Immunology

Lymph Node anatomy

- derived from *mesenchymal cells* - *follicles: B cell* proliferation + localization (outer cortex) - *paracorTex: T cells* - *inner cortex / paracortex*: *thymus dependent (di george)* - medullary sinus: macrophages (*filter blood*) - *Medullary cords: plasma cells*

IgE

-"BLANK" immunoglobulins are important in fighting helminths and protozoal organisms. -They are also associated with the pathologies of allergy and asthma.

Eosinophilic granulomatosis with polyangiitis (Churg- Strauss)

-A small to medium vessel vasculitis characterized by late onset asthma rhinosinusitis and eosinophilia. -Mononeuritis multiplex due to involvement of the Epineural vessels of peripheral nerves is common. *Histo: Necrotizing arteritis

Von Hippel-Lindau Disease

-AD -cerebellar hemangioblastomas CNS in association with congenital cyst of kidneys, liver and /or pancreas -can lead to phochomocytoma (associated with metanephrines = catecholamine breakdown products), renal cell carcinoma and cerebellar hemangioblastomas *surveillance includes plasma metanephrines, abdominal imaging, ophthalmologic exam and MRI of spine and brain

Type 3 hypersensitivity = Immune complex

-Antibody-antigen complex deposition -complement activation (neutrophils) -C3b binds to pathogens and enhances phagocytosis -bind to CR1 receptors on erythrocytes facilitating clearance in the liver and spleen Ex: High yield conditions are serum sickness(low serum C3 and C4 levels), Henoch-Schonlein purpura, systemic lupus erythematosus, Arthus reaction, poststreptococcal glomerulonpehritis, and rheumatoid arthritis.

IL-4

-From Th2 cells -Induces differentiation into Th2 cells. -Promotes growth of B cells. -Enhances class switching to IgE

IL-5

-From Th2 cells -Stimulates growth and differentiation of eosinophils.

Type 2 hypersensitivity= Cytotoxic

-IgG & IgM autoantibody -mediated Cytotoxic ANTIBODY mediated cell destruction (NK cells, eosinophils, neutrophils, macorphages) Ex: Autoimmune hemolytic anemia and Goodpasture syndrome Commonly tested type II hypersensitivities are pemphigus vulgaris, bullous pemphigoid, Grave's disease, ITP, and myasthenia gravis.

IL-12

-Induces differentiation of T cells into Th1 cells. -Activates NK cells.

IFN-gamma

-Secreted by Th1 cells -Secreted by NK cells in response to IL-12 from macrophages; -stimulates macrophages *to kill phagocytose pathogens.* and promoting GRANULOMA formation -granulomma characterized with a collection of epitheliod histiocytes, giant cells and rim of lymphocytes Also activates NK cells *to kill virus-infected cells.* Increases MHC expression and antigen presentation by all cells.

IL-2 ($)

-Secreted by all Helper T cells (TH1) -Stimulates the growth of CD4+ and CD8+ cells and B cells, natural killer cells and monocyte activation

IL-3

-Secreted by all T cells -Supports growth and differentiation of bone marrow stem cells. Functions like GM-CSF.

TNF-alpha

-Secreted by macrophages and activated T cells -*Mediates septic shock.* Activates endothelium (e-selectin and CAMs). -Fever -maintains granulomas in TB -IL-1, IL-6, TNF-alpha can mediate fever and sepsis

Type 4 hypersensitivity = Delayed type

-T-cell and Macrophage mediated *DEVELOP OVER DAYS Ex: Tuberculosis skin test and contact dermatitis Conditions include infectious (TB, leprosy, fungal), autoimmune, contact dermatitis, graft-vs.-host disease, and Stevens-Johnson syndrome. Contact dermatitis is a type IV hypersensitivity reaction. Patients present with an erythematous inflammatory response in the area of contact with the offending agent generally 24-48 hours after second exposure. This is associated with a previous sensitization to the affected area.

Sepsis

-TNF-alpha is released from activated macrophages and one of the important mediators (IL-1 and IL-6) fo the systemic inflammatory response -toxic inflammatory condition arising from the spread of microbes, especially bacteria or their toxins, from a focus of infection

Multiple Myeloma

-Typically presents as low back pain in the elderly population. The plasma cell is typically a dark blue staining cell with an eccentric nucleus of normal size ("clockface chromatin") and usually an area of perinuclear clearing ("fried-egg" appearance). *High serum IL-6 that drives plasma cell growth -The monoclonal B cells produce large amounts of IgG or IgA and increase the risk of bacterial infection due to decreased production of normal immunoglobulins. - "BLANK" is associated with an increased susceptibility to infection, Ig light chains in urine that are waxy, large and eosinophilic (Bence Jones protein), primary amyloidosis, normocytic anemia, renal insufficiency, and hypercalcemia due to the lytic bone lesions. *stimulate osteoclast via secreting RANKL and destroying osteoprtegerin -associated with elevated circulating paraproteins (monoclonal immunoglobulins)-->stacking of erythrocytes (rouleaux formation) -diagnosis is made with SPEP and UPEP Multiple myeloma (MM) is a malignancy of B cells with clonal proliferation of plasma cells causing replacement of neighboring bone marrow and lytic bone lesions. Will seen punched out lytic lesions. MM typically presents with bone pain, pathologic fractures, lytic bone lesions on radiograph, anemia, elevated creatinine, and hypercalcemia. These findings can be remembered with the mnemonic "CRAB" (Calcium elevation, Renal failure, Anemia, and Bone lesions). Other clues include an elevated total protein due to production of monoclonal or "M" protein. **MGUS = M protein is < 3 g/dl with out features of Multiple Myeloma**

