Block 1 Immunopathology Flashcards
(136 cards)
1
Q
Types of hypersensitivity rxns
A
1- immediate
2- Ab-mediated
3- Ag-Ab complex
4- T-cell mediated/ delayed type
2
Q
Timing of type 1 HS rxn
A
Immediate/initial: 5-30 min post exposure, subsides in 60 min
Late phase: 2-24 hrs lasting days
3
Q
Cells of type 1 HS rxn
A
Im: mast cell
Late: eos, neutros, basos, monocytes, CD4+ T-cells
4
Q
Risk factors for type 1 HS rxn
A
Atopy (predisposition bc of increase IgE or IL-4 producing TH2 cells, family hx)
Non-atopic: temp extremes/exercise - no IgE or TH2, but sensitive mast cells to non-immune stimuli
5
Q
Genetic factors in type 1 HS rxn
A
Genetically determined, family hx important
5q31: cytokines IL-3,4,5,9,13
6p: close to HLA complex
6
Q
Type 2 HS rxn mechanism
A
IgM or IgG Abs -> classical complement -> C3b, C4b -> MAC & lysis
ADCC: no phagocytosis but cell lysis; monos, neutros, eos, NK cells
7
Q
Myasthenia gravis & Graves disease
A
Type 2 HS rxn
MG: Ab against ACh-R -> downregulates ACh-R -> mm weakness, paralysis
GD: Ab against TSH-R -> hyperthyroidism
8
Q
AI hemolytic anemia & AI thrombocytopenic purpura
A
Type 2 HS by opsonization & phago of red cells (AHA) or platelets (ATP)
AHA: Ab against Rh antigen on RBC -> hemolysis, anemia
ATP: Ab against GP3b/2a integrin -> bleeding
9
Q
Pemphigus vulgaris
A
Type 2 HS by Ab-mediated activation proteases, disruption intercellular adhesions
Ab to epidermal cadherins -> skin vesicles/bullae
10
Q
ANCA vasculitis
A
Type 2 HS by neutro degran & inflam
Ab to neutro granule proteins -> vasculitis
11
Q
Goodpasture syndrome
A
Type 2 HS by complement and FcR-mediated inflam
Ab to noncollagen protein in BM kidney glomeruli, lung alveoli -> nephritis, lung hemorrhage
12
Q
Acute rheumatic fever
A
Type 2 HS by inflam, MF activation
Ab to strep cell wall Ag cross-rx with myocardial Ag -> myocarditis, arthritis
13
Q
Insulin-resistant diabetes
A
Type 2 HS by Ab inhibiting binding of insulin
Ab to insulin-R -> hyperglycemia, ketoacidosis
14
Q
Pernicious anemia
A
Type 2 HS rxn by neutralization of IF, decreasing absorption of B12
Ab to IF of gastric antrum parietal cells -> abnormal erythropoiesis, anemia
15
Q
Type 3 HS mechanism
A
Ag-Ab complex elicits inflam at site of deposition; systemic or localized
16
Q
SLE
A
Type 3 HS rxn
Ag = nuclear antigens -> nephritis, skin lesions, arthritis, etc.
