large granules which usually obscure the nucleus because of their density · Very dark blue or purple granules when stained with Giemsa or Wright stain, containing vasoactive amines (e.g. histamine) and anticoagulant (heparin); leukotrienes can be synthesized and released on demand · Structurally and functionally similar to mast cells - Normally mediate allergic reactions and function in hypersensitivity reactions · Numbers can increase in diseases not associated with hypersensitivity, e.g. chronic myelogenous leukemia (CML) à basophilia · Constitute < 1% of the total circulating leukocytes in adults

What is the major function of Natural Killer (NK) cells?

· Large spherical and granular lymphocyte · Can kill some type of tumor cells and virus-infected cells without prior exposure · Contain lytic granules and secretory lysosomes · Develop in the bone marrow and circulate in the blood

What is the major function of plasma cells?

· Large, differentiated B cells that are activated by antigen encounter · Produce large amounts of antibody specific to a particular antigen · Found in bone marrow and normally do not circulate in peripheral blood

What is the major function of Monocytes and macrophages?

· Make up the mononuclear phagocyte system · Participate in both inflammatory response and immune response · Monocytes (in blood) have large kidney-shaped nuclei and differentiate into macrophages · Matured monocytes (macrophages) migrate into tissues from the circulatory system · Long life in tissues, probably several months, but only ~ 3 days in the circulation · Mostly reside in tissues and engulf/phagocytose bacteria and cellular debris, and subsequently "present" bacterial antigens to lymphocytes as antigen-presenting cells (APCs) to further amplify and refine the immune response · On blood smear, macrophages are the largest cells seen, with irregular mononuclear structures and extensive rough ER, lysosomes/phagosomes, pseudopods · Monocytes have a spherical shape and reside in the blood; the shape of macrophages depends on what tissue it goes and matures

What is the major function of T cells?

· Mediates cellular immune response · Matures in the thymus (T = thymus) to become cytotoxic T cells (CD8), helper T cells (CD4), and regulatory T cells · The majority of circulating lymphocytes are T cells (80%) · Secrete cytokines after activation by APC to help aid active immune responses, and destroy virally-infected cells and tumor cells by binding to antigens on their surface · Spherical, with T-cell receptor on cell surface

What is the major function of eosinophils?

· Nuclei are usually bi-lobed · Large eosinophilic granules (stained red with Wright or Giemsa stain) contain histaminase and a helminthotoxin (major basic protein, or MBP) · Function in inflammatory responses to large parasites; increase in parasitic or helminthic infections) · Highly phagocytic for antigen-antibody complexes · Also involved in allergic reactions induced by IgE hypersensitivity (Type I) · Constitute 2-4% of the total circulating leukocytes in adults

What is the function of basophils/eosinophils in innate immunity?

· PMN granulocytes like neutrophils · Defend against parasites · Regulate vascular mediators · Activated basophils and eosinophils - Secrete toxic substances highly effective in killing bacteria and parasites - Are responsible for tissue damage during allergic reactions

What is the major function of B cells?

· Part of humoral immune response · Matures in bone marrow (B = bone marrow) and migrates to secondary lymphoid tissues · When encountering antigen, differentiate into plasma cells and memory cells · Functions are to produce antibodies, act as APCs, or become memory B cells Spherical, with very large nucleus and scant cytoplasm around it, and B-cell receptor on cell surface

Describe the pathophysiology, clinical manifestations, and general treatment options of each type of Acute leukemia

· Pathophysiology - Decreased stem cell input or ineffective erythropoiesis or both => anemia - Reduced megakaryocytes => dysfunctional platelets - Granulocytopenia or immunodeficiency => infections - Bone infiltration => bone pain -Signs/Symptoms: o Anemia, infection, easy bruising and bleeding - Nonspecific symptoms attributable to anemia and a hyper-metabolic state (Pallor, fatigue, fever, malaise, weight loss, tachycardia) - BM and periosteal infiltration (Bone and joint pain, especially in children with ALL) - Extramedullary infiltration by leukemic cells (Lymphadenopathy, splenomegaly, hepatomegaly) · Treatment - Chemotherapy, in various combinations - With supportive measures, e.g. blood transfusion, antimicrobials - *Allopurinol* to prevent uric acid production by cell death caused by treatment - Bone marrow/HSC transplants increased since 1980s - Stimulation of blood cell growth with hematopoietic drugs during chemo and BM transplant