Hyper IgE Syndrome (Job syndrome)

-also known as Job syndrome, is an autosomal dominant condition characterized by the TRIAD of ECZEMA, EOSINOPHILIA & RECURRENT SKIN AND PULMONARY INFECTIONS *STAT3 mutated -Deficient IFN gamma > PMN's fail to respond to chemotactic stimuli (C5a, LTB4) may also be classified as a T cell disorder b/c IFN gamma is the problem, but ultimately phagocytes can't get to where they need to go. High levels of IgE and eosinophils -Presentation triad -Eczema -Recurrent COLD (no inflammatory response) S. aureus abscesses (think of biblical Job with boils) -Coarse facial features: broad nose, prominent forehead (frontal bossing), deep set eyes, and "doughy" skin Also common to have retained primary teeth resulting in 2 rows of teeth In Job syndrome (or hyper-IgE syndrome), there is a myriad of problems stemming from a missing signaling cytokine, interferon gamma. Neutrophils are thus unable to find the site of infection and do not phagocytize bacteria, leading to infection and abscess formation. While interferon gamma is low, IgE is elevated. Signs on physical examination are coarse facial features, multiple sets of teeth, broad-based nose, deep-set eyes, and eczema.

Chronic Inflammation

-associated with increased circulating pro-inflammatory cytokines (IL-1, IL-6, TNF-alpha), which stimulates the liver to release acute-phase reactants (C-reactive protein, fibrinogen) -the presence of acute-phase reactants increases the erythrocyte sedimentation rate

Dermatomyositis ($)

-characterized by immune complex deposition in the perimysium and perifascicular regions. -immune complex deposition in the blood vessels, predominantly with CD4+ T and B lymphocytes in the perimysium and perifascicular regions. -Insidious onset of muscle weakness is the most common presenting feature, with gradual worsening over time. The distribution of weakness is typically symmetric and proximal. -Physical exam may demonstrate Gottron's patches, which is an erythematous and scaly eruption that occurs over the metacarpophalangeal and interphalangeal joints. A violaceous heliotrope rash can erupt over the upper eyelids. A diffuse, flat erythematous V-shaped lesion over the neck and chest can occur, and is known as a shawl sign. There is associated erythroderma with extensive areas of skin redness. -The patient may have mechanic's hands, which is a roughening and cracking of the skin of the tips of the fingers. -Laboratory analysis will reveal an elevated creatine kinase, but aldolase or lactate dehydrogenase may also be abnormal. -Anti-Jo 1 antibodies are also present in the serum. -The definitive test for establishing the diagnosis of dermatomyositis is muscle biopsy. *associated with adenocarcinoma Tx: systemic glucocorticoids Dermatomyositis is an inflammatory disease involving the muscles and skin where patients present with proximal muscle weakness and pathognomonic cutaneous manifestations of a heliotrope rash (violaceous or erythematous periorbital lesions with or without edema) and Gottron papules (erythematous papules and plaques usually seen over the bony prominences of the main joints of the digits of the upper extremities). The most specific antibody associated with dermatomyositis is the anti-Mi-2 (a nuclear helicase) antibody.

B lymphocytes

-form in the bone marrow and release antibodies that fight bacterial infections -immature B cels become naive B cells A. B Cell activation occurs via 1. Antigen binding by surface IgM or IgD; results in maturation to IgM- or lgD 2. B-cell antigen presentation to CD4+ helper T cells via MHC class II. i. CD40 receptor on B cell binds CD40L on helper T cell, providing 2nd activation signal. ii. Helper T cell then secretes IL-4 and IL-5 (mediate B-cell isotype switching, hypermutation, and maturation to plasma cells).

IgA

-found along mucosal surfaces such as respiratory epithelia and the gastrointestinal tract. -They provide opsonization of foreign pathogens and prevent their invasion into the bloodstream.

Rheumatoid Arthritis

-immune response dictated against autoantigens in the joints -infiltrating CD4+ T cells secrete cytokines that promote inflammatory synovitis -stimulate B cells to produce rheumatoid factor (IgM antibody specific for Fc component of IgG) and anti-citrullinated protein antibodies that contribute to chronic inflammation and joint destruction Rheumatoid arthritis is a chronic systemic inflammatory disease that usually affects multiple small joints and is more common in women. It presents with morning stiffness and symmetric swelling of multiple joints, most often beginning in the hands and feet. Radiographs will reveal bony erosions within the joints. Rheumatoid nodules are common skin manifestations seen along the olecranon process. Biopsy of the nodule will reveal small vessel vasculitis and granuloma formation.

KRAS mutation causing anti-EGFR resistance

-lead to constitutive activation of the epidermal growth factor receptor (EGFR) pathway, promoting increased cell proliferation and growth -tumors with this mutation are resistant to treatment with anti-EGFR drugs (ie. cetuximab and panitumab)

Features of drug-induced lupus

-linked to drugs metabolized by N-acetylation in the liver -slow acetylators are at a greater risk

Thrombocytopenia

-low platelet count -deficiency of clotting factor

Granulomatosis with polyangiitis (Wegener)

-nasal mucosal ulcerations (saddle nose) and glomerulonephritis are most characteristic -associated w/ c-ANCA, which targets neutrophil proteinase 3

Tumor Lysis Syndrome (TLS)

-oncologic emergency with rapid lysis of malignant cells -usually the result of chemotherapy or sometimes radiation -may occur 24 hours-7 days after antineoplastic therapy is initiated -develops when chemotherapy or irradiations causes the destruction of a large number of rapidly dividing malignant cells -intracellular contents are rapidly released into the bloodstream *Hyperphosphatemia, Hypocalcemia, Hyperkalemia and Hyperuricemia & increase LDH

