Robbin's Autoimmune Diseases Flashcards
autoimmunity is carried out by what two major mechanisms
Auto-antibodies
self reactive t cells
Systemic diseases that are caused by autoantibodies and immune complexes are primarily characterized as
connective tissue disorders
or
collagen vascular disorders
*even though autoantibodies are not directly targeting blood vessels or connective tissue
What is immunologic tolerance
unresponsiveness to an antigen that is induced by exposure specific lymphocytes to that antigen
antigen-induced deletion of self-reactive t and b cells during maturation
central tolerance
Gene responsible for self tolerance in central tolerance
AIRE
*defect is APCED or something
Which cells can undergo receptor editing
B cells that were initially self-reactive
Mechanisms by which Self reactive T cells are deleted from the repertoire in the periphery
Anergy
Suppression by TREGS
Activation induced cell-death
Define Anergy
Anergy–> lack of B7 costimulatory signal–> T cell then undergoes apoptosis
what goes on in Suppression by TREGS
t regs bind to self antigens–> they supress cd4/cd8 t cells that are binding locally to self-peptides on MHC molecules by secreting IL-10 and TGF-Beta
end result is dampens t cell response, also competes for binding of B7 on apc
T regs express what?
CD25
*one of the Il-2 receptor subunits, require IL-2 for their proliferation and survivial
Tregs express what
Foxp3
*responsible for the development of regulatory cells
Mutations in Foxp3 result in what disease
IPEX
diabetes, diarrhea, eczematous dermatitis
WHat goes on in Activation induced cell death?
FasR (member of TNF family) is activated by FasL upon self-recognition–> apoptosis
Activation induced cell death is important for what?
deletion of self-reactive B cells by FasL expressed on T cells
defect in Fas, FasL or Caspase 10 results in what
ALPS
Most autoimmune disease cannot be explained by
defects in a single gene
several autoimmune disease are linked to the
HLA locus--> especially class II gene Dr and DQ
RA locus
HLA DR4 (HLA DRB1)
Ankylosing Spondylitis locus
HLA B27
Rheumatic heart disease is caused by
molecular mimicry of GAS to host tissue–> viruses and other microbes share cross-reactive antigens with host tissue–> in an attempt to make an immune response to the pathogen, the host is left with self-reactive antibodies that bind to “immitation” epitopes and recruit inflammatory cells–> damage of the tissue
epitope spreading
autoimmune attack only furthers the autoimmune response–> damage to self tissues uncovers host antigens in a newly immunogenic form–> body makes even more anti-self responses
Main causes/characterizations of of LUPUS
Loss of self tolerance mechanisms, leading to production of a large number of autoantibodies that can damage tissue directly or in the form of immune complex deposits
main areas that SLE attacks
skin, kidneys, serosal membranes, joints and heart
Lupus is associated with an enormous array of
Anti Nucelar Antibodies–this is very sensitive but 50/50 specific
ratio of SLE female:male
9:1
race most likely to have lupus
Black women
Loci for SLE
HLA DR2 and HLA DR3
Pathogenis of SLE involes
- susceptibility of genes
2 external TRIGGERS
genetic factors for SLE(3)
Familial association
HLA association
genetic deficiencies of C1q, C2, C4–>defective clearance of immune complexes and apoptotic cells debris
Environmental factors of SLE (4)
UV radiation
Smoking
Sex hormones
Drugs–> procainimide and hydralazine–> SLE-like disease without glomerulonephritis
Immunologic Abnormalities in SLE–>(3)
- Abnormally large amounts of Type I interferons– AB
- TLR signals TLR 9 DNA and TLR 7 RNA–> activate self-specific B cells
