Exam 3 Immunopathy

Question 1

Describe type I hypersensitivity reactions and provide examples

Answer 1

• Reaction where injury is caused by TH2 cells, IgE antibodies, mast cells and other leukocytes.
• Examples: anaphylaxis, bronchial asthma, allergies (hay fever and food)

Question 2

Describe type II hypersensitivity reactions and provide examples

Answer 2

• Reaction where secreted IgG and IgM injure cells by promoting phagocytosis or lysis and injury tissue through induction of inflammation.
• Examples: myasthenia gravis, Graves disease, Goodpasture syndrome

Question 3

Describe type III hypersensitivity reactions and provide examples

Answer 3

• Reaction where IgG and IgM antibodies bind antigens usually in circulation and the antigen-antibody complex deposits in tissues and induces inflammation.
• Examples: SLE

Question 4

Describe type IV hypersensitivity reactions and provide examples

Answer 4

• Reactions where sensitized T lymphocytes (TH1, TH17 and CTLs) are the cause of tissue injury.
• Examples: RA, MS

Question 5

Types of transplantation grafts

Answer 5

1. Autograft: self tissue
2. Isograft: identical twins
3. Allograft: other human, different genetic background
4. Xenograft: different species

Question 6

What is the underlying cause of transplant rejection?

Answer 6

• Immune damage caused by recipient’s response to allograft HLA antigens

Question 7

Describe mechanisms of graft rejection

Answer 7

1. ) Cellular rejection: type IV hypersensitivity reaction
   a. ) host CTLs bind and react to class I HLA Ag presented by allogeneic APCs (direct pathway), differentiate into CTLs, release perforins and granzymes leading to apoptosis of graft cells
   b. ) TH cells bind and react to class II HLA Ag presented either by allogeneic APCs (direct pathway) or via host APCs (indirect pathway), release cytokines recruiting mononuclear cells, which release IFN-gamma and TNF that leads to inflammatory tissue damage.
2. ) Humoral rejection: type II and III hypersensitivity reactions
   a. ) type II: abs binds to surface HLA in graft endothelium = activation of complement = acute inflammation or vasculitis
   b. ) type III: abs against host Ag form immune complexes in circulation and deposit in graft endothelium or in situ = fixing of complement = necrotizing vasculitis

Question 8

Describe the 3 types of transplant rejection in terms of

a. ) timing
b. ) mechanism
c. ) histological features

Answer 8

1. ) Hyperacute
   a. ) timing: mins to hours (including intra-operatively)
   b. ) mechanism: type III - Preformed abs (previous sensitization via pregnancy, transfusion or prior transplant) where destruction occurs via type III response – immune complex = complement activation
   c. ) histological features: fibrinoid necrosis, thrombosis, ischemia
2. ) Acute
   a. ) timing: days to months (1-3)
   b. ) mechanism: type II, III and IV response - CD8 cells infiltrate tubular and vascular membranes - CD4 cells produce cytokines = interstitial inflammation - Anti-graft abs deposit in graft vasculature = complement activation
   c. ) histological features: lymphocytic infiltrates, tubular necrosis (in case of kidneys), necrotizing vasculitis, intimal thickening (accumulation of fibroblasts, foamy macrophages, myocytes)
3. ) Chronic
   a. ) timing: months (4-6) to years
   b. ) mechanism: type II, III and IV response - as above, but chronically leading to proliferative lesions (d/t humoral response) and cytokine induced proliferation of vascular SM and production of collagen in EMC
   c. ) histological features: vascular changes, interstitial fibrosis, tubular atrophy (in case of kidneys), chronic inflammation

Question 9

Describe liver transplant rejection on acute vs chronic basis

Answer 9

1. Acute: cellular response in which portal lymphocytic infiltrates cause damage. Triad seen = portal tract inflammation, bile duct epithelial damage, endothelial damage (portal vein, hepatic artery). Cells seen: lymphocytes, plasma cells, macrophages and eosinophils.
2. Chronic: cellular response as above, but on chronic basis leads to bile duct destruction/disappearance, which is compounded by ischemia from ab-mediated damage to hepatic arterioles. Fibrosis (foam cells, myointimal hyperplasia, luminal obliteration)

Question 10

Describe heart transplant rejection on acute vs chronic basis. Complications?