Metastatic Melanoma

-pleomorphic cells with brown pigment -Positive for S-100 and HMB-45

cytotoxic chemotherapy

-pt's develop hyperphosphatemia, hperkalemia, hyperuricemia, elevated lactate dehydrogense

NK cells

-recognize and kill cells with decreased MHC class 1 antigen -they are large lymphocytes that contain perforins and granzymes in cytoplasmic granules *CD56 Activity enhanced by IL-2, IL-12, IFN-alpha, and IFN-beta

Polymyositis

-the inflammatory cells invade within the fascicle of individual muscle fibers -a persistent inflammatory muscle disease that causes weakness of the skeletal muscles. It is classified as a chronic inflammatory myopathy, one of only three such diseases. It presents with an insidious onset of symmetrical proximal muscle weakness without a rash, which differentiates it from dermatomyositis. Muscle atrophy may be present in long-standing disease. -This picture shows the degeneration of muscle fibers caused by the Anti-Jo-1 antibodies -Cytotoxic T-cell humoral mediated process directed against muscle fascicles -elevated muscle enzyme (CK and aldolase) -Positive for ANA and anti-jo-1 -Biopsy: Endomysial mononuclear infiltrate and patchy necrosis

Adenoma to Carcinoma Sequence "AK-53"

1. APC inactivation -Normal mucosa to small adenomatous polyp (adenoma) 2. KRAS activation -Increase in size of the adenoma 3. p53 inactivation -malignant transformation of adenoma to carcinoma -normally promotes repair to damaged DNA

Primary immunodeficiency diseases

1. Ataxia-telengiectasia 2. Chediak-Higashi Syndrome 3. Chronic Granulomatous Disease (CGD) 4. DiGeorge syndrome 5. Severe Combined Immunodeficiency 6. Terminal Complement def. 7. Wiskott-Aldrich syndrome

Mast Cell and Allergic Response

1. Cromolyn and nedocromil are mast cell-stabilizing agents that inhibit mast cell degranulation independent of the triggering stimulus *2nd line tx for allergic rhinitis and bronchial asthma

CD4 + Helper T cells activation

1. Extracellular antigen (e.g. foreign protein) is phagocytosed, processed, and presented on MHC class II, which is expressed by antigen presenting cells (A PCs). 2. B7 on APC binds CD28 on CD4+ helper T cells providing 2nd activation signal. -"28 divided by 7 equals 4" 3. Activated CD4+ helper T cells secrete cytokines that "help" inflammation and are divided into two subsets. i. TH1 subset secretes -IFN-gamma (activates-macrophage, promotes B-cell class switching from IgM to IgG, promotes TH1 phenotype and inhibits TH2 phenotype). -Il-2 (T cell growth factor and CD8+ T cell activator) ii. TH2 subset secretes -IL-4 & IL-13(facilitates B-cell class switching to IgE) -IL-5 (eosinophil chemotaxis and activation, and class switching to IgA) -IL-10 (inhibits TH1 phenotype)

CD 8+ Cytotoxic T cells activation

1. Intracellular antigen (derived from proteins in the cytoplasm) is processed and presented on MHC class I, which is expressed by all nucleated cells and platelets . 2. IL-2 from CD4+ T 1 cell provides 2nd activation signal. 3. Cytotoxic T cells are activated for killing. 4. Killing occurs via i. Secretion of perforin and granzyme; perforin creates pores that allow granzyme to enter the target cell, activating apoptosis(caspases are key mediators for apoptosis). ii. Expression of FasL, which binds Fas on target cells, activating apoptosis

Routes of metastasis

1. Lymphatic spread: carcinomas spread thru lymphatics. makes sense bc carcinoma (epithelial) 2. Hematogenous spread: sarcoma (mesenchymal tumor aka CT) tend to spread thru blood vessels exceptions to this - carcinomas spread into blood. renal cell carcinoma (renal vein) hepatocellular carcinoma (hepatic vein) follicular carcinoma of thyroid choriocarcinoma (cancer of trophoblasts) 3. Seeding of body cavities: seeding spread is characteristic of ovarian carcinoma - seeding of the omentum. OMENTUM CAKING

Bone metastases

1. Osteolytic (lucent): Due to osteoclast stimulation, tend to represent aggressive cancer 2. Osteoblastic (sclerotic): Due to osteoblasts, indicates a more indolent course

Paget Disease of bone (Phases)

1. Osteolytic phase -osteoclast-dominant 2. Mixed -osteoclastic-osteoblastic 3. Osteosclerotic phase -osteoblast-dominant -mosaic pattern and prominent cement lines

Acute Phase Reactants

1. Positive APR's -serum levels rise in acute inflammatory states and include: --CRP --Complement Coagulation factors --Ferritin --hepcidin --ceruloplasmin -haptoglobin -vWF *Procalcitonin is a unique APR that rises with bacterial source and decreases with a viral source 2. Negative APR's -Serum levels fall in acute inflammatory states and include: --albumin --transferrin --transthyretin (Prealbumin)

Oncogenes Vs. Tumor Suppressor Genes: alleles mutated in cancer

1. Protooncogenes (RET,BRAF) -gain of function and promote cell division -only one allele must be damaged to increase risk of cancer formation 2. Tumor Suppressor genes (TP53,RB, BRCA 1/2 and MEN 1) -loss of function and unregulated growth -both alleles must be inactivated to increase risk of malignancy

Macrophages

1. Resolution and healing—Anti-inflammatory cytokines (e.g., IL-10 and TGF-Beta) are produced by macrophages. 2. Continued acute inflammation—marked by persistent pus formation; IL-8 from macrophages recruits additional neutrophils. 3. Abscess—acute inflammation surrounded by fibrosis; macrophages mediate fibrosis via fibrogenic growth factors and cytokines. 4. Chronic inflammation—Macrophages present antigen to activate CD4+ helperT cells, which secrete cytokines that promote chronic inflammation.