17
Q
PSGN
A
Type 3 HS rxn
Ag = strep cell wall Ag “planted” in glomerular BM -> nephritis
18
Q
Polyarteritis nodosa
A
Type 3 HS rxn
Ag = hep B virus Ag in some cases -> systemic vasculitis
19
Q
Reactive arthritis
A
Type 3 HS rxn
Ag = bacterial Ag (e.g. Yersinia) -> acute arthritis
20
Q
Serum sickness
A
Type 3 HS rxn
Ag = various proteins like foreign serum protein (horse anti-thymocyte globulin) -> arthritis, vasculitis, nephritis
21
Q
Arthus reaction
A
Type 3 HS rxn
Ag = various foreign proteins that diffuse into vascular wall & binds preformed Ab -> precipitate complex in vessel wall -> fibrinoid necrosis
*Ischemia made worse by superimposed thrombus
22
Q
Morphology of type 3 HS rxn
A
H&E: necrotic tissue and deposits of immune complexes, complement, plasma protein -> smudgy eosinophilic deposit
Immunofluorescence: granular lumpy deposits of Ig and complement
EM: electron-dense deposits along glomerular BM
23
Q
Type 1 DM
A
Type 4 HS rxn
T-cell directed to panc islet beta cells -> insulitis (islet inflam), destruction of islet beta cells, diabetes
24
Q
MS
A
Type 4 HS rxn
T-cell directed to protein Ag in CNS myelin -> demyelination in CNS with perivascular inflammation, paralysis, ocular lesions
25
RA
Type 4 HS rxn
| T-cell directed to unknown Ag in joint synovium -> chronic arthritis with inflam, destruction articular cartilage, bone
26
Crohn disease
Type 4 HS rxn
| T-cell directed to unknown Ag (role for commensal bacteria) -> chronic intestinal inflam, obstruction
27
Peripheral neuropathy/ Guillan-Barre syndrome
Type 4 HS rxn
| T-cell directed to protein Ag of peripheral nerve myelin -> neuritis, paralysis
28
Contact sensitivity (dermatitis)
Type 4 HS rxn
| T-cell directed to various environmental Ag (poison ivy urushiol) -> skin inflam with blisters
29
Cytokines involved in type 4 HS rxn
APC -> IL-12 -> activate TH1 cell
TH1 -> IFN-g, TNF -> activate MF; & IL-2 to self-activate
TH17 -> IL-17, IL-22 -> inflammation
30
Important genes for autoimmunity
PTPN-22: most frequently implicated in AI
NOD-2 polymorphisms: cytoplasmic sensor of microbes
IL-2-R (CD25) & IL-7-R alpha chains
31
Methods of triggering AI
Induction of costimulators on APCs by microbe; molecular mimicry
32
SLE antibodies & susceptibility
Numerous, especially ANA (anti-nuclear)
| F>M, childbearing age, AA & Hispanics 2-3x higher
33
Criteria for SLE (must meet 4 of 11)
Malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal disorder, neurologic dis, hematologic dis, immunologic dis, ANAs
34
Types of ANAs possibly seen in SLE
Anti- DNA, histone, nonhistone protein bound to RNA, nucleolar antigen
35
Anti-dsDNA Abs
Often seen in SLE
36
Anti-histone Abs
Drug-induced lupus, and SLE
37
Anti-Smith (core proteins of small nuclear RNP particles) antibody
SLE
38
Anti-RNP/U1RNP Ab
Systemic diffuse & limited (CREST) sclerosis
39
Anti-RNP Abs: SS-A (Ro) and SS-B (La)
Sjögren syndrome
40
Anti-DNA topoisomerase Ab (Scl-70)
Diffuse systemic sclerosis
41
Anti-centromere Abs
CREST (limited scleroderma)
42
Anti-histidyl-tRNA synthetase Ab Jo-1
Inflammatory myopathies
43
Indirect immunofluorescence: homogenous or diffuse nuclear staining
Chromatin, histones, dsDNA (sometime)
44
Indirect immunofluorescence: rim or peripheral staining
dsDNA
45
Indirect immunofluorescence: speckled pattern
Most commonly observed but least specific: Abs to non-DNA nuclear constituents, including Sm-antigen, RNP, SS-A & SS-B reactive antigens
46
Indirect immunofluorescence: nucleolar pattern
Few discrete spots within nucleus: anti-RNA Abs (systemic sclerosis)
47
Anti-phospholipid-B2-glycoprotein complex Abs
Bind cardiolipin Ag -> false positive syphilis test in lupus patients