Answer 10

• Rejection is cell-mediated. Lymphocytic infiltrates lead to myocyte damage and necrosis. Histology resembles viral myocarditis.
• Acute: lymphocytes surrounding myocytes
• Chronic: lymphocytes stimulate allograft cells to produce GFs that promote vascular SM and ECM
• Complications = graft arteriopathy (change resembling CAD, ie. with intimal thickening, accumulation of foamy macrophages) causing silent MI as heart is denervated, infections (EBV)

Question 11

Describe 3 complications resulting from hematopoietic cell transplants. Describe histologic features of acute/chronic GVHD.

Answer 11

1. ) GVHD (graft versus host disease): type IV reaction via CD4 (via cytokines) and CD8 attack recipient tissue where targets are skin, liver and GI tract
   a. ) Acute: epithelial necrosis. Triad: exfoliative rash, enteritis (blood diarrhea), hepatic involvement (bile duct necrosis) = jaundice
   b. ) Chronic: fibrosis of dermis with destruction of skin appendages, esophageal strictures and liver/bile duct damage manifested by jaundice.
2. ) Graft failure / rejection: some host NK cells or T cells survive irradiation and react against graft
3. ) Immunodeficiency: irradiation leads to immunodeficiency and susceptibility to serious, recurrent infections especially d/t viruses such as CMV and EBV. Autoimmune disorders can also develop.

Question 12

Discuss the etiology of autoimmune diseases in terms of genes, microbes, gender

Answer 12

• Genes:
  a. ) Certain MHC (D Locus) genes confers higher susceptibility to loss of self tolerance
  b. ) PTPN-22 polymorphism
• Microbes: certain infections cause cross-reactivity with self-tissue, increased expression of APC co-stimulation molecules and non-specific B and T cell stimulation (EBV and HIV)
• Gender: higher in females

Question 13

Mechanisms that explain autoimmunity

Answer 13

1. ) Failure of T cell anergy
2. ) Failure of apoptosis of self-reactive cells
3. ) Failure of T cell mediated suppression (by T-regs)
4. ) Cross-reactivity/molecular mimicry (microbes)
5. ) Polyclonal lymphocyte activation
6. ) Emergence of sequestered Ag
7. ) Exposure of cryptic ag determinants

Question 14

SLE.

a. ) Incidence and prevalence
b. ) Genetic factors
c. ) Age and sex association
d. ) Clinical criteria for diagnosis
e. ) Etiology
f. ) Pathogenesis
g. ) Lab diagnosis
h. ) Clinical presentation (include organs affected and corresponding histology)