Mediators of acute inflammation

1. TLRs -Activated by pathogen-associated molecular patterns (PAMPs) that are commonly shared by microbes -CD14 (a co-receptor for TLR4) on macrophages recognizes lipopolysaccharide (a PAMP) on the outer membrane of gram-negative bacteria. -TLR activation results in upregulation of NF-kB, a nuclear transcription factor that activates immune response genes leading to production of multiple immune mediators. 2. arachidonic acid metabolites a. Cyclooxygenase produce prostoglandins PGE2 mediaties fever and pain -vasodilation b. 5-Lipoxygenase produces LT (leukotrienes) LTB4 attracts neutrophils (also bacterial products, 5-HETE(leuoktriene precursor), IL-8 and C5a) -vasoconstriction and bronchospasm 3. mast cells Activated by (1) tissue trauma, (2) complement proteins C3a andC5a, or (3) cross-linking of cell-surface IgE by antigen Histamine first phase Leukotrienes is involved in delayed response 4. complement i. Classical pathway- C1 binds IgG or IgM that is bound to antigen. ii. Alternative pathway—Microbial products directly activate complement. iii. Mannose-binding lectin (MBL) pathway—MBL binds to mannose on microorganisms and activates complement. 5. Hageman factor -activation of coagulation and fibrinolytic systems *Bradykinin and PGE2 mediates pain

Sjogren's syndrome (Type IV Hypersensitivity)

A. Autoimmune destruction of lacrimal and salivary glands 1.Lymphocyte-mediated damage (type IV HSR) with fibrosis B. Classically presents as dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia), and recurrent dental caries in an older woman (50-60 years)—"Can't chew a cracker, dirt in my eyes" 1. May progress to ulceration of corneal epithelium and oral mucosa C. Can be primary (sicca syndrome) or associated with another autoimmune disorder, especially rheumatoid arthritis 1. Rheumatoid factor is often present even when rheumatoid arthritis is absent. D. Characterized by ANA and anti-ribonucleoprotein antibodies (anti-SSA/Ro and anti-SSB/La) 1. Pregnant women with anti-SSA are at risk for delivering babies with neonatal lupus and congenital heart block E. Increased risk for B-cell (marginal zone) lymphoma, which presents as unilateral *Lymphocytic Sialadenitis

Scelroderma (Systemic Sclerosis)

A. Autoimmune disorder characterized by sclerosis of skin and visceral organs B.Fibroblast activation leads to deposition of collagen. 1. Autoimmune damage to mesenchyme is possible initiating event. 2. Endothelial dysfunction leads to inflammation (increased adhesion molecules), vasoconstriction (increased endothelin and decreased NO), and secretion of growth factors (TGF-beta and PDGF-->Pulmonary HTN) C. Limited type—Skin involvement is limited (hands and face) with late visceral involvement. 1. CREST syndrome: Calcinosis/anti-Centromere antibodies, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyty Telangiectasias of the skin. D. Diffuse type—Skin involvement is diffuse with early visceral involvement. (any organ) 3. Highly associated with antibodies to DNA topoisomerase I (anti-Scl-70). Limited type = anti-centromere ab Diffuse type = anitbodies to DNA topoisomerase I (anti-Scl-70) Scleroderma or systemic sclerosis is an autoimmune disease characterized by induration and thickening of the skin, chronic inflammatory infiltration of numerous visceral organs (which can lead to fibrosis), fibroproliferative vasculopathy, and immune alterations. The micro- and macrovascular fibrosis leads to increased peripheral vascular resistance, causing increased blood pressure. Intimal cell proliferation and luminal narrowing of intrarenal arteries can cause "scleroderma renal crisis" presenting as severe hypertension and progressive oliguria. ACE inhibitors are the most effective antihypertensive drugs used in these patients because of their ability to inhibit vasoconstriction, thus preventing further vascular damage and "scleroderma renal crisis."

Severe Combined Immunodeficiency (SCID)

A. Autosomal recessive Defective cell-mediated and humoral immunity B. Etiologies include 1. Cytokine receptor defects—Cytokine signaling is necessary for proliferation and maturation of B and T cells. 2. Adenosine deaminase (ADA) deficiency—ADA is necessary to deaminate adenosine and. deoxyadenosine for excretion as wasteproducts; buildup of adenosine and deoxyadenosine is toxic to lymphocytes. 3. MHC class II deficiency-MHC class II is necessary for CD4+ helper T cell activation and cytokine production. C. Characterized by susceptibility to fungal, viral, bacterial, and protozoal infections, including opportunistic infections and live vaccines *Lab shows low to absent CD3+ T cells and hypogammaglobinemia D. Treatment is sterile isolation ('bubble baby') and stem cell transplantation.

Complement Deficiencies

A. C5-C9 deficiencies—increased risk for Neisseria infection (N gonorrhoeae and N meningitidis) B. C1 inhibitor deficiency—-results in hereditary angioedema, which is characterized by edema of the skin (especially periorbital) and mucosal surfaces

Hyper IgM syndrome

A. Characterized by elevated IgM B. Due to mutated CD40L (on helper T cells) or CD40 receptor (on B cells) 1. Second signal cannot be delivered to helper T cells during B-cell activation. 2. Consequently, cytokines necessary for immunoglobulin class switching are not produced. C. Low IgA, IgG, and IgE result in recurrent pyogenic infections (due to poor opsonization), especially at mucosal sites.