Describe the pathophysiology, clinical manifestations, and general treatment options of each type of Chronic myelogenous leukemia (CML)

· Pathophysiology: 3 phases 1. Chronic phase (2-5 years) o An initial no symptom period that may last months to years 2. Accelerated phase (6-18 months) Primary symptoms develop Excessive proliferation of malignant cells, *splenomegaly, hepatomegaly, hyperuricemia* 3. Terminal blast phase (3-6 months) o Rapid and progressive leukocytosis with an increase in basophils o Then blast cells/promyelocytes dominate · Treatment - Tyrosine kinase inhibitors (TKIs) for patients with Ph chromosome o *Imatinib* highly specific for CML o Newer drugs (dasatinib, nilotinib) - Older chemotherapy regimens for Ph-negative cases, or relapses after TKI o Hydroxyurea, busulfan, interferon - Stem cell transplantation

What is the major function of neutrophils?

· Polymorphonuclear neutrophil (PMN), i.e. multi-lobed nucleus · Granules contain digestive enzymes and inflammatory mediators that destroy contaminating microorganisms and ingest them and debris via phagocytosis · Acute inflammatory responder cells - chief phagocytes in early inflammation; increased in infections · Predominate in the blood but major function is in the tissues at sites of injury or infection · Constitute about 40-60% of the total circulating leukocytes in adults - "First line of defense" against bacterial pathogens; low numbers (leukopenia) lead directly to a high incidence of significant bacterial infections

What types of cytokines does each type of helper T cells secrete? What are the functions of these cytokines?

· Produce cytokines and activate different immune cells 1. Th1 cells secrete IL-2 & INF-γ o Activate MΦ o Activate B cells to produce opsonizing Abs 2. Th2 cells secrete IL-4 & IL-5 o Promote B-cells to become plasma cells to make neutralizing Ab

What are Interleukins (IL)?

· Produced primarily by MΦs and lymphocytes in response to a pathogen, or other products of inflammation · Many types - IL-1: pro-inflammatory cytokine - IL-10: anti-inflammatory cytokine

What is the major function of lymphocytes?

· Refer to B and T cells that mediate adaptive immunity, and NK cells that are part of innate immunity · Lymphocyte precursors leave bone marrow (BM) early and mature outside of the marrow to become normally functioning immune cells in either the blood or lymphatic system · Crucial roles in recognizing "self" vs. "non-self" and modulating all aspects of the immune response · B and T cells are small cells, with large dark nuclei nearly filling the entire cell · Constitute about 25-36% of the total circulating leukocytes in adults Major cells of the adaptive immunity

What is the function of Mast cells in innate immunity?

· Reside in connective tissues and mucous membranes · Involved in defense against pathogens · Often associated with allergy and anaphylaxis · Activation causes - Physical injury, chemical agents, immunologic processes - Chemical release in two ways 1. Degranulation 2. Synthesis of lipid-derived chemical mediators

What is Tumor necrosis factor α (TNF-α)?

· Secreted by MΦs in response to pathogen invasion · Induces fever · Increases synthesis of inflammatory proteins · Causes muscle wasting (cachexia) and intravascular thrombosis

What is the function of neutrophils in innate immunity?

· Short-lived PMN granulocytes · *First cells to be recruited to the site of infection* · Primary function is phagocytosis but die afterwards · Granules contain toxic substances that kill pathogens · Attack pathogens by activating a *respiratory burst* - Main products of the respiratory burst are strong oxidizing agents (e.g. H2O2, free oxygen radicals) · Dead PMNs are phagocytosed by macrophages - Pus is a creamy exudate primarily made up of dead PMNs - Pus-forming bacteria involve large numbers of PMNs

Describe the path of antigen processing and presentation by MHC molecules for extracellular and intracellular pathogens respectively.

· TCR recognizes Ag only in the form of peptide:MHC complexes, not unprocessed Ag · Peptide Ag is presented by MHC Class I or II at the cell surface · 2 types of pathogens 1. Intracellular (i.e. propagate within cells) o Viruses o Intracellular bacteria o CD8 cytotoxic T cells (CTLs) 2. Live in the extracellular spaces o Bacteria o Shedded virus particles o CD4 T cells (helper T cells or Th)

List the major hematopoietic organs and tissues at each developmental stage of a human being.