Answer 14

a. ) 1/700 (1/245 black) females
b. ) HLA-DQ locus
c. ) 9:1 F:M ratio, onset bw 2nd-3rd decade of life
d. ) Malar (butterfly) rash, discoid rash, photosensitivity, oral ulcers, arthritis (2+ joints), serositis (ST elevation in all leads), renal disorder. Neurologic disorder, hematologic disorder (100% of patients), immunologic disorder, ANA abs
e. ) Genes, environment triggers (UV, viruses, drugs, hormones), immune system defect (self-reactive TH escape tolerance, defects in elimination of self-reactive B cells)
f. ) B and T cells specific for self-nuclear antigens, defective clearance of apoptotic bodies = increase burden of nuclear antigens, overall high level of AN IgG antibodies. Type II implicated in hematologic abnormalities and type III implicated in visceral lesions.
g. ) ANAs directed against 4 categories of nuclear ag including DNA, histones, proteins:RNA, nucleolar material.
- Homogenous fluorescence pattern seen in drug induced SLE (anti-histones ab).
- Rim fluorescence pattern seen in SLE with renal involvement and active flares (anti-dsDNA ab).
- Speckled fluorescence pattern seen in SLE (anti-smith ab to ribonucleoprotein).
- Nucleolar fluorescence pattern also seen in SLE.
- Antibodies specific to lupus = anti-dsDNA, anti-smith, anti-blood cells, anti-phospholipid (hyercoagulability in vivo).
h. ) Any organ, commonly skin, joints, kidneys and serous membranes. Presentation is mild dermatological and joint symptoms to life-threatening organ failure and cytopenias. Death d/t renal failure, infection and/or CAD.
- Skin (facial rash, also trunk or extremities): degeneration of basal layer, lymphocytic infiltrates, deposition of IgG and complement at junction
- Joints (hands, knees, ankles commonly): mononuclear inflammatory synovitis, no joint destruction
- Vascular changes: immune complexes deposit in vascular beds and complement activated (type III). If acute = fibrinoid necrosis of arteries/arterioles. If chronic = layered fibrous thickening (onion-skin appearance)
- Kidneys: major cause of morbidity and mortality. Lupus nephritis = glomerular changes with frank necrosis d/t immune complex induced inflammation with proliferation of endothelial/epithelial and mesangial cells. Tubulointerstitial changes also seen.
- Serosal membranes (principally involving pleurae and pericardium): Acutely, exudation of fibrin. Chronically, proliferation of fibrous tissue = adhesions.
- Heart: pericarditis, myocarditis, endocarditis (Libman-Sacks vegetations), accelerated CAD
- Lungs: pleuritis with effusion. Acutely, pneumonitis with alveolar damage, edema and hemorrhage. Chronically, interstitial and vascular fibrosis leading to pulmonary fibrosis and pulmonary HTN.
- CNS: focal deficit, seizures, psychosis. Mild histopathological changes. Vasculitis: small vessel thickening with intimal proliferation, ischemia and microinfarcts

Question 15

Describe forms of Lupus

Answer 15

1. ) SLE: see above
2. ) Drug-induced: drugs such as D-penicillamine, procainamide, hydralazine, isoniazid causes a lupus-like syndrome with pos anti-histones and anti-dsDNA abs with multiple organ involvement, presence of rash, fever, arthralgias and serositis. Remission following cessation of drugs.
3. ) Chronic discoid: variety of skin lesions without systemic features
4. ) Subacute cutaneous: diffuse superficial nonscarring photosensitive lesions with mild systemic disease

Question 16

Sjögrens syndrome

a. ) Age and sex association
b. ) Pathogenesis
c. ) Lab diagnosis
d. ) Clinical presentation (include organs affected and corresponding histology)
e. ) Complications

Answer 16

a. ) Female predominance, especially during middle ages
b. ) Thought that infection by superAg (eg. EBV, HepC or other microbe) triggers CD4 T cell rxn against glandular epithelial cells with induction of polyclonal B cell hyperactivitiy auto-ab production against nuclear antigens.
c. ) ANAs to ribonucleoproteins SS-A (Ro) and SS-B (La) is common. This is associated with speckled pattern. - 75% of cases also positive to RF (rheumatoid factor).
d. ) Primary form (sicca syndrome) with xerostomia (dry mouth) w/fissure, ulcers, dental caries; keratoconjunctiva sicca, nasal septa erosition, dysphagia, dyspareunia (painful intercourse) = ~40% of cases. 25% of cases have extraglandular involvement (interstitial nephritis, pulmonary fibrosis, peripheral neuropathy, synovitis). Other cases (~60%) associated with other autoimmune disorders.
- Glands: activated CD4 T cells, B cells, plasma cells into ducts. Follicle formation with germinal centers. Ductal epithelial hyperplasia leads to obstruction of ducts. Acinar atrophy, fibrosis, fat replacement.
e. ) 40% increased risk of B cell lymphoma

Question 17

Systemic sclerosis

a. ) What is it? Variants?
b. ) Age and sex association
c. ) Pathogenesis
d. ) Lab diagnosis
e. ) Clinical presentation (include organs affected and corresponding histology)

