Diseases of the Immune System III Flashcards
self-tolerance
normal state of non-responsiveness to ones own antigens
requirements for autoimmunity
1 immune specific reaction to autoantigen
2 evidence it is not due to tissue damage
3 absence of another cause
type I DM
autoreactive T cells and antibodies - against pancreatic beta cells
multiple sclerosis
autoreactive T cells against CNS myelin
goodpasture syndrome
autoreactive antibodies against BM of lung and kidney
SLE
autoreactive antibodies against DNA, platelets, RBCs, protein phospholipid complexes
central tolerance
T and B cells in central lymph organs
T cells - negative selection in thymus
-AIRE - stimulates expression of self-antigens in thymus
B cells - receptor editing in bone marrow
peripheral tolerance
T and B cells in peripheral tissues
anergy, T-reg cell suppression, deletion
anergy
T cells - don’t get costimulator CD28
- lose ability to signal
- also express CTLA-4 and PD-1
- inhibitory signals
B cells - don’t get T cell help
-become unable to respond
CTLA-4 and PD-1
inhibitory signal to T cell activity
-knocked out of this gene - autoimmunity
CD28
costimulator for T cell activation
suppression by T-reg cells
CD4 T cells with CD25 and FoxP3
-develop in thymus in response to self antigen
Foxp3
on T-reg cells
-mutation - autoimmune disease
IPEX
CD25
on T-reg cells
-polymorphisms - MS and other autoimmunities
deletion by activation induced cell death
CD4 T cells that recognize self antigen - apoptosis
- proapoptotic Bim - mito patway
- also Fas-FasL death receptor pathway
FAS
mutation - autoimmune lymphoproliferative syndrome
immune-privileged sites
antigens hidden from immune syndrome
-testis, eyes, brain
released with trauma - elicit immune response
post-traumatic orchitis and uveitis
mechanisms of autoimmunity
genes and environmental triggers
AIRE
expression of self-antigens in thymus
-aid with central tolerance
PTPN-22
genetic association with autoimmunity
- rheumatoid arthritis, type I DM
- inability to control tyrosine kinase
- excessive lymphocyte activation
NOD-2
genetic association with autoimmunity
- crohns disease
- cytoplasm sensor for microbes
B cell negative feedback
Fc receptor for IgG antibodies
-switches off antibody production
infection and autoimmunity
may upregulate costimulators on APCs
also, some microbes may have antigens that are similar to self-antigens (molecular mimicry)
molecular mimicry
rheumatic heart disease
-streptococcal proteins similar to myocardial proteins
general features of autoimmunity
progressive
Th1 - M0 / Th17 - neutrophils and monocytes
systemic lupus erythematous
SLE
- autoantibodies
- injury to skin, joints, kidney, serosa, etc.
predominantly in woman of childbearing age
usually arises in 20s or 30s
autoantibodies in SLE
diverse
- ANAs - antinuclear antibodies
- against DNA, histones, non-histones bound to RNA, nucleolar antigens
-also - to blood cells
-antiphospholipid
-
patterns of nuclear fluorescence
1 - homogenous diffuse nuclear staining
2 - peripheral staining
3 - speckled pattern
4 - nucleolar pattern
homogenous diffuse nuclear staining
chromatin/histones
peripheral staining
double strand DNA
speckled pattern staining
non-DNA nuclear constituents
nucleolar pattern staining
RNA
-systemic sclerosis
criteria for SLE
must meet 4 of 11
- malar rash - butterfly rash on cheeks
- discoid rash
- photosensitivity
- oral ulcer
- arthritis
- serositis (pleuritis / pericarditis)
- renal disorder
- neuro disorder
- hematologic disorder
- immuno disorder
- antinuclear antibodies
diagnostic for SLE
autoantibodies to smith antigen and double strand DNA
false positive for syphilis
SLE patients
-autoantibody for beta-2 glycoprotein complex also binds cardiolipin (in syphilis test)
antiphospholipid antibodies
in 40-50% SLE patients
-epitopes of plasma proteins revealed when proteins in complex with phospholipids
lupus anticoagulant (in vitro) -however, individuals in hypercoagulable state**
results in secondary antiphospholipid antibody syndrome
genetics of SLE
defect in B cell tolerance
also, deficiency in complement components favoring tissue deposition
UV light
exacerbates SLE
sex hormones
influence on SLE
drugs that induce SLE response
hydralazine
procainamide
D-penicillamine
tissue injury in SLE
type III - antibody-mediated
type IV - immune complex mediated
LE cell
any phagocytic leukocyte that has engulfed the denatured nucleus of injured cell
-seen in SLE
characteristic lesions in SLE
blood vessels, kidneys, CT, skin
blood vessels and SLE
fibrinoid depositi in walls
kidney and SLE
lupus nephritis
-immune complexes in glomeruli
5 patterns of lupus nephritis
class 1 - minimal mesangial class 2 - mesangial proliferative class 3 - focal proliferative class 4 - diffuse proliferative class 5 - membranous
mesangial lupus glomerulonephritis
no or slight (class 1) or moderate (class 2) mesangial proliferation with deposits of Ig and complement
no involvement of capillaries
focal proliferative glomerulonephritis
class 3
fewer than 50% involvement of glomeruli