· The process of blood cell development from undifferentiated common hematopoietic stem cells (HSCs), primarily in the bone marrow after birth, in yolk sac of embryo, and in liver and spleen of fetus

What are the underlying mechanisms of type II hypersensitivity?

· Type II: Ag-Ab (immune) complexes of foreign Ag (can be drug modified) and IgM or IgG, causing ADCC or complement-mediated inflammation (e.g. blood transfusion, penicillin response) · Ab-mediated cytotoxic reactions from interaction of Ab (mainly IgG & IgM) with tissue-specific cell-bound Ag - Extrinsic: processed Ag from pathogen infected cells - Intrinsic: self Ag (e.g. autoimmune diseases) - Modified Ag: chemically reactive molecules bind cell components and alter their structure to create a new epitope (e.g. penicillin modification caused RBC lysis) · The Ag-Ab interaction initiates cell death and tissue damage - Complement activation by antibodies - Cell destruction through phagocytosis - Soluble Ag may enter the circulation and deposit on tissues=> tissue damage by complement and neutrophil granules - Ab-dependent cell-mediated cytotoxicity (ADCC) - Causes target cell malfunction (e.g. Grave's disease) · May cause physiological changes underlying a disease other than cell death - E.g. Ab binds to Ag that is an hormone receptor as agonists or antagonists to alter receptor signaling · May take hours to days to develop type II reactions

What is the major function of mast cells?

• Typically round cellular shape with secretory granules and found in vascularized connective tissues • Contain basophilic granules and originate from the same precursors as basophils • Central cells in inflammation and type I hypersensitivity reactions • Activated by IgE, physical/chemical injury, or complement proteins, causing degranulation which releases histamine, heparin, and other inflammatory mediators

Know the differences between primary and secondary responses.

• When primary response is terminated, most effector cells die • During primary response some clones produce memory B and T cells - Memory T cells patrol the body - Memory B cells make better Ab Memory cells allow faster and stronger immune responses when encountering the same pathogen again => secondary response 1. Primary response - Clear first infection - Lag phase o B cell differentiation is occurring - After 5-7 days, low-affinity IgM for a specific Ag is detected, followed by IgG response - Produce short-lived effector cells and long-term memory B cells and T cells 2. Secondary response - Rapid, strong, more sensitive, and more abundant due to the presence of memory cells - Clones of specific memory B and T cells expanded - Ab switched from IgM to IgG, IgA, IgE isotypes - Often clears infection before symptoms occur

Are B cells and T cells produced during primary response?

Yes, Know that both memory B cell and T cells are to be produced during primary response.

Case: A 17-yo girl is brought to the physician's office for evaluation of a sore throat and fever. Her symptoms started ~1 week ago and have been worsening. She has been extremely fatigued and has spent most of the last 3 days in bed. She denies any ill contacts and has no significant medical history, takes no medications. •On examination, she is tired and ill appearing. Her temperature is 101.3F (38.5C). •Examination of her pharynx shows her tonsils to be markedly enlarged, almost touching in the midline. They are erythematous and covered with white exudates. She has prominent cervical adenopathy, which is mildly tender. •A cardiovascular examination is normal, and her abdomen is soft, non-tender, and without palpable organomegaly. •A rapid streptococcal antigen test in the office is negative. You send a throat culture and decide to start amoxicillin for strep pharyngitis, assuming that the office test was a false negative. 1.What is the most likely diagnosis of this patient? 2.What is the most likely cause of her infection? How is it normally spread? In what human cells does this infection occur? 3.Is it appropriate to treat the patient with amoxicillin?

1. EDV 2. B cells and kissing 3. No

Describe the major system effects of acute inflammation.

1. Fever - Produced by cytokines such as IL1, IL6, and TNF-α 2. Leukocytosis (= increase in the # of leukocytes) - An accelerated release of leukocytes from bone marrow (clinically useful) 3. Acute phase response - C-reactive protein (CRP) (clinically useful) - Spread of micro-organisms or foreign substances (e.g. toxins) - SHOCK (e.g. anaphylactic shock), the severe systemic manifestations of inflammation

Know how subtypes of leukocytosis and leukopenia are named, e.g. neutrophilia & neutropenia, monocytosis & monocytopenia, etc.