Wiskott-Aldrich syndrome

A. Characterized by thrombocytopenia, eczema, and recurrent infections (defective humoral and cellular immunity); bleeding is a major cause of death B. Due to mutation in the WASP gene; X-linked WATER Wiskott-Aldrich syndrome (WAS) is an inherited disease causing variable amounts of IgM deficiency. Patients present with thrombocytopenia, cellular and humoral deficiency and often have a history of purulent infections with encapsulated bacteria.

X-linked agammaglobulinemia ($$)

A. Complete lack of immunoglobulin due to disordered B-cell maturation 1. pre-and pro-B cells cannot mature-->leading to low/absent circulating mature B cells(CD19, CD20, CD21). -due to the absence of B cells, primary lymphoid follicles and germinal centers will not form within lymph nodes B. Due to mutated Bruton tyrosine kinase; X-Iinked C. Presents after 6 months of life with recurrent bacterial, enterovirus (e.g., polio and coxsackievirus), and Giardia lamblia infections; maternal antibodies present during the first 6 months of life are protective. D. Live vaccines (e.g., polio) must be avoided.

DiGeorge Syndrome

A. Developmental failure of the third and fourth pharyngeal pouches 1. Due to 22q11 microdeletion B. Presents with T-cell deficiency (lack of thymus); hypocalcemia (lack of parathyroids); and. abnormalities of heart, great vessels, and face

infectious mononucleosis (mono)

A. EBV infection that results in a lymphocytic leukocytosis comprised of reactive CD8+ T cells; CMV is a less common cause. 1. EBV is transmitted by saliva ("kissing disease"); classically affects teenagers B. EBV Primarily infects 1. Oropharynx, resulting in pharyngitis 2. Liver, resulting in hepatitis with hepatomegaly and elevated liver enzymes 3. B cells C. CD8+ T-cell response leads to 1. Generalized lymphadenopathy (LAD) due to T-cell hyperplasia in the lymph node paracortex 2. Splenomegaly due to T-cell hyperplasia in the periarterial lymphatic sheath (PALS) 3. High WBC count with atypical lymphocytes (reactive CD8+ T cells) in the blood D. The monospot test is used for screening 1. Detects. IgM antibodies that cross-react with horse orsheep red blood cells (heterophile antibodies) 2. Usually turns positive within 1 week after infection 3. A negative monospot test suggests CMV as a possible cause of IM. 4. Definitive diagnosis is made by serologic testing for the EBV viral capsid antigen. E. Complications 1. Increased risk for splenic rupture; patients are generally advised to avoid contact sports for one month, usually a year. 2. Rash if exposed to ampicillin 3. Dormancy of virus in B cells leads to increased risk for both recurrence and B-cell lymphoma, especially if immunodeficiency (e.g., HIV) develops.

Common Variable Immunodeficiency (CVID)

A. Low immunoglobulin due to B-cell or helper T-cell defects B. Increased risk for bacterial, enterovirus, and Giardia lamblia infections, usually in late childhood C. Increased risk for autoimmune disease and lymphoma

IgA Deficiency

A. Low serum and mucosal IgA; most common immunoglobulin deficiency B. Increased risk for mucosal infection, especially viral; however, most patients are asymptomatic. C. Can present with recurrent sinopulmonary and GI infections *associated with Celiac disease

Chediak-Higashi syndrome

AR - Giant granules in neutrophils, infections, oculocutaneous albinism - Caused by defect in microtubule polymerization in neutrophil and NK cell function Chediak-Higashi is an autosomal recessive disease creating a defect in lysosomal enzymes. This causes deficient bactericidal effect on the bacteria, leading to recurrent pyogenic infections from Staph and Strep. The lysosomes and melanosomes become large, trapping melanin and causing oculocutaneous albinism with silvery hair, light eyes, light skin, and photosensitivity.

HLA subtypes associated with diseases: B8

Addison disease, myasthenia gravis, Graves disease "Don't Be late(8), Dr. Addison, or else you'll send my patient to the grave.

"Bamboo spine" on x-ray

Ankylosing spondylitis (chronic inflammatory arthritis: HLA-B27, TNF-alpha and IL-17) *Bridging syndesmophytes

Multiple Myeloma (HISTO)

B cell development is particularly affected, which reduces plasma cell diversity and limits the generation of targeted immunoglobulins against infectious agents

CREST syndrome

Calcinosis, Raynaud's, esophageal dysmotility, Sclerodactyly, Telangiectasia -Anti-centromere antibodies

HLA subtypes associated with diseases: DQ2/DQ8

Celiac Disease "I ate (8) too (2) mucin gluten at Dairy Queen."