Answer 17

a. ) Autoimmune dz characterized by chronic inflammation, destruction of small vessels and progressive tissue fibrosis. Affects GIT, kidney, heart, lungs, musculoskeletal system. - Diffuse variant: skin involvement at onset, early visceral involvement, rapid progression - Limited variant (CREST syndrome): limited skin involvement of face, forearms and fingers with late visceral involvement. CREST = calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia
b. ) 3:1 F:M, 50-60 yo
c. ) Unknown trigger activates CD4 T cells to secrete cytokines that promote fibrogenesis (TGF-beta, IL-1, PDGF and FGF) and cause microvascular damage. Ultimately this leads to fibrosis. B cells also activated to produce ANAs. d.) Anti-Scl-70 (to topoisomerase: speckled pattern) in mostly diffuse variant case. Anti-centromere (nucleolar and centromere-specific patterns) in mostly CREST (limited variant) case.
e. ) See above for clinical presentation. Cause of death: renal, cardiac, pulmonary, GI dysfunction/failure.
- Skin: Early = edema and CD4 T cell infiltrates. Late = epidermal thinning, dermal appendage fibrosis, subcut calcifications, contractures and mask facies. Vascular endothelial damage and fibrosis (dense collagen) = ischemia and autoamputation of digits.
- GI (90% of cases): Collagen and fibrotic deposition in esophagus = esophageal dysmotility, LES dysfunction = reflux. Small bowel = mucosal thinning, loss of villi/microvilli and submucosal fibrosis = malabsorption.
- Musculoskeletal: Early = nondestructive hyperplasia and inflammation of synovium. Late = fibrosis of synovial and peri-articular CT. In 10 % of cases, myositis with lymphocytic infiltrates and fiber atrophy occurs.
- Renal (2/3rd cases): thickening of interlobular arteries by proliferation of intimal cells = deposition of collagenous or mucinous material = hyaline change. May result in HTN.
- Pulmonary (50% of cases): mild interstitial pneumonitis, alveolar fibrosis = respiratory insufficiency = pulmonary HTN = cor pulmonale
- Cardiac (1/3rd of cases): pericarditis with effusion. Perivascular lymphoid infiltrates leads to arteriolar thickening and interstitial fibrosis and restrictive cardiomyopathy.

Question 18

Rheumatoid arthritis (RA)

a. ) Age and sex association
b. ) Genetic factors
c. ) Pathogenesis
d. ) Lab diagnosis
e. ) Clinical presentation (include organs affected and corresponding histology)

Answer 18

a. ) 3-5:1 F:M, any age commonly 40-70s
b. ) HLA-DRB1, PTPN22
c. ) Antigenic trigger unknown. Initial synovitis with ongoing autoimmune rxn mediated by activated CD4 T cells which produce cytokines that activate macrophages and other immune cells that release degradative enzymes and promote inflammation. IL-1 leads to proliferation of synovial cells and fibroblasts. TNF leads to leukocyte recruitment. Production of rheumatoid factor, which is an IgM auto-ab to Fc region of IgG. Anti-CCP (citrulinnated peptides) or T cell response to CCP contributes to chronic RA. Ultimately pannus formation; destruction of cartilage and bone, fibrosis and ankylosis (stiffness of joint). Vasculitis d/t immune complexes (RF-IgF).
d. ) Loss of joint space via imaging, extra-articular nodules (skin, lungs, spleen, heart), rheumatoid factor
e. ) Mild discomfort to progressive disability. Features include: malaise, fatigue, pain, swelling, stiffness and deformity of small and large joints. Cause of death = amyloidosis, vasculitis, drug therapy complications: bleeding/infection.
- Joint: non-suppurative proliferative destruction synovitis, edema, synovial cell hyperplasia, stromal and perivascular infiltrates. Fibrin deposites on synovial surface. Articular cartilage erosion and osteoclastic destruction of subchondral bone
- Extra-articular lesions (25% of cases): granulomatous inflammation= central fibrinoid necrosis of collagen surrounding macrophages.