- Failure of B cell tolerance
Model fo SLE sequence
- UV radiation–>apoptosis
- defective clearance
- unable to maintain self-tolerance
- host picks up self nuclear-antigens and makes and immune response to it
- autoantibodies bind to self-tissue, activate compliment and phagocytes eat host–> more cell death
- net result is cyclic antigen release and immue activation resulting in the production of high-affinity autoantibodies
Auto Ab’s seen in SLE
ANA’s
Ab’s against RBC’s
Anti-phospholipid Ab’s
Types of ANA’s
Ab's against DNA Histones nonhistone proteins bound to RNA nucleolar antigens
Are ANA’s diagnostic for SLE
NO
IFA testing is 95% senstive but only like 50% specfiic
ANA’s can be in ppl without SLE
Specific assays for SLE
dsDNA Smith antigens (Sm)
Most organ damage in SLE is caused by
Immune-Complex deposition
During a SLE flair pt.s will have decreased levels of what in their serum analysis
C3-C4–> because it is a Type III hypersensitivity
–> Ab-SelfAntigen complex is having compliment fixed on it so that is can be taken up by phagocytes
SLE, as it related to ORGAN DAMAGE can be classified as what type of Hypersensitivity
Type III– Immune Complex
SLE as it related to DESTRCUTION OF RED BLOOD CELLS can be classified as what type of hypersensitivity
Type II- Altered Host
Disease related to Anti-dsDNA
SLE diagnostic
Anti-Sm
SLE diagnostic
Anti-RNPU1
SLE, mixed connective tissue disorder
Anti SS-A (Ro) and anti SS-B (La
Sjrogen, SLE
Anti SCL 70
Systemic Sclerosis–> this is diagnostic
Anti Topo 1
Scleroderma
Anti histones
SLE
Anti-centromere
limited scleroderma (CREST), Systemic scleroderma--> diagnostic
Anti phospholipid
SLE
Autoantibodies against phospholipids result in SLE pt.’s to exhibit
–>spontaneous abortion
thrombotic episodes–> but actually this interferes with clotting tests and are called lupus anticoagulants
Type II hypersensitivity involved with SLE
auto-ab’s to RBC’s, Leukocytes, and platelets==> resulting in many cytopenias
LE bodies/Hematoxylin bodies
nuclei of damaged cells bound to ANA’s
LE cells
nuclei + ANA that has been taken up by a phagocyte
SLE–> can lead to what involving Blood Vessels
acute necrotizing vasculitis
–> ANY tissue, small arteries and arterioles
necrosis and fibrinois deposition of within vessel walls containing antibody, DNA, compliment frags, fibrinogen
also perivascular leukocyte infiltrate is commonly seen
Most serious form of SLE renal lesions
35-60%
Diffuse Lupus Nephritis (IV)-- over half glomeruli >MARKED GLOBAL INCREASE IN CELLULARITY > more than half glomeruli involved >bowman's space is narrowed >wire loops--> AB complexes >hematuria, proteinuria >renal insufficiency >HYPERTENSION
FOCAL LUPUS NEPHRITIS
20%-35%
NOT AS BAD–> PRESENT IN LESS THAN HALF OF THE GLOMERULI AND MAY BE RESTRICTED TO ONLY A PORTION OF A GIVEN GLOMERULUS
MEMBRANOUS LUPUS NEPHRITIS
THICKENING OF THE CAPILLARY WALL DUE TO DEPOSITION OF SUB-ENDOTHELIAL IMMUNE COMPLEXES
SLE NEPHRITIS IS MEDIATED BY WHICH AB ISOFORM
IgG
Advancing sclerotic lupus nephritis
complete sclerosis of over 90% of the glomeruli
corresponds to clinical ESRD
Skin finding with SLE
MALAR rash from photosensitivity
Histo findings of SLE skin
> LIQUEFACTIVE DEGENERATION OF BASAL LAYER
EDEMA AND DERM-EPI JUNCTION
MONONUCLEAR INFILTRATES AROUNG BLOOD VESSELS AND SKIN APPENDAGES
SLE findings in the spleen
ionion skin lesions–> thickening of penicilliary arteries and perivascular fibrosis
SLE affects the heart mainly in the form of
- -> pericarditis
- ->libmann sacks endocarditis (non-bacterial verrucous endocarditis)
- -> CAD–> from immune complexes lodging in arteries
Most common CNS lesion involved with SLE