High affinity IgE receptor activation

Cross-linking of multiple membrane-bound IgE antibodies by a multivalent antigen results in aggregation of the Fc(epsilon)RI receptors, causing degranulation and the release of preformed mediators (histamine and tryptase)

Calcineurin inhibitors (HISTO)

Cyclosporine & Tacrolimus: -reduce renal blood flow and cause direct damage to renal endothelial and tubular cells -histo = early arteriolar hyalinization and tubular vacuolization *despite nephrotoxicity these agents remain beneficial for preventing acute kidney injury

HLA subtypes associated with diseases: DR3

Diabetes mellitus type 1, SLE, Graves disease, Hashimoto thyroiditis "2-3, SLE"

T cell maturation process

Double negative (subcapsular zone) --> cortex --> double positive --> if insufficient affinity for self MHC then apoptosis = positive selection by cortical epithelial cells --> single positive in medulla --> if they have excessive affinity for self antigens for MHC then apoptosis = negative selection

Inflammation

Figure 24.9 1: Neutrophils are the first leukocytes recruited during the acute inflammatory process. They squeeze through the gap between endothelial cells (extravasation) and follow the gradient of inflammatory mediators to the site of inflammation. 2: Neutrophils quickly phagocytose pathogens. While this is happening, complement proteins are activated by the presence of pathogens and help with opsonization (they bind to microbes so leukocytes can more easily eat them). Some can also kill pathogens by forming a channel in their membranes. Neutrophils phagocytose pathogens immediately before destroying themselves Antibodies bound to pathogens activate complement system Aids in opsonization, kills pathogens by lysis Dendritic cells phagocytose pathogens, present antigens to T lymphocytes, activating adaptive immune system Ends with tissue repair

Enthesitis

Group of conditions characterized by inflammation, fibrosis, and calcification around tendons, ligaments, and muscle insertions.

HLA subtypes associated with diseases: DR5

Hashimoto thyroditis "Hashimoto is an odd doctor (DR3, DR5)"

HLA subtypes associated with diseases: A3

Hemochromatosis

Interleukins AGAIN

IL-1 -Increase Neutrophil & Macrophage migration Il-10 -attenuates inflammatory response, so does TGF-beta

Hot T-bone stEAK (IL-1 - 6 actions)

IL-1: fever (hot) IL-2: Stimulates T cells IL-3: stimulates bone marrow IL-4: stimulates IgE production IL-5: stimulates IgA production IL-6: stimulates aKute phase reactants production

Type 1 hypersensitivity = Immediate($)

IgE mediated hypersensitivity -IgE produced by plasma cells and B lymphocytes bind to high affinity IgE Fc receptors on basophils and mast cells -wheal and flare reaction Ex: Allergies, Anaphylaxis, Urticaria Eczema, hives, urticaria, conjunctivitis, rhinitis, asthma, and gastroenteritis are common clinical manifestations.

Molecular basis of HPV oncogenesis

Inactivation of RB-protein activity by HPV can lead to formation of head and neck squamous cell carcinoma

Interleukin-12

Induces differentiation of T cells into Th1 cells. Activates NK cells.

MHC 1 vs MHC 2

MHC 1 = CD8 T cells, intracellular origin (binds to a peptide from viral proteins in ER, then moves to membrane) MHC 2 = CD4 T cells, extracellular origin (binds to a peptide from bacterial proteins in vesicles, then moves to membrane)

Interleukins (IL)

Macrophages Secrete: Interleukins 1, 6, 8, 12, TNF-alpha TH1 cells secrete: Interferon-gamma TH2 cells secrete: Interleukins 4, 5, 10

Interleukin-8 (IL-8)

Major Chemotactic factor for neutrophils

DDX of back pain

Malignancies with a propensity for bony metastasis include -Prostate, Breast, Kidney, Thyroid, Lung "Pb KTL or lead kettle"

HLA subtypes associated with diseases: DR2

Multiple sclerosis, hay Fever, SLE, Goodpasture syndrome "Multiple hay pastures have dirt."

liposarcoma

Multivacuolated lipoblasts with scalloped nuclear membrane describes the histological findings of "BLANK", a malignant tumor of fat. "BLANK" usually present on the extremities as a dome-shaped lesion with painful swelling, numbness, enlargement of varicose veins, or decreased range of motion due to the size of the tumor. Systemic complaints (e.g., weight loss and fatigue) will also be present.

Nuclear Factor kappa B signaling

NF-kBeta normally presents in the cytoplasm in a latent, inactive state bound to inhibitor protein, IkB. -destruction of IkB-->translocation of free NF-kB to the nucleus

NMYC amplification

Neuroblastoma

Leukocyte extravasation

Neutrophils exit from blood vessels at sites of injury and inflammation in 4 steps: 1.) Rolling 2.) Tight binding 3.) Diapedesis 4.) Migration

HLA subtypes associated with diseases: B27

PAIR (aka - seronegative arthropathies): Psoriatic arthritis Ankylosing spondylitis arthritis of IBD Reactive arthritis (formerly Reiter syndrome) via Chlamydia, Campylobacter, Salmonella, Shigella, Yersinia

Psammoma bodies

Papillary thyroid carcinoma Serous papillary carcinoma of the endometrium and ovary Meningiomas Malignant Mesothelioma

Field cancerization

Process whereby exposure to carcinogens creates a field of molecularly altered cells that have an increased potential to malignantly transform -HNSCC via tobacco -Basal cell CA of skin via UV light -Colorectal carcinoma due to epithelial exposire to dietary carcinogens

1 hit GOF and 2 hit LOF

Proto-oncogenes Tumor supressor genes

WT1 gene

TUMOR SUPPRESSOR GENE. A/w: Wilm's Tumor

anti-PD-1 & anti-CTLA-4 antibodies

The binding of programmed cell death protein (PD-1) to one of its ligands(PD-L1) down regulate the immune response by inhibiting cytotoxic T cells -many types of cancers of aid immunodetection by increasing expression of PD-L1 on their surface -monoclonal antibodies against PD-1 up regulate the T cell response and promote tumor cell apoptosis

Positive Selection

Thymic cortex. T cells expressing TCRs capable of binding self-MHC on cortical epithelial cells

Negative Selection

Thymic medulla. T cells expressing TCRs with high affinity for self antigens undergo apoptosis or become regulatory T cells. Tissue-restricted self-antigens are expressed in the thymus due to the action of autoimmune regulator (AIRE); deficiency leads to autoimmune polyendocrine syndrome-1.