Question 19

What is juvenile idiopathic arthritis? Include symptoms, organs involved, variants, diagnosis.

Answer 19

• Occurs in children less than 16 yo with 2:1 F:M ratio. Symptoms = large joint oligoarthritis – knees, wrists, elbows, ankles; pericarditis, myocarditis, pulmonary fibrosis, glomerulonephritis.
• Still’s disease variant = febrile illness with hepatosplenomegaly, rash and leukocytosis.
• ANA pos, no RF factor or nodules

Question 20

What is MCTD? Diagnosis.

Answer 20

• Syndrome with overlapping features of SLE and systemic sclerosis. Distinctive d/t minimal renal disease and good response to steroid therapy.
• Anti-U1RNP (ribonucleoprotein)

Question 21

Correlate each of the following patterns of immunofluorescent staining for ANAs with the specific antibody represented by each, and disease(s) associated with each:

a. ) homogenous (diffuse)
b. ) rim (peripheral)
c. ) speckled
d. ) nucleolar

Answer 21

a. Homogenous = anti-dsDNA, anti-histones – seen in drug-induced SLE
b. Rim = anti-dsDNA – seen in SLE with renal involvement and disease flares
c. Speckled = anti-histones, anti-RNPs, anti-Smith (Sm) – seen with SLE (anti-Sm), systemic sclerosis (specifically anti-Scl-70 in diffuse variant), MCTD, Sjögrens syndrome (anti-SS-A/B)
d. Nucleolar = anti-nucleolar RNA – seen with SLE, systemic sclerosis (specifically CREST/limited variant)

Question 22

Match each of the following autoantibodies with the major autoimmune disease(s) with which it is associated:

a. ) anti-smith (Sm)
b. ) anti-dsDNA
c. ) anti-histone
d. ) anti-SS-A (Ro) and anti-SS-B (La)
e. ) anti-Scl-70
f. ) anti-centromere
g. ) anti-nuclear RNP

Answer 22

a. ) SLE
b. ) SLE (with renal involvement and active flares)
c. ) SLE (drug-induced)
d. ) Sjögren’s syndrome
e. ) Systemic sclerosis (diffuse variant)
f. ) Systemic sclerosis (CREST/limited variant)
g. ) Specific for SLE mostly

Question 23

Agammaglobulinemia of bruton.

a. ) genetics
b. ) etiology
c. ) pathogenesis
d. ) immunologic defect
e. ) clinical features
f. ) methods of diagnosis
g. ) therapeutic approach
h. ) complications

Answer 23

a. ) genetics: XR, most common in males
b. ) etiology: mutation in tyrosine kinase gene (c/s 21)
c. ) pathogenesis: failure of normal pre-B cells to undergo further differentiation d/t defect in Bruton tyrosine kinase responsible for pro/pre-B cell signal transduction. This causes absence of mature B cells in blood and peripheral lymphoid tissue.
d. ) immunologic defect: agammaglobulinemia
e. ) clinical features:
- Following depletion of maternal abs, recurrent sinus, oropharyngeal and respiratory infections (d/t pyogenic bacteria such as Staph, strep, H.influenzae, which are normally cleared by complement via opsonization with abs).
- Susceptible to enteric viruses or protozoa d/t lack of IgA.
f. ) methods of diagnosis: lab work indicating absence of Ig
g. ) therapeutic approach: parenteral Ig replacement
h. ) complications: Increased frequency of autoimmune disorders d/t breakdown in self-tolerance or d/t chronic inflammation (d/t chronic infections).