1. Granulocyte disorders -Neutrophilia & neutropenia, eosinophilia & eosinopenia, basophilia & basopenia 2. Monocyte disorders -Monocytosis & monocytopenia) 3. Lymphocyte disorders -Lymphocytosis: common in acute viral infections -Lymphocytopenia: neoplasia and immune deficiencies

What are the structural characteristics of each type of leukocyte?

1. Granulocytes - The most common leukocytes, of which neutrophils are most abundant, followed by eosinophils and basophils - Contain membrane-bound granules (enzymes, prostaglandins, and inflammatory mediators) capable of destroying microorganisms - Capable of ameboid movement and migrating through vessel walls (diapedesis) to sites of action - Polymorphonuclear (PMN) - Inflammatory and immune functions 2. Agranulocytes - Monocytes are immature macrophages; macrophages reside in tissues - Lymphocytes mature to T cells, B cells/plasma cells - Fewer membrane-bound granules than granulocytes - Mononuclear - Inflammatory and immune responses

Know the main properties and function of each of the 5 antibody isotypes. Which one is the first to be made and which one is the most abundant?

1. IgM · *First Ab made* during primary response by plasma cells in LN, spleen & BM · Less flexible for Ag binding due to lack of a hinge - Thus secreted as a pentamer with 10 low-affinity Ag binding sites to achieve high avidity · Binds strongly only to pathogens with repetitive epitopes · Strong activator of complement · The large size restricts its penetration into infected tissues 2. IgD · *First Ab made, like IgM* · Real function not known - Possible role in B cell activation and allergic reactions 3. IgA · Monomeric form secreted into the bloodstream · Dimeric form important in mucosal immunity and high level in breast milk · Subclasses: IgA1, IgA2 4. IgE · Exists as a bound form mainly on mast cells in tissues beneath epithelial surfaces (skin, respiratory & GI tracts) · Binds to very high affinity Fc receptor (FcεRI) on mast cells, basophils and eosinophils · "Natural" infections that cause IgE-bound mast cell activation are by parasites (e.g. worms, flukes, ticks, mites) · Pathogen binding to IgE-coated mast cells crosslinks FcεRI and contributes to the inflammation process - Activates mast cells - Induces degranulation to release inflammatory mediators (e.g. histamine) - Stimulates violent smooth muscle contractions - Ejects parasites/pathogens via sneezing, coughing, vomiting, diarrhea · Also involved in type I hypersensitivity reactions and other allergic reactions - In allergy & asthma, same reactions (to parasites) are triggered by IgE responses to non-harmful substances (e.g. pollens, food) - Allergy & asthma common in developed countries due to IgE responses to allergen 5. IgG- *Most abundant*

What are the 3 types of recognition molecules are involved in recognizing the antigen?

1. Immunoglobulin (Ig) o B-Cell Receptor (BCR) and antibody (Ab) 2. T-cell receptor (TCR) 3. Major histocompatibility complex (MHC) o MHC class I and class II molecules

Describe the cellular events that take place when the innate immune system responds to a cut on your foot.

1. Inflammatory factors (or mediators) are produced by tissue resident effector cells upon "insult" - Eicosanoids (prostaglandins & leukotrienes) - Cytokines (interleukins, interferons, TNF, chemokines) - Other toxic substances (histamine, bradykinin, serotonin) 2. Local vasodilation & increased vascular permeability and leakage 3. Recruitment of phagocytes and other inflammatory cells 4. Killing of injured or infected cells or damaged tissue cells · Vascular responses - Blood vessel dilation (vasodilation), causing slower blood velocity and increased blood flow to the site of injury - Increased vascular permeability and leakage of fluid out of the vessel (exudation), causing swelling - Leukocyte (neutrophil) adherence to the inner walls of the vessels and migration thru the vessels

List and compare major differences between innate and adaptive immune responses.

1. Innate: Second line of defense (with no adaptation to specific pathogens); non-specific (but can recognize certain molecular shapes shared among many pathogens) - Macrophages, neutrophils, natural killer (NK) cells, mast cells - Complement proteins, cytokines 2. Adaptive: Third line of defense (with adaptation to defend against specific pathogens); highly specific - Humoral: B cells make antibodies specific for any new antigen - Cellular: T cells mediate cellular responses via variable receptors (T cell receptors)

Besides fever, what are the additional systemic effects of these 3 inflammatory cytokines?