-crescent formation, fibrinoid necrosis, endothelial/mesangial proliferation
-hematuria/proteinuria
diffuse proliferative glomerulonephritis
class 4
greater than 50% involvement of glomeruli
-crescent formation, fibrinoid necrosis, endothelial/mesangial proliferation
-hematuria/proteinuria
membranous glomerulonephritis
class 5 thickened capillary walls
severe proteinuria and nephrotic syndrome
subepithelial deposits of antibody/complement in glomeruli
membranous glomerulonephritis
between BM and visceral epithelial cells
subendothelial deposits of antibody/complement in glomeruli
proliferative glomerulinephritis
-wire loops
between endothelium and BM
wire loops
subendothelial deposits create thickened capillary wall
skin and SLE
facial malar area - butterfly
also bullae, urticaria, ulcerations, maculopapular lesions
worsened with UV exposure
deposition of Ig and complement
joints and SLE
nonerosive synovitis
CNS and SLE
antibodies against synaptic membrane
serosa and SLE
acute - fibrous exudate on surface
later - thickened, opaque and fibrous
cardiovascular and SLE
non-bacterial verrucous endocarditis
- affects valves
- 1-3mm warty deposits on any heart valve
infective endocarditis
larger deposits than SLE
spleen and SLE
splenomegaly
capsular thickening
follicular hyperplasia
lungs and SLE
pleuritis and pleural effusion
clinical features of SLE
typically young woman
- butterfly rash on face, fever, pain in joints
- photosensitivity
- ANAs found
- anemia / thrombocytopenia
- mental aberrations
- CAD
course of SLE
rare/acute - die within weeks
-with therapy - flare ups and remission
- during flare-up - hypocomplementemia
- Tx - corticosteroids (immunosuppressant)
common cause of death - renal failure
chronic discoid lupus erythematous
skin manifestations of SLE - but no systemic problems
skin plaques - face and scalp
positive ANA test
rarely have double strand DNA antibodies
subacute cutaneous lupus erythematous
predominant skin involvement
-widespread and nonscarring
mild systemic symptoms
antibodies to SS-A
HLA-DR3 genotype
drug-induced lupus erythematous
hydralazine, procanamide, isonaizid, d-penicillamine
-development of ANAs
renal and CNS involvement are rare
lots of antibodies for histones
HLA-DR4 genotype
rheumatoid arthritis
chronic inflammatory
-affects joints
-also skin, vessels, lungs, heart
-
sjogren syndrome
keratoconjunctivitis sicca (dry eyes) and xerostomia (dry mouth)
destruction of salivary and lacrimal glands
autoantibodies against SS-A and SS-B
-both are ribonucleoprotein antigens
often associated rheumatoid arthritis
sicca syndrome
decreased saliva
rheumatoid factor
antibody against IgG
lymphoma vs. intense reactive chronic inflammation
look at clonality of cells present
- monoclonal - lymphoma
- polyclonal - inflammation
clinical features of sjogren syndrome
women aged 50-60
keratoconjunctivitis - causes blurry vision, burning, itching
xerostmia - difficulty swallowing food, decreased taste, cracks in mouth
parotid gland enlargement
rare - glomerular lesions
-but do see phosphaturia, uricosuria, renal tubular acidosis
mikulicz syndrome
combination of lacrimal and salivary gland inflammation
diagnosis of sjogren syndrome
Bx of lip - minor salivary glands
node in sjogren
initially T and B cells
tendency to more B cells
can lead to marginal zone lymphoma (B cell malignancy)
systemic sclerosis
chronic inflammation
widespread damage to small vessels
progressive interstitial and perivascular fibrosis in skin
excessive fibrosis throughout body
slceroderma
aka systemic sclerosis
diffuse scleroderma
widespread skin involvement at onset and progression to visceral involvement early
limited scleroderma
skin involvement only fingers, forearms, face
-visceral involvement late
some patients develop CREST
CREST syndrome
associated with limited scleroderma
calcinosis - deposits in soft tissue
raynauds phenomenon - reduced color in digits/toes
esophageal dysmotility - difficulty swallowing
sclerodactylyl - local thickening of skin of digits/toes
tenalgiectasia - blood vessels near surface of skin
pathology of scleroderma
CD4 T cell response to antigen in skin
ANAs - against DNA topoisomerase I (pulmonary fibrosis) and anticentromere antibody (CREST)
marfan syndrome
mutation of fibrillin I gene
skin and scleroderma
begins in fingers goes centrally
-edema and perivascular infiltrates with CD4 cells
fibrosis of dermis
-subQ calcifications
clawlike hands
alimentary tract and scleroderma
fibrosis of muscles in esophagus
GERD can occur
lungs and scleroderma
pulmonary HTN and interstitial fibrosis
clinical features of scleroderma
50-60 year old
-more likely female
skin thickening, raynauds phenomenon, dysphagia, respiratory difficulty
CREST - in limited scleroderma
-pts with CREST usually have limited involvement of skin - only fingers, forearms, face
inflammatory myopathies
inflammation of skeletal muscles
dermatomyositis
polymyositis
inclusion-body myositis
mixed CT disease
mix of SLE, systemic sclerosis, and polymyositis
ANAs to U1 ribonucleoprotein
polyarteritis nodosa
necrotizing inflammation of vessels