Question 24

Common variable immunodeficiency

a. genetics
b. etiology
c. pathogenesis
d. immunologic defect
e. clinical features
f. methods of diagnosis
g. therapeutic approach
h. complications and prognosis

Answer 24

a. ) genetics: unclear, equal M:F
b. ) etiology: sporadic and inherited forms, typical onset in 2nd-3rd decades of life
c. ) pathogenesis:
- intrinsic B cell differentiation defect
- abnormal T cell signaling to B cells
- Ultimately, inability of B cells to differentiate into plasma cells. Main feature = hypogammaglobulinemia usually of all Ab classes, occasionally isolated to IgG
d. ) immunologic defect: hypogammaglobulinemia
e. ) clinical features:
- Recurrent bacterial infections of sinuses and respiratory tract
- Increase enteroviral and protozoal infections d/t lack of IgA
f. ) methods of diagnosis: hypogammaglobulinemia
g. ) therapeutic approach: parenteral Ig replacement
h. ) complications and prognosis: increase incidence of autoimmune disorders (such as RA), increase risk of lymphoid cancers and gastric cancers

Question 25

Selective IgA deficiency

a. genetics
b. etiology
c. pathogenesis
d. immunologic defect
e. clinical features
f. methods of diagnosis
g. therapeutic approach
h. complications and prognosis

Answer 25

a. ) genetics: ?, most common primary immunodeficiencies affecting 1/600 Americans
b. ) etiology: familial or acquired (associated with measles or toxo infections)
c. ) pathogenesis: B cell maturation failure?, cellular immunity intact
d. ) immunologic defect: serum/secretory IgA absent or low
e. ) clinical features:
- asymptomatic or recurrent GI, respiratory, GU infections
f. ) methods of diagnosis: low IgA, other isotypes normal, ~40% have anti-IgA ab
g. ) therapeutic approach: parenteral IgA replacement, those with anti-IgA abs will have anaphylactic reaction when transfused
h. ) complications and prognosis: increased tendency to develop autoimmune disorders (such as RA and SLE)

Question 26

Hyper-IgM syndrome

a. genetics
b. etiology
c. pathogenesis
d. immunologic defect
e. clinical features
f. methods of diagnosis
g. therapeutic approach
h. complications and prognosis

Answer 26

a. ) genetics: X-linked pattern in 70% of cases (gene for CD40L), also AR in some cases involving mutation in CD40 gene and AID (activation induced deaminase) enzyme necessary for class switching
b. ) etiology: see genetics
c. ) pathogenesis: Failure of T cells to induce B cell isotype switching from IgM to IgG/A/E as there is a disruption in the CD40L (on TH cells):CD40 (on B cells). Also failure of T cells to activate macrophages to remove intracellular microbes.
d. ) immunologic defect: failure to isotype switch from IgM to A/G/E
e. ) clinical features: - Recurrent pyogenic infections - Infections by intracellular organisms
f. ) methods of diagnosis: IgM normal or elevated, other isotypes absent
g. ) therapeutic approach: bone marrow transplant, Ig replacement therapy
h. ) complications and prognosis - IgM reactions against blood cells = autoimmune lysis - Hyperplastic accumulations of IgM B cells in GI tract lymphoid tissue – can be fatal

Question 27

DiGeorge Syndrome.

a. genetics:
b. etiology
c. pathogenesis
d. immunologic defect
e. clinical features
f. methods of diagnosis
g. therapeutic approach
h. complications and prognosis

Answer 27

a. ) genetics: ~ 90% show micro-deletion of band on c/s 22 (CATCH-22), part of spectrum of disorders, 1:1 M:F
b. ) etiology: partial or complete interruption of 3rd/4th pharyngeal pouch development
c. ) pathogenesis: aplasia or hypoplasia of thymus = T cell deficiency, also aplasia or hypoplasia of parathyroids = hypoparathyroidism = hypocalcemia
d. ) immunologic defect: T cell deficiency
e. ) clinical features:
- abnormalities of face (low-set ears, midline clefts, small mandible) and cardiac (VSD, right subclavian from pulmonary artery)
- hypocalcemia
- viral and fungal infections common
f. ) methods of diagnosis: normal Ig levels, low/no T cell numbers
g. ) therapeutic approach: if hypoplasia of thymus, immune defect resolves by age 5. If aplasia, requires thymus transplant.
h. ) complications and prognosis: cardiac anomalies usually result in morbidity and mortality