1. Liver: Acute phase proteins=> activation of complement, opsonization 2. Bone Marrow and Epithelium: Neutrophil mobilization=> Phagocytosis 3. Hypothalamus: Increased body temp=> Decreased viral and bacterial replication 4. Fat/Muscle: Protein and energy mobilization to generate increased body temp=> Decreased viral and bacterial replication

What are secondary lymphoid organs/tissues? What are their major functions?

1. Spleen · Largest secondary lymphoid organ; site of fetal hematopoiesis; filters & cleanses the blood · Serves as a reservoir for lymphocytes & other blood cells · Plays an active role in the production of antibodies and complement White pulp - Masses of lymphoid tissue containing macrophages and lymphocytes - Chief site of immune and phagocytic functions - Removes infectious agents and uses them to activate lymphocytes, mounting immune response - Sub-structures o Peri-arteriolar lymphatic sheath (PALS): T-cell zone o Follicles and germinal centers: B cells o Marginal zone: macrophages/APCs and differentiated/specialized B cells o Medullary cords: lymphocytes and plasma cells Red pulp (RBCs) Phagocytosis of old, damaged, and dead blood cells, especially red blood cells (RBCs) 2. Lymph Nodes (LN) · Secondary lymphoid organs; mostly in clusters throughout the body, e.g. in the neck, armpit, groin · Human lymph nodes are bean-shaped and range in size from a few millimeters to 1-2 cm · Part of the lymphatic system structurally, transporting lymphatic fluid back to the circulation · Part of the immune and hematologic systems functionally, facilitating maturation and function of lymphocytes, monocytes/macrophages, and activation of immune response - Cleanse the lymphatic fluid of microorganisms and foreign particles by monocytes/macrophages - Microorganisms in lymph stimulate formation of antibody-producing plasma cells - Become larger and tender during infection, due to increased rate of proliferation of lymphocytes · Follicle: site of B-cell localization and proliferation; medullary cords: closely packed lymphocytes and plasma cells; medullary sinuses: macrophages; paracortex/PALS: T cells

Relate IM pathophysiology to general treatment options.

1. Supportive, e.g. rest and alleviation of symptoms with analgesics and antipyretics o No aspirin because of its association with Reye syndrome 2. Penicillin or erythromycin to treat Streptococcal pharyngitis o No ampicillin to avoid causing rash 3. Avoid strenuous activity and contact sports 4. Use steroids for severe complications

Case: Anna had never been happy with her nose so she planned to have a plastic surgery. After saving for 3 years, she consulted a plastic surgeon and shortly after had the surgery. A few days later Anna was changing the dressings of gauze on her nose when she noticed increased swelling and pain at the incision site. By the next day she had a fever above 100°F. Anna went back to the surgery clinic, where they took a swab of pus from the infected area for culture and prescribed an antibiotic. The next day the lab called to tell Anna she had a Staphylococcus aureus infection, which induced localized inflammation that causes capillary endothelial cell damage and gives the bacteria access to the circulation. 1. How did the bacteria infection start in the first place? 2. Where did the bacteria come from? 3. Which system of Anna's body responded to the bacteria infection? What is the purpose of this response? What's this process called? Briefly describe the steps involved in this response. 4. What cells and molecules are involved? What does each do? 5. What caused swelling and pain? What's in the pus? 6. What caused fever? What does fever tell you? 7. If not treated, what could happen next?

1. Surgery allowed the bacteria to break through the protective skin layer 2. Injury allowed it to get inside 3. Innate- inflammatory response, four steps 4. First responder: tissue resident effector cells, resident macrophages for infection, dendritic cells, neutrophils, more macrophages, cytokines, toxic substances from the granules 5. *(IL-6, TNF alpha, IL1 beta)* 6. Activate immune system 7. Systemic effects

What are Interferons (IFN)?