Interferes with in vitro clotting tests (aka Lupus anticoagulant): increases PTT, hypercoagulable state (spont miscarriages, venous and arterial thromboses)
48
Genetic risk for SLE
HLA-DQ locus (anti-dsDNA, anti-Sm, anti-PL Abs)
| Early complement component deficiency: C2, C4, C1q (can't remove Ag-Ab complex)
49
Pathogenesis of SLE
Failure of self-tolerance in B cells (make ANAs), CD4+ helper T for nucleosomal Ag also escape tolerance
? role of type 1 IFNs
TNF-like BAFF promotes B-cell survival
50
Environmental factors for SLE
UV light exacerbates disease (may induce apoptosis, alter DNA to make immunogenic)
Sex hormones (pregnancy, menses)
Drugs: hydralazine, procainamide, d-penicillamine -> SLE-like response
51
Mechanism of tissue injury in SLE
Immune complexes (type 3 HS), autoAb to RBC, WBC, platelets
52
LE (lupus eryth.) cell
Neuto or MF that has engulfed the denatured nucleus of an injured cell
53
Acute necrotizing vasculitis
Can be b/c of SLE, fibrinoid deposits in tissue b/c immune comlpexes -> eventual fibrosis
54
Morphologic classes of lupus nephritis
1: minimal mesangial
2: mesangial proliferative
3: focal proliferative
4: diffuse proliferative
5: membranous
* None is specific for lupus
55
Mesangial lupus glomerulonephritis (GN)
Mesangial cell proliferation, immune complex deposition without involvement of glomerular capillaries; increase in mesangial matrix & # cells
56
Focal proliferative GN
57
Diffuse proliferative GN
Global, >50% glomeruli involved; hematuria & proteinuria, hypertension, mild-severe renal insufficiency; most severe form of lupus nephritis & most common
58
Membranous GN
Diffuse thickening of capillary walls ("wire loop"), severe proteinuria or nephrotic syndrome
59
Skin morphology of SLE
H&E: vacuolar degeneration of epidermal basal layer, dermal edema, perivascular inflam, vasculitis w/ fibrinoid necrosis
Immunofl: Ig, complement deposits at dermo-epidermal jxn (also seen in scleroderma, dermatomyositis)
60
SLE heart morphology
Pericarditis, non-bacti verrucous endocarditis, other serial cavity involvement, warty deposit on either side of any valve, CAD
Acute: fibrinous exudate
Chronic: thickened, opaque, shaggy fibrous tissue
61
SLE joint morphology
Nonerosive synovitis, little deformity, different from RA, but painful joints
62
SLE CNS morph
Not clear pathogenesis; psychoses or convulsions, ? Ab against synaptic membrane protein, ? acute vasculitis vs. intimal proliferation -> occlusion small vessels
63
SLE spleen morphology
Splenomegaly, capsular thickening, follicular hyperplasia
| Onion-skin lesions (central arteries concentric intimal/SM hyperplasia)
64
SLE lung morph
Pleuritis, pleural effusion (50% pts), alveolar injury w/ edema/hemorrhage, chronic interstitial fibrosis & 2' pulm HTN
65
SLE bone marrow, lymph node morph
BM: hematoxylin bodies (also in other organs)
LN: enlarged, hyperplastic follicles, necrotizing lymphadenitis, "infections"
66
Course & prognosis SLE
Variable, flare-ups and remissions, acute cases rarely -> death
Tx: corticosteroids, immunosuppressants
90% 5-y, 80% 10-y survival
Most common COD: renal failure, infections
67
Chronic discoid lupus erythematosus
Skin manifestations of SLE, rarely systemic
Skin plaques, variable edema, scaliness, follicular plugging
Skin atrophy w/ elevated red border (face, scalp)
68
Immune characteristics of discoid lupus
35% positive ANA test, rarely dsDNA Abs
| Ig & C3 at dermoepidermal junction (like SLE)
69
Subacute cutaneous lupus
Predominant skin involvement, widespread superficial rash w/o scarring (usually), mild systemic symptoms
70
Subacute cutaneous lupus immune characteristics
Abs to SS-A Ag and HLA-DR3 genotype
71
Drug-induced lupus: drugs causing it, symptoms