Collagen

Type 1: Bone (1=bONE) Type 2: Cartilage (car 2 lage) Type 3: pliable seen in blood vessels, granulation tissue, embryonic tissue -Collagenase removes type 3 collagen and requires ZINC as a cofactor Type 4: Basement membrane

IL-10

What IL down-regulates cell mediated immunity? -anti-inflammatory cytokine

Paget disease of bone (osteitis deformans)

What is the name for the common idiopathic alteration of bone exhibiting abnormal resorption and deposition(INCREASED BONE TURNOVER), resulting in distortion and weakening of the affected bones and bowing of bones? -elevated serum alkaline phosphatase via increased osteoclastic activity initially -Calcium, phosphorus and PTH are all normal levels -XR shows thickening of cortical and trabecular bone

TH2 cells

What subset of CD4 T cells is responsible for mast cell and eosinophil precursor proliferation? -activate B cells to produce IgE; -activate eosinophils

Cachexia

a condition of physical wasting away due to the loss of weight and muscle mass that occurs in patients with diseases such as advanced cancer or AIDS -via TNF-alpha (also IL-q and IL-6)suppressing appetite and increasing basal metabolic rate

Common colonic polyps

adenomatous and serrated are neoplastic polyps that have malignancy potential -increasing polyp size is the most important risk factor for cancer; villous histology and high-grad dysplasia are additional risk factors

Polymyositis (CHART)

anti-tRNA synthetase (anti-Jo-1) autoantibodies *patchy endomysial inflammatory infiltrate on biopsy *Dermatomyositis causes perifasciular inflammation

Langerhans cells

are dendritic cells found in the skin that act as profession la antigen presenting cells, These cells are derived from the myeloid cell line and they possess characteristic racquet-shaped intracytoplasmic granules known as Birbeck granules

Graft vs. Host Disease (GVHD)

can occur following transplantation of organs rich in lymphocytes(eg. Liver). T lymphocytes found in the donor organ become sensitized against the MHC antigens of the recipient and subsequently attack the host's tissues. The skin, liver and gastrointestinal tract are most frequently affected.

Reactive arthritis

classically presents in a triad of nongonococcal urethritis, conjunctivitis, and arthritis. It is an HLA-B27 assoicated arthropathy that occurs within several weeks following a geniturinary or enteric infection. It is one of the seronegative arthropathies and can cause sacroiliitis in 20% of patients.

Cytokeratin

commonly used immunohistochemical marker of epithelial-derived tissues. (ie breast cancer)

Leukopenia

deficiency of white blood cells -neutrophils and lymphocytes

IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome

genetic deficiency of FOXP3--> autoimmunity. Characterized by enteropathy, endocrinopathy, nail dystrophy, dermatitis, and/or other autoimmune dermatologic conditions. Associated with diabetes in male infants.

Chronic Granulomatous Disease (CGD)

happens in children who have diminished levels of cytochrome B and fail to form superoxide anions -> defective oxygen dependent killing, have impaired ability to oxidize NADPH(w/ in neutrophils) and destroy bacteria through the oxidative pathway -> defective phagocytes Nitroblue tetrazolium: Nitroblue tetrazolium test is used to screen for CGD. Leukocytes are incubated with NBT dye, which turns blue if NADPH oxidase can convert O2 to superoxide 0-2, but remains colorless if NADPH oxidase is defective. *Susceptible to 5 catalase positive organsims: -S. Aureus -Burkholderia cepacia (Pseudomaons cepacia) -Serratia marcescens -Nocardia -Aspergillus

Eosinophils

have bilobed nuclei and numerous eosinophilic granules in the cytoplasm and are important in allergic disease and defense against parasitic infection. The eosinophilic granules predominantly contain major basic protein, which, once released, acts as a potent anthelminthic toxin. Major basic protein also damages epithelial and endothelial cell and is a major cause of chronic lung damage in asthma.

ionizing radiation

induces DNA damage through DNA double-stranded fractures and the formation of oxygen free radicals elimination of free radicals: 1. Antioxidants (e.g., glutathione and vitamins A , C, and E) 2. Enzymes i. Superoxide dismutase (in mitochondria)—Superoxide (02)-->H202 ii. Glutathione peroxidase (in mitochondria)—2GSH + free radical -> GS-SG and H2O iii. Catalase (in peroxisomes)—H202--> 02 and H20 3. Metal carrier proteins (e.g. transferrin and ceruloplasmin)

Interferon-gamma signaling pathway

inherited defects involving the interferon-gamma signaling pathway results in disseminated mycobacterial disease in infancy or early childhood