1. Type I (IFN-α, IFN-β) - Induce production of antiviral proteins - Activate NK cells to kill infected cells 2. Type II (IFN-γ) - Made by NK, CD4 T cells, and CD8 T cells - Increases microbicidal activity of MΦs

Lines of defense

1st: non-specific chemical, physical 2nd: Innate, non-specific recognition, rapid, constant 3rd: Adaptive, highly specific

Which of the following is TRUE for type I hypersensitivity? A: It is caused by soluble immune complexes formed in the circulation and later deposited on the basement membranes in tissues and blood vessels, eliciting inflammatory responses B: It is the main type of hypersensitivity responsible for allergic reactions, mediated by allergen cross-linking IgE bound on mast cells causing a release of vasoactive substances C: It is mediated by activated T cells D: It is antibody mediated cytotoxic reaction irritated by interaction of antibodies with cell-bound antigens

B: B: It is the main type of hypersensitivity responsible for allergic reactions, mediated by allergen cross-linking IgE bound on mast cells causing a release of vasoactive substances A is Type III C is Type IV D is Type II

Which of the following is the major player in poison ivy caused immune reaction called contact dermatitis? A: Neutrophil B: CD4 helper Th1 cell C: Antibody D: Complement

B: CD4 helper Th1 cell

Which of the following cell types recognize peptide antigens presented by MHC class I molecules? A: Red blood cells B: CD8 expressing T cells C: CD4 expressing T cells D: B cells

B: CD8 expressing T cells

Which of the following statements is INCORRECT? A: During an infection, neutrophils recruited first B: During infection, neutrophils recruited last C: Macrophages are longer-lived than neutrophils D: Macrophages respond first to invaders at site of infection

B: During infection, neutrophils recruited last Macrophages are resident

Which is NOT true about innate immunity? A: It induces inflammatory response by recruiting inflammatory cells to site of infection B: Each time the body is exposed to an infectious agent, response improved C: Specificity is not involved D:

B: Each time the body is exposed to an infectious agent, response improved

Which antibody isotype mediates Type I hypersensitivity reactions, leading to an immediate degranulation of mast cells and the release of histamine? A: IgA B: IgE C: IgM D: IgG

B: IgE

Which of the following does not describe physical urticaria? A: May be caused by pressure, stress or friction B: It is a prototypical histamine releasing reaction C: Thought to involve IgE production D: Might be alleviated by omalizumab

B: It is a prototypical histamine releasing reaction

Which two cell types are the most important phagocytic cells in the innate immune system? A: B cells and T cells B: Neutrophils and macrophages C: Eosinophils and basophils D: Fibroblasts and natural killers

B: Neutrophils and macrophages

The sensitizing chemical in the poison ivy that triggers contact dermatitis via type IV hypersensitivity is A: Histamine B: Pentadecacatechol C: TNF-α D: Granzyme

B: Pentadecacatechol

Which of the following statements about MHC Class 2 receptors is FALSE? A: Expressed on B cells B: Present antigens to CD8 T cells C: Expressed on APCs D: Activates helper T cell

B: Present antigens to CD8 T cells

Which of the following does NOT describe the innate immune system? A: Rapid response B: Slow response C: Does not have memory D: Constant activity during response

B: Slow response

Which of the following is a primary lymphoid organ? A: Tonsils B: Thymus C: Spleen D: Lymph nodes

B: Thymus

How the commensal flora within GI tracts functions to compete with harmful pathogens?

Commensal flora within GI tracts competes with pathogens for nutrition and by changing environment conditions (e.g. pH)

What type of cells are involved in IM? Know its causes and the peak age group in which IM develops.

Infectious mononucleosis (IM) • Acute Epstein-Barr virus (EBV) infection of B cells, usually thru saliva, also called 'kissing disease' • IM arises when initial infection occurs during adolescence or later - Peaks at 15-19 yo

Describe how inflammatory mediators and major cytokines contribute to this process.

Inflammatory factors (or mediators) are produced by tissue resident effector cells upon "insult" - Prevent and limit infection and further damage - Promote healing of damaged tissues following the clearance of pathogens - Initiate adaptive immune response

Know the 2 major types of phagocytes and how phagocytic killing works.

Monocytes/Macrophages (MΦ)/Neutrophils · Long-lived tissue resident phagocytes differentiated from monocytes · Able to cross capillary vessels and move outside of vascular system to search for pathogens · *Arrive at the infection site >=24 hours later than neutrophils* · Most efficient phagocytes that can engulf large numbers of microbes or other cells · Display pattern recognition receptors (PRRs) (e.g. toll-like receptors (TLRs)) that recognize pathogen-associated molecular patterns (PAMPs) shared by many pathogens · Binding of pathogen PAMPs to PRRs on a MΦ triggers engulfing of the pathogen via the generation of a "respiratory burst", similar to neutrophils · Pathogens stimulate MΦs to produce chemokines, attracting other immune cells to site of infection

How is the adaptive immune system highly specific due to diversified pools of B cell receptor/antibody and T cell receptor?