```
Hydralazine, procainamide, INH, d-penicillamine
Multiple organs (renal and CNS uncommonly), only ⅓ patients with ANAs have symptoms, which remit with drug withdrawal
```
72
Drug-induced lupus: immune characteristics
ANAs, anti-histone Abs, rarely anti-dsDNA
73
Rheumatoid arthritis
Chronic inflammation affecting primarily jj, sometimes extra-articular tissues, skin, blood vessels, lungs, heart
Due to unknown synovial Ag
74
Sjögren syndrome
Immune-mediated destruction of lacrimal and salivary glands (keratoconjunctivitis sicca, xerostomia)
75
Sicca syndrome
```
Primary = isolated disorder
Secondary = more common, in association with other AI disorders like lupus, RA
```
76
Mechanism of Sjögren syndrome
Lymphocytic infiltration and fibrosis of lacrimal and salivary glands (CD4+ Th, B, plasma cells)
77
Immune characteristics of Sjögren syndrome
75% have rheumatoid factor (reactive with self-IgG)
50-80% ANAs
90% Anti-SS-A (Ro), SS-B (La)
*None are diagnostic
78
HLA associations with Sjögren syndrome
Primary: H8, DR3, DRW52; DQA1,B1 loci
| Anti-SS-A or B Abs: DQA1,B1 loci
79
Possible pathogenesis of Sjögren syndrome
Aberrant T- and B-cells, ? triggered by viral infection of salivary glands -> cell death = released tissue self-Ag (? a-fodrin cytoskeletal protein, ? viruses EBV, HCV, human retrovirus T-cell lymphotropic virus type 1)
80
Morphology of Sjögren syndrome
Periductal, perivascular lymphocytic infiltration; ductal epithelium hyperplasia then atrophy/scar
81
Comorbidities/ risk factors of Sjögren syndrome
```
Women 50-60 years old
Increased risk lymphoma (40x)
Keratoconjunctivitis
Xerostomia
Bronchitis, pneumonia
⅓ extra glandular disease (SS-A Ab), rarely glomerular lesions, tubular fxn defect frequent (renal tubular acidosis, uricosuria, phosphaturia, tubulointerstitial nephritis)
60% patients have other AI disorder
```
82
Mikulicz syndrome
Lacrimal, salivary gland inflam from any etiology (sarcoidosis, leukemia, lymphoma, AI, etc.)
83
Essential test to dx Sjögren syndrome
Biopsy of the lip (minor salivary glands)
84
Characteristics of systemic sclerosis
Chronic inflammation (AI), widespread damage to small blood vessels, progressive interstitial and perivascular fibrosis in skin and multiple organs
85
Most commonly affected organs in systemic sclerosis & COD
Skin, GI, kidneys, heart, mm, lungs
May be confined to skin for years, usually progresses to visceral involvement
COD: renal or cardiac failure, pulmonary insufficiency, intestinal malabsorption
86
Diffuse vs. limited systemic sclerosis
Diffuse: widespread skin involvement at onset
Limited: skin confined to fingers, forearms, face, late visceral involvement, benign clinical course
87
CREST syndrome
Occurs in some patients with limited systemic sclerosis
Calcinosis
Raynaud's phenomenon
Esophageal dysmotility
Sclerodactyly
Telangectasia
*Rare/late inv of viscera, esophagus, pulmonary HTN, biliary cirrhosis
88
Antibodies associated with CREST syndrome
Anti-centromere antibodies
89
Causes of extensive fibrosis in systemic sclerosis
? exogenous agent trigger activates T/B cells, other leukocytes; cytokines/trigger -> blood vessel injury, narrowing; cytokines & ischemia -> fibroblasts increase ECM deposition
90
ANAs associated with systemic sclerosis
DNA-topoisomerase 1 (anti-Scl-70): highly specific, 10-20% patients, increases pulmonary fibrosis, peripheral vascular disease
Anti-centromere Ab: 20-30% patients, CREST or limited cutaneous SS
Rarely, pts have both
91
Clinical features of systemic sclerosis
Raynaud's phenomenon, dysphagia, abdominal pain/ weight loss/ anemia, malignant HTN, mild proteinuria, pulmonary disease (major COD b/c renal treatments effective)
92