Systemic Lupus Erythematosus (SLE)

is an autoimmune disease characterized by the formation of: -Nonspecific --antinuclear antibodies (ANA) -Highly specific --Anti-dsDNA --Anti-Sm(ith) antibodies(against snRNPs = normally remove introns from RNA transcripts, essential component of spliceosomes) --Anticardiolipin Ab (antiphoslolipid Ab) Antihistone antibody is characteristic of drug-induced lupus. *Can be caused via HYDRALAZINE, PROCAINOMIDE and ISONIAZID *MC in African American women -Lupus Nephritis occurs primarily due to the formation of immune complexes containing DNA and anti-DNA in the circulation. -These are deposited in the glomerulus where they result in complement activation, recruitment of inflammatory cells and renal injury. (Type 3 Hypersensitivities) -Deficiency of early complement proteins (C1q, C4, and C2) is associated with "BLANK" Symptoms: -Raynaud phenomenon -Malar 'butterfly' rash or discoid rash, especially upon exposure to sunlight -oral or nasopharyngeal ulcers -MC cardiac symptoms is pericarditis and Libman-sacks endocarditis (small, sterile vegetations on both sides of the valve) -Arthritis (usually involving > 2 joints) -Serositis (pleuritis and pericarditis) -Psychosis or seizures -Renal damage --i. Diffuse proliferative glomerulonephritis is the most common and most severe form of injury (membranous glomerulonephritis also occur) TX: Avoid sunlight Glucocorticoids (to surpress immune system) The characteristic histopathology will reveal a band-like deposition of immune complexes along the dermal/epidermal junction (this is referred to as the "lupus band test") as well as vacuolar changes in the basal columnar cells.

Vimentin

is an intermediate filament present in mesenchymal tissue and can be used to detect sarcomas

Waldenstron's macroglobulinemia

is characterized by plasma cell infiltration of the bone marrow. Classic finding is an IgM spike on serum plasma electrophoresis (SPEP).

Leukocyte Adhesion Deficiency (LAD)

is due to absence of CD 18 antigens necessary for the formation of integrins. Clinical Features are caused by failure of leukocyte chemotaxis and include recurrent skin and mucosal infections without purulence (NO PUS), delayed separation of the umbilical cord and persistent leukocytosis.

Anaphylaxis

is the result of widespread mast cell and basophil degranulation and the release of preformed inflammatory mediators, including HISTAMINE and TRYPTASE -Tryptase is relatively specific to mast cells and can be used as a marker for mast cell activation Treatment: -Epinephrine via alpha 1, beta 1 & 2 stumulation

Sacroilitis

joint erosion with subchondral sclerosis and eventual ankylosis associated with ankylosing spondylitis

Anemia

lack of a normal number of red blood cells

Abscess formation

largely driven by neutrophil recruitment and activation leading to the release of cytotoxic granules that kill bacteria but also cause liquefying necrosis of surrounding tissue.

IgD

molecules are expressed on naive, mature B-cells, along with IgM molecules

CD 14

monocytes and macrophages

Chromogranin A and synaptophysin

neuroendocrine tumors

Benign lipoma

or tumor of adipocytes, are the most common soft-tissue neoplasms. They present as soft, painless, mobile masses. Biopsy will reveal mature, univacuolated adipocytes.

CCND1 (cyclin D1)

over-expression is seen in breast, lung, and esophageal cancers and certain types of lymphomas

Bladder cancer

presents classically with painless hematuria and is associated with smoking, radiation, aniline dyes, artificial sweeteners, cyclophosphamide, and working with rubber, leather, textiles, and paint products. The relationship between risk factors and the development of bladder carcinoma is a widely tested topic.

Asplenic patients

prone to infection via encapsulated microbes = Strep pneumo H. influenza N. meningitidis

Bechet's syndrome

recurrent oral ulcers, genital ulcers, uveitis Behcet's syndrome is classically characterized as a triad of symptoms that include recurring crops of mouth ulcers (aphthous ulcers), genital ulcers, uveitis.

Gottron's papules

red flat papules over knuckles a/w dermatomyositis

HLA subtypes associated with diseases: DR4

rheumatoid arthritis diabetes mellitus type 1 "4 walls in a rheum (room)"

IgM

secreted as pentamer molecules, and are therefore very good at agglutinating antigens and sequestering them in one location. *1st antibody produced

ankylosing spondylitis

simultaneous erosion of bone and new bone formation -symptoms are worse with prolonged rest and in the morning -relieved with excercise Naproxen is a non-steroidal anti-inflammatory drug (NSAID) that reversibly inhibits the cyclooxygenase (COX) enzyme. This is used in the initial treatment of ankylosing spondylitis, an inflammatory autoimmune disease that causes inflammation in the sacroiliac and lumbar spine joints.

Lymphocytic Sialadenitis

sjorgen syndrome aids in diagnose

MHC Class I ($)

synthesized in RER. *participates in ENDOGENOUS antigen presentation to CD8+ lymphocytes (Cytotoxic lymphocytes).* *ALL NUCLEATED CELLS EXPRESS MHC Class I.* -HLA-A/B/C

MHC Class II ($)

synthesized in RER. *participation in EXOGENOUS antigen presentation to CD4+ lymphocytes (TH Cells). * -present extracellular antigens processed in acidified lysosomes by antigen-presenting cells *MHC II are found on macrophages, dendritic cells and B cells.* -HLA-DP/DQ/DR *ABSENT OF MHC CLASS II EXPRESSION IMPAIRS ACTIVATION OF B AND T CELLS, RESULTING IN A FORM OF SEVERE COMBINED IMMUNODEFICIENCY

immunosenescence

the gradual advanced age-related deterioration of the immune system that increases the risk for, and severity of, infection in the elderly

Acute Transplant rejection reaction

via cell mediated immunity or antibody mediated, and less then 6 months s/p transplant

Vinca alkaloids: vincristine, vinblastine

work by blocking polymerization of beta tubulin with alpha tubulin to form microtubules. This arrests the cell-cycle in metaphase. These drugs are useful for treatment of acute lymphocytic leukemia (ALL), Hodgkin's and non-Hodgkin's lymphomas, Wilms' tumor, neuroblastoma, and pediatric sarcomas. Microtubules are also very important in the functioning of neurons, and the neurotoxicity of the vinca alkaloids is attributed to disruption of these functions.