Immunopathy III Flashcards
1
Q
SLE incidence
A
- predominantly affects female (9F:1M ratio
- 1/700 females affected
- 1/245 and more severely in black females
- occurs from menarche-menopause (typically in 2nd or 3rd decade
2
Q
SLE multifactorial etiology
A
- Genetic = HLA-DQ locus
- Environment = UV radiation, viruses, drugs, hormones
- Immune response:
- -> Self-reactive helper T cells escape tolerance and drive autoantibody production by B cells; defects in elimination of self-reactive B cells peripherally and in bone marrow
3
Q
lupus autoantibodies
A
- Hallmark of disease = autoantibodies called antinuclear antibodies (ANAs), reflect loss of tolerance, act as mediators of cell/tissue injury
- ANAs are directed against 4 categories of nuclear Ag: DNA, histones, proteins bound to RNA, nucleolar Ag
- immunofluorescent staining patterns suggest underlying disease and level of disease activity
4
Q
SLE Effects
A
- any organ may be involved
- Type III mechanism observed in visceral lesion (DNA - anti-DNA immune complexes), especially in kidneys
- Type II mechanism occurs against blood cells in which Abs opsonize red and white cells and platelets promoting phagocytosis and lysis
5
Q
SLE effect on Joints
A
- polyarthralgia of hands, knees, ankles is a common manifestation in 90% of cases
- -> arthritis is a clniical criterion
- Mononuclear inflammatory synovitis occurs but without joint destruction
6
Q
SLE effects on skin
A
- Erythematous rash may be found on the face, trunk, or extremities and is often exacerbated by exposure to ultraviolet light (photosensitivity); the malar or butterfly rash across the cheeks and nasal bridge is a clinical criterion
- skin may also show vesicles, macules, papules and ulcers
- Histologically, basal layer degeneration occurs due to deposition of immunoglobulin (IgG) and complement at the dermal-epidermal junction
- -> perivascular lymphocytic infiltrates and immune complex vasculitis
7
Q
SLE effects on Blood vessels
A
- Circulating immune complex (ANAs-nuclear proteins) deposit in vascular beds, activate complement –> acute, damaging inflammatory reaction (Type III)
- Acute vasculitis with fibrinoid necrosis of arteries/arterioles may occur in any tissue
- Chronic lupus shows fibrous thickening of vessels in a layered, onion-skin fashion, often seen in the spleen
8
Q
SLE effects on Kidneys
A
- Major cause of morbidity and mortality, affecting 50-70% of patients
- lupus nephritis is the prototype of immune complex glomerulonephritis (GN)
- mechanism of injury is immune complex deposition in glomeruli, basement membranes, larger blood vessels; also thombosis due to antiphospholipid Ab
- tubulointerstitial changes also occur with immune complex deposits in tubular basement membranes
9
Q
Lupus Nephritis
A
- prototype of immune complex glomerulonephritis (GN)
- glomular changes:
- -> includes frank necrosis, are prominent due to immune complex induced inflammation with proliferation of endothelila, epithelial and mesangial cells
10
Q
what are the 5 patterns of GN
A
- normal = no discernible morphologic abnormality
- mesangial GN
- focal proliferative GN
- duffiuse proliferative GN
- membranous GN
11
Q
SLE effects on serosal membranes
A
- 50% of cases demonstrate inflammation of the serous membranes or serositis, often with effusion, principally involving the pleurae and pericardium
- in the acute form, exudation of fibrin occurs
- chronically, proliferation of fibrous tissue –> thickened membranes, adhesion of lung lobes and of visceral and parietal pleurae
12
Q
SLE effects of Heart
A
- Fibrinous pericarditis with effusion in 25-50% of cases
- myocarditis may reflect severity of disease process in other organs and is characterized by interstitial lymphocytic infiltrates and fibrinoid necrosis of small vessels
- Nonbacterial endocarditis, called libman-Sacks endocarditis = exhibits warty lesions occuring onany valve and on either surface of the affected valve
- accelerated coronary artery disease due to steroid therapy or immune damage.