More focused and forceful response

Describe the pathophysiology, clinical manifestations, and general treatment options of each type of Chronic lymphocytic leukemia (CLL)

Most common leukemia type · Pathophysiology - B cells become malignant due to disrupted normal programmed cell death - Initially accumulated in the BM then to LNs and other lymphoid tissues => *splenomegaly and hepatomegaly* - Fail to develop into antibody-producing cells => decreased antibody production => susceptibility to recurrent infections that are commonly sensitive to antibodies - Abnormal hematopoiesis => anemia, neutropenia, thrombocytopenia · Treatment - Symptom amelioration - Supportive care o Transfusion of packed RBCs for anemia o Platelet transfusions for bleeding o Antimicrobials for infections - Specific therapy o Chemotherapy +/- corticosteroids (e.g. ibrutinib, a novel inhibitor of Bruton tyrosine kinase) o Monoclonal antibody therapy (e.g. rituximab, alemtuzumab, obinutuzumab) o Radiation therapy

Which type of leukocyte is the most abundant in total leukocyte count?

Neutrophils

Abundance order

Neutrophils Lymphocytes Monocytes Eosinophils Basophils Never Let Monkeys Eat Bananas

What are the two highly specialized effector mechanisms?

Third line of defense after pathogen breaches innate immune responses 1. the B cell/antibody-mediated humoral immunity 2. the T cell mediated cellular immunity.

Know which regions of a TCR form the antigen-binding site.

Tip of α and β chain

What are the underlying mechanisms of type III hypersensitivity?

· Type III: deposition of immune complexes activate complement and initiate chronic inflammation (e.g. serum sickness) · Soluble Ag-Ab (immune) complexes are formed in the circulation and later deposited on basement membranes in tissues and blood vessels - Not organ-specific · This deposition of immune complexes activates complement system and other immune cells, eliciting inflammatory response to cause tissue damage · Same isotypes of Ab (IgG and IgM) as type II hypersensitivity reactions but different mechanisms · Clinical manifestations include skin rashes, kidney inflammation, arthritis, fever · Develop at least 3-4 days after exposure to Ag - Serum sickness is a classic example of transient immune complex-mediated syndrome · Continued exposure to the same Ag can cause chronic reactions - Subacute bacterial endocarditis, chronic viral hepatitis, systemic lupus erythematosus (SLE)

Describe the development of contact dermatitis by poison ivy.

· Type IV hypersensitivity reactions · Through direct contact with - Plants' excretions (poison ivy/oak) - Microbe-derived substances (e.g. tuberculin skin reactions) - Drugs, chemicals, metals (chromium, nickel, gold) · Classic example: the response to poison oak/ivy - Small molecules form complex with proteins (e.g. CD28) on skin cells, and presented to Th1 by APCs to get it sensitized - Sensitized Th1 cells secrete cytokines and chemokines to activate MΦs and attract monocytes/MΦs to the site of contact, inducing a recurrence of inflammation - During secondary exposure Th1 memory cells become activated to cause more severe DTH · Pentadecacatechol from poison oak/ivy - Urushiol (poison oil) derivatives - Highly reactive molecule that readily crosses skin - Forms covalent bonds with many proteins · Peptides bound with pentadecacatechol are presented to Th1 cells by MHC II - Stimulate MΦs inflammatory response - Stimulate CTLs (indirectly) · Immunological memory (via memory Th1 cells) leads to more severe secondary response

How different is type IV hypersensitivity from the other types? What are the mechanisms of type IV?

· Type IV: delayed type of hypersensitivity mediated by Ag-specific T cells (e.g. poison ivy, tuberculin test) · Delayed-type hypersensitivity (DTH) - 2-3 days after exposure to the sensitizing Ag · May be against self-Ag or exogenous Ag (e.g. allergens) · T cell-mediated immune response mostly from Th1 and MΦ activation that causes tissue damage - It does not involve antibody! - Caused by Th1 cells that release cytokines and activate MΦs à phagocytosis - Sometimes caused by Th2 mediated responses in which eosinophils predominate - Occasionally caused by cytotoxic T cells (CTLs) à direct killing · Closely associated with autoimmune diseases · Can cause chronic inflammation resulting in tissue lesions, scarring, and granuloma formation · DTH can be elicited in infections by living microbes, in which inflammation and granuloma formation cause serious damage

What are the functions of antibodies?