Question 28

SCID (severe combined immunodeficiency).

a. genetics
b. etiology
c. pathogenesis
d. immunologic defect
e. clinical features
f. methods of diagnosis
g. therapeutic approach
h. complications and prognosis

Answer 28

a. ) genetics: 50-60% of cases XR mutation in gamma-chain subunit of cytokine receptor, AR form with defects in adenosine deaminase or class II MHC expression
b. ) etiology: defect of gamma-chain of cytokine receptor, defect in adenosine deaminase, failure of class II MHC expression
c. ) pathogenesis: Defect in gamma-chain subunit in cytokine receptor = failure of IL function = impaired lymphocyte development, proliferation and function. ADA = accumulation of lymphotoxic metabolites. Failure of class II MHC = impaired T cell recognition of antigen.
d. ) immunologic defect: severe T cell defect (more common), more rare = T and B cell defect
e. ) clinical features:
- Early onset (~3 months) with thrush, diaper rash and failure to thrive
- Recurrent infections from all microbe classes
f. ) methods of diagnosis: ? low B / T cell count ?
g. ) therapeutic approach: bone marrow transplantation, gene therapy for ADA, vector for gamma-chain of cytokine receptor
h. ) complications and prognosis: Bubble boy
- Opportunistic infection causing death typically within first year

Question 29

Wiskott-Aldrich Syndrome

a. genetics
b. etiology
c. pathogenesis
d. immunologic defect
e. clinical features
f. methods of diagnosis
g. therapeutic approach
h. complications and prognosis

Answer 29

a. ) genetics: X-linked defect in WASP gene (WA syndrome protein)
b. ) etiology: WASP gene defect
c. ) pathogenesis: WA protein responsible for maintenance of cytoskeleton and linkage of membrane receptors to cytoskeleton. This leads to progressive depletion of T and B cells.
d. ) immunologic defect: impairment of both cellular and humoral immunity (Ab levels normal or elevated with exception of IgM, which is low), abs all decrease over time
e. ) clinical features: immunodeficiency, thrombocytopenia, eczema
- Hemorrhagic diathesis (tendency)
- Recurrent respiratory infections
- Pyogenic bacteria, virus and fungi infections
f. ) methods of diagnosis: see immunologic defect
g. ) therapeutic approach: bone marrow transplant
h. ) complications and prognosis: death without transplant, increase in lymphoid malignancies

Question 30

Discuss AIDs in terms of:

a. ) Definition and diagnostic criteria
b. ) Risk factors
c. ) Etiology
d. ) Pathogenesis
e. ) Immunologic defects
f. ) Clinical presentation
g. ) Associated infections and neoplasms
h. ) Therapeutic approaches
i. ) Complications and prognosis

Answer 30

a) Definition and diagnostic criteria: HIV infection that targets immune system and CNS causing immunosuppression, allowing for opportunistic infections, rare neoplasms and neurologic abnormalities
b) Risk factors: homosexual/bisexual males, heterosexual contact, IV/subcut drug users, recipients of transfused blood/blood products
c) Etiology: HIV infection
d) Pathogenesis:
1. ) mechanisms of T cell loss
- Virus replication in infected CD4 cells leads to death of cell (cytopathic effect)
- T cell activation leads to activation-induced apoptosis
- Expression of HIV peptides on CD4 cells leads to CTL-induced apoptosis
- Ultimately: decreased response to soluble antigens, decreased lymphokine secretion, decreased killing of tumor cells by NK cells, decreased specific cytotoxicity, depressed Ig production in response to new antigen, macrophages(decreased chemotaxis, reduced IL-1 secretion, poor antigen presentation)
e) Immunologic defects:
- CD4 T cell lymphopenia
- Polyclonal B cell activation with hypergammaglobulinemia; however, impaired B cell response to new ag
- Altered macrophage function with decrease MHC II expression and ag presentation
f) Clinical presentation
- Early = viremia, fever, sore throat, myalgias
- Middle/chronic = lymphadenopathy, weight loss, night sweats, fatigue, fever +- rash
- Final/crisis = fever, fatigue, weight loss, opportunistic infections, neoplasms
g) Associated infections and neoplasms
- Toxo (brain), pneumocystosis (lungs), candidiasis, cryptococcosis, coccidiomycosis, histo, mycobacteriosis, CMV (lungs), HSV, VZV
- Neoplasms: KS (HHV-8), B cell lymphoma, lymphomas of brain, invasive carcinomas of cervix and anus
h) Therapeutic approaches: inhibitors (fusion/RT/integrase/protease)
i) Complications and prognosis: opportunistic infections, neoplasms