13
Q
infective endocarditis (IE)
A
- large, irregular DESTRUCTION masses on valve cusps can extend to chordae
14
Q
Rheumatic heart disease (RHD)
A
- small, warty vegetations along lines of closure of valve leaflets
15
Q
nonbacterial thrombotic endocarditis (NBTE)
A
- small, blad vegetations at the line of closure
16
Q
libman-sacks endocarditis (LSE)
A
- small-medium sized vegetations on either/both sides of valve leaflets
17
Q
SLE effects on lungs
A
- pleuritis with effusion occurs in 50% of cases
- pneumonitis from deposition of immune complexes in alveolar septa may occur –> alveolar damage, edema and hemorrhage
- chronic, progressive lupus may cause interstitial fibrosis
- pulmonary vascular involvement with fibrosis may cause pulmonary hypertension
18
Q
SLE effects on CNS
A
- involvement is common and neurologic disease is a clinical criterion
- varying manifestations: focal neurologic deficit, seizures, neuropsychiatric symptoms (psychosis)
- histopathology mild compared to symptom
- small vessel thickening by intimal proliferation leads to ischemia, microinfarcts
19
Q
describe the clinical course of SLE
A
- variable: ranges from mild dermatologic or joint symptoms to life threatening organ failure and cytopenias
- depends on organ involved and extent of damage
- 90% live 5 years
- 80% live 10 year
- COD: renal failure, infection (immunosuppressive therapy), CNS disease, Coronary artery disease (CAD)
20
Q
describe drug induced form of SLE
A
- Drug induced LE
- Lupus-like syndrome with multiple organ involvment, +ANAs, rash, fever, arthralgias, serositis; no renal or CNS pathology
- Incriminated drugs: D-penicillamine, Procainamide, Hydralazine, Isoniazid
- Drug cessation –> remission
21
Q
Define Sjogren’s syndrome
A
- autoimmune destruction of exocrine glands, primarily lacrimal and salivary glands
- female predominance (90% of cases, typically during middle age, 50s)
- DRY EYES, DRY MOUTH
- 40% isolated, primary form called sicca syndrome
22
Q
describe Chronic discoid LE
A
- marked by variety of skin lesions (plaques, erythema, scaling, atrophy) often involving the face and scalp with SCARRING but without systemic features
- ANAs are detected but anti-dsDNA is rare
- systemic disease develops in 5-10% of cases
23
Q
Clinical course of Sjogrens
A
- Drying of mucous membranes –> xerostomia, keratoconjunctivitis sicca, nasal septal erosion and perforation, dysphagia, dypareunia
- lymph nodes are often massively hyperplastic
- 40% increased risk of B cell lymphoma due to emergence of single dominant clone from background of polyclonal B cell proliferation
24
Q
define systemic sclerosis
A
- autoimmune disorder characterized by chronic inflammation, destruction of small vessels and progressive tissue FIBROSIS
- 3F to 1 M (50-60 years of age)
25
Q
describe the pathogenesis of Systemic sclerosis
A
- unknown trigger activates CD4+ T cells to secrete cytokines that promote fibrogenesis (TGF-BETA**), trigger also causes microvascular damage
- B cells are also activated to produce ANAs: anti-DNA topoisomerase I Ab, anti-centromere Ab
26
Q
describe subacute cutaneous LE
A
- shows diffuse, superficial, NON-SCARRING, photosensitive lesions with mild systemic disease
- may be an intermediate phase between purely cutaneous and systemic lupus
27
Q
describe the pathogenesis of Sjogren’s syndrome
A
- CD4+ T cells against glandular epithelial self-Ag initiate the disorder, possibly induced by viral infections (EBC, Hep C)
- Systemic B cell hyperactivity –> ANAs (75% of cases also positive for rheumatoid factor)
- Specific ANAs to ribonucleoproteins SS-A (Ro) and SS-B (La) common in 90%
28
Q
describe the morphology of Sjogren’s
A
T (activated CD4+), B, plasma cells infiltrate ducts and vessels in target glands
- follicle formation with germinal centers
- ductal epithelial hyperplasia –> obstruction
- acinar atropy, fibrosis, fat replacement of parenchyma
29
Q
Clinical course of Sjogrens
A
- Drying of mucous membranes –> xerostomia, keratoconjunctivitis sicca, nasal septal erosion and perforation, dysphagia, dypareunia