· Virus neutralization · Opsonization · Antibody-mediated cell cytotoxicity (ADCC) · Activation of complement · Crosstalk with receptor signaling as agonist · Receptor internalization · Phagocytosis

Describe the major functions of the "complement system" in immune defenses.

· Work together to promote pathogen killing by: 1. Lysis: forming holes via membrane attack complex (MAC), causing pathogen to swell & burst 2. Opsonization: "tagging" pathogens to enhance phagocytosis 3. Activation of inflammatory response: o Increasing microbicidal activity of granulocytes, e.g. histamine release from mast cells o Attracting and triggering recruitment of inflammatory cells (chemotaxis) - Enhancing clearance of immune complexes · Trigger release of histamine and other vasoactive substances from mast cells and basophils, increasing capillary permeability

What type of lymphocytes gives rise to Burkitt lymphoma? What are the major manifestations? What are the possible causes? Pathophysiological effects?

• B-cell lymphoma - High mitotic rate and clonal proliferation of B cells => very fast-growing tumors - "Starry-sky" pattern of benign macrophages engulfing apoptotic malignant lymphocytes - Genetic translocation of c-myc on chr 8 and immunoglobulin heavy chain of chr 14 • Tumor mass of jaw and facial bones in African Burkitt lymphoma - Closely associated with EBV infection - Also occurs frequently in patients with AIDS · Chemotherapy with radiation therapy - *Intensive chemotherapy with rituximab* - *Radiotherapy with cyclophosphamide*

Know the cell origin of malignant transformation, major characteristics, and general treatment options for non-Hodgkin lymphoma.

• Clonal expansion of B cells, T cells, NK cells - Most (80-85%) arise from B cells - Both precursor or mature cells may be involved · Characteristics - Nodular - Or diffuse (most in children) • Symptoms - Many with asymptomatic peripheral lymphadenopathy, or abnormal lymphocytes in circulation - Weight loss, fever, night sweats, and asthenia indicate disseminated disease; hepatomegaly and splenomegaly; congestion/edema of face and neck Overlapping with leukemia • Treatment - Combination chemotherapy +/- radiation therapy - *Rituximab* (anti-CD20 monoclonal antibody) +/-chemotherapy - HSC transplantation (for relapses)

Understand the malignant nature of leukemia, e.g. change of cell numbers, effects on hematopoiesis.

• Clonal malignant disorder of blood and blood-forming organs - Uncontrolled proliferation of malignant leukocytes o Excessive accumulation of leukemic cells o Overcrowding of bone marrow o Decreased production and function of normal hematopoietic cells

Know the cell origin of malignant transformation, major characteristics, and general treatment options for Hodgkin lymphoma.

• Localized malignant growth of lymphoid cells, primarily involving LNs • Clonal transformation of cells of B cell origin in the germinal center => *Reed-Sternberg cells* Characteristics: o Large nodules (palpable LNs) o Presence of Reed-Sternberg cells =>local inflammation • Symptoms • An early sign is painless LN enlargement • Fever, cough, weight loss, night sweats, itching, splenomegaly, and hepatomegaly • Treatment - one of the most curable forms of cancer • Chemotherapy, e.g. bleomycin, vinblastine, dacarbazine *(ABVD) (first-line therapy)* • Radiation therapy, surgery, HSC transplantation (for relapses)

Know that Multiple Myeloma is caused by malignant transformation of plasma cells, which leads to a series of pathophysiological effects.

• Malignant proliferation of plasma cells => MM cells - Produces abnormal antibodies (M-protein) - Bence Jones protein (free immunoglobulin light chain) - Produce IL-6, IL-1, TNF-alpha • Infiltrate BM and aggregate into tumor masses in skeletal system - Disrupt normal blood production and destroy bone tissues - Hypercalcemia, renal failure, bone lesion, prone to infection and other complications • Possible causes - Chromosomal translocations of oncogenes with immunoglobulin heavy chain - Chromosomal deletions • Combination drug therapy, high-dose chemotherapy with HSC transplantation, radiation therapy