Inflammatory myopathies
Immune-mediated injury and inflam of mainly sk mm
E.g. dermato-, poly-, inclusion body -myositis
Occurs alone or with other immune diseases
93
Mixed connective tissue disease
Mixed clinical features of SLE, SScl, polymyositis
U1-RNP-Abs
Modest renal involvement (responds to c-steroids)
Can evolve to SLE, SScl
Complications: pulmonary HTN, renal disease ~SScl
94
Polyarteritis nodosa, other vasculitides
Noninfectious, involve any type of vessel, many clinical settings
PN: necrotizing inflam of vessel walls, strong evidence of immunological pathogenetic mechanism
95
Primary immunodeficiencies
Genetically determined
Affect adaptive (T, B, or T/B) & innate immunity (NK, phagocytes, complement)
Most manifest in infants with recurrent infection
96
Bruton's X-linked agammaglobulinemia mechanism
Failure of B cell dev d/t Btk mutation
| On Xq21.22: no light chains = pre-B cell R can't deliver signal to continue maturation
97
Bruton's X-linked agammaglobulinemia clinical
Appears ~6 mos b/c maternal IgG
| Recurrent bacterial URI, viral infections (GI), polio vaccine -> poliomyelitis, Giardia lamblia (dec IgA)
98
Bruton's X-linked agammaglobulinemia lab features
Absent/dec B cells, Ig, plasma cells
Normal pre-B cells in BM, normal T-cell med rxns
Underdeveloped germinal centers
99
Bruton's X-linked agammaglobulinemia comorbidities and tx
AI diseases increase in frequency - paradoxical, arthritis, dermatomyositis, breakdown of self-tolerance ? d/t chronic infxns; *Paradoxical
Tx: Igs
100
Common variable immunodeficiency characteristics
Hypogammaglobulinemia, affecting all the classes or only IgG, sx in later childhood/ adolescence
M=F, sporadic and inherited, relatives have high incidence of IgA def
101
CVID comorbidities
High fx AI diseases (20%, including RA)
| Inc risk of lymphoid malignancy, and gastric cancer
102
CVID morphology
Hyperplastic B-cell areas in lymphoid tissues d/t defective regulation (normal feedback inh by IgG absent)
103
Mechanism of CVID
Intrinsic B cell defects and abnormal Th cell-mediated activation of B cells
BAFF-R, ICOS
104
CVID clinical
Recurrent sinopulmonary pyogenic infections, ~20% recurrent herpesvirus infxn, enterovirus -> meningoencephalitis, G. lamblia diarrhea
105
IgA deficiency characteristics
1/600 of Euro descent in US
Low levels serum and secretory IgA
Familiar/acquired (toxoplasmosis, measles)
106
IgA def symptoms
Asymptomatic: decreased mucosal defense, resp infxn, GI, UTI
Symptomatic: recurrent sinopulmonary infxns, diarrhea
107
IgA def mechanism
Impaired differentiation of naive B cells to IgA-producing cells
*BAFF gene
108
IgA def comorbidities
May also be IgG2,4 def = prone to infxns
Inc risk resp tract allergy, AI disease (SLE, RA)
Assc. with CVID
*Fatal anaphylaxis with blood transfusion
109
Hyper IgM syndrome mechanism
Make IgM, no class switching b/c defective Th cells
X-linked (70%): CD40L gene on Xq26
AR: CD40 gene, AID (DNA editor)
110
Hyper IgM comorbidities
Can cause AI hemolytic anemia, thrombocytopenia, neutropenia
Recurrent pyogenic infxns (low level IgG to opsonize)
Pneumocystitis jiroveci pneumonia
111
DiGeorge syndrome
Dev failure of 3,4 pharyngeal arches: thymus, parathyroids, thyroid clear cells
Abnormal mouth, ears, facies
22q11 deletion in 90% pts or T-box TF gene family
112
DiGeorge clinical
T-cell mediated immunity impaired = fungal, viral infxns
| Also tetany, congenital defects of heart and great vessels
113
DiGeorge lab
Depleted T cell zones in tissues (paracortex in LN, periarteriolar sheath of spleen)
Normal or dec Ig levels
114
SCID characteristics, clinical, tx
Humoral and cell-mediated problems
Sx in infants: oral thrush, diaper rash, failure to thrive, morbilliform rash