- lymph nodes are often massively hyperplastic
- 40% increased risk of B cell lymphoma due to emergence of single dominant clone from background of polyclonal B cell proliferation
30
Q
describe the cardiac changes in systemic sclerosis
A
- Pericarditis with effusion occurs in 33% of cases
- perivascular lymphoid infiltrates
- –> arteriolar thickening
- –> interstitial fibrosis –> restrictive cardiomyopathy which causes centricular filling to be limited thereby reducing cardiac output
31
Q
describe the pathogenesis of Systemic sclerosis
A
- unknown trigger activates CD4+ T cells to secrete cytokines that promote fibrogenesis (TGF-BETA**), trigger also causes microvascular damage
- B cells are also acivated to produce ANAs: anti-DNA topoisomerase I Ab, anti-centromere Ab
32
Q
describe limited variant of systemic sclerosis
A
- limited to skin involvement of face, forearms, fingers
- late visceral involvement, relatively benign course
- anti-centromere Ab in up to 90% of cases
- Called CREST symptoms
33
Q
describe the symptoms of CREST
A
- Calcinosis = calcium deposits in the skin
- Raynaud’s phenomenon = spasm of blood vessels in response to cold or stress
- Esophageal dysmotility = acid reflux and decrease in motility of esophagus
- Sclerodactyly = thickening and tightening of the skin on the fingers and hands
- Telangiectasia = dilation of capillaries causing red marks on surface of skin
34
Q
Describe diffuse variant of systemic sclerosis
A
- widespread skin involvement at onset
- early visceral involvement
- rapid progression
- Ab to DNA topoisomerase I (anti-Scl-70) occurs in 70% of cases
35
Q
describe the skin morphology of systemic sclerosis
A
- early findings = edema with lymphocyte (CD4+) infiltrates
- later findings = epidermal thinning, dermal/appendage fibrosis, subcutaneous calcifications
- vascular endothelial damage, thickening of the basal lamina
- fibrosis and ischemia lead to contractures with claw fingers, digital amputation, mask facies
36
Q
describe the gastrointestinal changes in systemic sclerosis
A
- esophagus = collagenization and fibrosis of muscularis causing esophageal dysmotility, LES dysfunction and ultimately resulting in REFLUX
- Small bowel = mucosal thining, loss of villi/microvilli, submucosal fibrosis resulting in MALABSORPTION
37
Q
descrie the musculoskeletal changes in systemic sclerosis
A
- early stage = nondestructive hyperplasia and inflammation of synovium
- Late stage = fibrosis of synovial and periarticular connective tissue
- 10% of cases myositis with lympcytic infiltrates and fiber atrophy
38
Q
describe the renal changes in systemic sclerosis
A
- occurs in 2/3 of cases
- thickening of interlobular arteries by concentric proliferation of intimal cells, deposition of collagenous or mucinous material and hyaline change
- interlobular artery exhibits marked luminal narrowing due to pronounced intimal thickening
- May result in hypertension in 30% of cases
39
Q
describe pulmonary changes in systemic sclerosis
A
- Occur in 50% of cases
- mild interstitial pneumonitis
- alveolar fibrosis –> respiratory insufficiency
- pulmonary hypertension from endothelial dysfunction –> cor pulmonale
40
Q
describe the cardiac changes in systemic sclerosis
A
- Pericarditis with effusion occurs in 33% of cases
- perivascular lymphoid infiltrates
- arteriolar thickening
- interstitial fibrosis –> restrictive cardiomyopathy which causes centricular filling to be limited thereby reducing cardiac output
41
Q
describe the clinical course of systemic sclerosis
A
- Usually progressive
- 10 year survival rate varies from 35-70% depending on organs involved
- COD = renal, cardiac, pulmonary, GI dysfunction or failure
42
Q
Anti-double stranded DNA
A
SLE
- Peripheral rim stain
43
Q
Anti-histone
A
drug induced LE
- Diffuse homogeneous stain
44
Q
Scl-70
A
Systemic sclerosis - Diffuse
45
Q
Scl-70 and Anti-centromere
A
- Scleroderma (CREST)
- Centromere pattern
46
Q
Sjogren syndrome
A
Ro, La