small vessel angiopathy with nononflammatory intimal proliferation–>sometimes there are neuropscyological symptoms
anti-cd20 tx for SLE
rituximab
pt.’s with lupus are at increased risk of
opportunistic infection
Most common causes of death with lupus
- renal failure
- intercurrent infections
- CV disease
Characteristics of Sjogren Syndrome
can occur by itself (sicca syndrome)
or in conjunction with another autoimmune disease– usually RA
Dry eyes (keratoconjunctivitis) Dry mouth (xerostomia)
*immune mediated destruction of lacrimal and salivary glands
Most likely mode of pathogenesis for Sjogren Syndrome
CD4 t cells react against an unknown antigen in the ductal epithelial cells of he exocrine glands
Ab’s associated with Sjogren
ANA, RF, SS-A, SS-B,
But none of this is diagnostic
is there a viral cause suspected with sjogren
yes–> which one it is is unknown
Histo findings of Sjogren
intense lymphocyte infiltration (CD4) of gland tissue and plasma cell infiltration
occasionally forming lymphoid follicles with a germinal center
Sjogren pt.’s with primary Sicca syndrome and high levels of SS-A ab’s develop what
extraglandular problems involving skin, cns, kidneys etc.
about 60% of pt.’s with Sjogren have what
another autoimmune disease
Pt.’s with Sjogren’s also are susceptible to what
40 times more likely to develop non-hodgkin B cell lymphoma–> from robust polyclonal B cell proliferation
general characteristics of Scleroderma
- excessive fibrosis of multiple tissue
- obliterative vascular disease
- production of many autoab’s
2 main types of systemic scleroderma
> Diffuse
>Limited
characteristics of diffuse scleroderma
> initial widespread skin involvement
>rapid visceral progression
Characterstics of limited scleroderma
> mild skin involvement (fingers and face only)
>late visceral involvement
Limited scleroderma is also known as
CREST syndrome
findings of CREST syndrome
Calcinosis Raynaud phenomenon Esophageal dysmotility Sclerodactyly Telangectasia
what is thought to preclude Scleroderma pathogenic sequence
injury to endothelial cells–> migration of activated T cells to injured tissues
domminant self-reactive cell type in scleroderma
> TH2–» responds to endothelial damage and recognizes self antigen
then releasesfcytokines–>induce alternative macrophage activation and collagen deposition by fibroblasts
Cytokines released by Th2 cells involving scleroderma
IL 10 and TGFBeta–> tells fibroblasts to do their thang–> result in fibrosis
Ultimate result of Scleroderma autoimmune sequence
ischemic injury
what leads to ischemic injury in scleroderma
endothelial cell proliferation and intimal fibrosis–> leads to narrowing of the small vessels–> ischemic injury over time
ANA’s unique to SS
anti topo 1 ab (anti Scl-70)
anticentomere ab
ANA specific to CREST (limited ss)
anti CENTROMERE
ANA ab specific to diffuse ss
anti topo 1
sum up the skin histopath is SS
thickening of the dermis due to deposition of compact collagen and thinning of the epidermis, atrophy of dermal appendages
loss of blood flow from SS can result in
autoamputation
Effects of SS on GI tract
replacement of muscularis with collagen results in “rubber-hose” like loss of flexibility–> usualy the distal 1/3 of esophagus is affected and the result is esophageal dysmotility
most diasgnostic indicator for SLE
CBC
SS can lead to GERD and then
Barrett’s esophagus
squamous–>columnar
secondary pulmonary hypertenison is associate with what disease
SS
pt.s with Mixed connective tissue disease have high titers of what
U1RNP
two other features of mixxed connective tissue diease
- scarcity of renal disease
2. great response to corticosteroids