Numerous severe infxns
BM transplant in 1 year, ? retroviral gene therapy
115
SCID genetics
X-linked: 50-60% cases, mutation in y-chain subunit of cytokine receptors
AR: ADA def -> ? accumulation toxic products; also other AR forms
116
SCID lab
Thymus small, no lymph cells; lobules of undiff epithelial cells (fetal thymus, X-linked); hypoplastic lymphoid tissue in all T or T/B cell areas
117
Wiskott-Aldrich syndrome symptoms, genetics, tx
Immunodeficiency with thrombocytopenia and eczema
Xp11.23 link membrane receptors
Inc risk lymphoma
Tx: BM transplant
118
WAS lab
Thymus normal, progressive 2' depletion T-cells, variable loss cellular immunity
*No Abs to polysaccharide Ags, poor response to protein Ags
Dec IgM, normal IgG, inc IgA & E
119
C2 deficiency
Little or no increase in infection susceptibility, but inc incidence of SLE-like AI disease
*Alt pathway adequate b/c properdin, factor D def rare
Recurrent pyogenic infxns
120
C3 deficiency
Needed for class, alt pathways = susc to serious recurrent pyogenic infxns
Inc risk immune-complex mediated glomerulonephritis -> MAC def = susc to Neisseria
121
Hereditary angioedema
AD: C1 inhibitor def
Edema in skin, larynx, GI tract -> life-threatening asphyxia or n/v/d after minor trauma/ emotional stress
Tx: C1-I concentrates
122
PNH
Mutation in GPI linkage enzymes (CD55/DAF and CD59)
| Uncontrolled complement act -> hemolysis
123
Factor H mutations
Complement regulator; 10% of hemolytic uremic syndrome; microvascular thrombosis in kidneys
124
Amyloid
Pathogenic proteinaceous substance deposited in extracellular space in various tissues/organs
125
Amyloidosis onset, diagnosis, lab findings
Insidious onset, biopsy required for dx
On H&E, amorphous eosinophilic, hyaline, extracellular substance accumulating and encroaching on adjacent cells -> atrophy
Congo red stain has apple green birefringence d/t amyloid polarization
126
Chemical makeup of amyloid
95% fibril proteins, 5% P component, other GPs
| 3 common forms: AL, AA, A-beta
127
AL amyloid
Amyloid light chain: Ig light chain produced by plasma cells
| lambda > kappa
128
AA amyloid
Amyloid-assc: unique non-Ig protein synth by liver
| SAA = inflam state as part of acute phase response
129
A-beta amyloid
beta amyloid precursor protein -> cerebral lesions in AD
130
Other proteins in amyloid deposits
TTR, B2-microglobulin, prion disease of CNS
| Other minor include serum amyloid P component, proteoglycans, highly sulfated glycosaminoglycans
131
Transthyretin (TTR)
Normal serum protein transports thyroxine, retinol
Mutant form in familial amyloid polyneuropathies
Dep in heart of aging: senile systemic amyloidosis
132
B2-microglobulin
Normal serum protein; amyloid fibril subunit AB2m in hemodialysis assc amyloidosis
133
2 categories of amyloid proteins
Normal: inherent tendency to fold improperly, associate, and form fibrils *when production inc
Mutant: prone to misfolding and aggregation
134
Amyloidosis morphology
```
Enlarged, firm, waxy spleen
Congo red birefringence
Spleen deposits are sago (deep in splenic follicles) or lardaceous (in sinuses, CT, red pulp)
Liver replaced, fxn ok
Heart conduction sys
Tongue deposits -> macroglossia
```
135
Amyloidosis clinical
Proteinuria, nephrotic syndrome, failure, uremia; cardiac insidious CHF, conduction, disturbances, arrhythmias, restrictive pattern
GI: asx, malabsorption, diarrhea (tongue, speech, swallowing probs)
136
Amyloid dx and prognosis
Dx: biopsy of kidney, rectum, gingiva, fat pad -> CONGO RED stain
Serum/urine protein electrophoresis for light chains
Radiolabeled SAP - follow for binding to deposits
Prog: poor, 2 yr median survival rate, worse if plasma cell-assc myeloma