Question 31

What is amyloidosis?

Answer 31

• Group of disorders characterized by EC deposition and accumulation of abnormal, misfolded protein material generically termed amyloid. These depositions may occur locally in one organ or tissue or systemically in many organs.

Question 32

What is amyloid? Components of each.

Answer 32

• Amyloid is abnormally misfolded protein with beta-pleated sheet configuration that consists of:
  a. ) Fibrils (majority) with +15 distinct types. Most common are amyloid light chain type and amyloid associated types.
  b. ) P component (glycoprotein)

Question 33

What is the AL amyloid protein? Where is it found?

Answer 33

• It is the fibrillar component of amyloid derived from plasma cells and seen with monoclonal B cell proliferation or plasma cell disorders (in some cases of multiple myeloma) as a result of limited immunoglobulin light chain (lambda – L) proteolysis.
• Found in heart, GI tract, peripheral nerves, skin and tongue.

Question 34

What is the AA amyloid protein? Where is it found?

Answer 34

• It is the fibrillar component of amyloid derived from limited proteolysis of the SAA protein (acute phase protein) normally produced by the liver in times of chronic inflammatory states.
• This is seen in RA, renal cell carcinoma, IBD, Hodgkin’s lymphoma and subcut drug abuse. Systemic distribution, tends to involve kidneys, liver, spleen, LNs and adrenals.

Question 35

What is the ATTR protein? Where is it found?

Answer 35

• It is the fibrillar component of amyloid derived from aggregation of mutant transthyretin protein, which in normal form is responsible for thyroxine and retinol transport.
• Seen in polyneuropathy (in peripheral nerves) and in senile systemic amyloidosis.

Question 36

What is alpha-beta2 microglobulin? Where is it found?

Answer 36

• Beta-2 microglobulin is normal serum protein and component of MHC class I. The amyloid protein tends to deposit in synovial tissues, joints and tendon sheaths leading to destructive arthropathy in ppl undergoing hemodialysis

Question 37

What is Abeta protein?

Answer 37

• Amyloid beta protein is found plaques and cerebral vessel walls in Alzheimer’s dz leading to cerebral hemorrhage in some cases.

Question 38

Describe amyloid in terms of:

a. ) distribution (organ and architecture)
b. ) gross appearance
c. ) microscopic and ultrastructural appearance
d. ) tinctorial properties

Answer 38

a. ) many organs involved, including kidney, spleen, liver, heart
b. ) iodine stain of gross specimens reveals brown color
c. ) When staining with Congo red and subjecting to polarized light, shows apple green. H&E shows pink material. EM shows non-branching fibrils in parallel and interlacing patterns. Specific organs: kidneys shows glomerular deposits; spleen shows follicular deposits or sinusoidal deposits; liver shows deposits in space of Disse; heart shows subendocardial or interstitial deposits.
d. ) ???

Question 39

Describe clinical course of amyloidosis

Answer 39

• Depends on extent of deposits and organs involved.
• If in circulation, can lead to ischemic atrophy or organ
• In kidneys: leads to nephrotic syndrome and renal failure
• Cardiac: conduction disturbance, restrictive cardiomyopathy, CHF
• GI: macroglossia, dysphagia, speech abnormalities, malabsorption
• Presentation as localized tumor can be misdiagnosed for tumor - Systemic has poor prognosis