Autoimmunity (and Tolerance) Flashcards
what are the 3 types of criteria for “declaring” autoimmune disease?
direct proof
indirect proof
circumstantial evidence
direct proof
transient disease in newborn due to passive autoimmune antibodies
indirect proof
identify target human antigens and reproduce disease in animal model systems
circumstantial evidence
statistical demonstration of factors that associate with increased risk; clinical improvement with immunosuppresive therapy
which 3 hypersentivities are associated with autoimmune diseases?
Type 2, 3, and 4
which exogenous factors influence expression of autoimmune diseases?
hormones
infectious agents
environment
what is the genetics of autoimmune diseases?
what are the HLA haplotypes associated with autoimmunity?
DQ2, DQ8, DR2, DR3, DR4, DR5, B27
- linkage disequilibrium?
what is the B27 HLA allotype associated with?
Ankylosing spondylitis
Between males and females, which is more susceptible to autoimmune diseases?
females
what are the 4 immune privileged sites?
brain, eye, uterus (fetus), testes
Autoreactive “Bad” B cells should be eliminated but this is not always the case. But even though they survive, they should not be able to react without ___ cells?
T cells
how can you lose immune tolerance?(2)
- self-reactive B and T cells
- dysfunctional negative selection gives rise to autoimmune diseases
How does self-reactive B and T cells lead to immune tolerance?
- T cells reacting strongly to self fail to be eliminated
- B cells recognizing autoantigens exist in circulation
what are the ways that dysfucntional negative selection give rise to autoimmune diseases?(4)
1- defect in the AIRE gene
2- APECED and APD
- Finns, Sardinians, Iranian Jews
- patients also suffer from candiasis-ectodermal dystrophy
APECED or APD caused by?
a defect in the AIRE gene
what are APECED or APD?
two diverse groups of autoimmune diseases caused by defect in AIRE gene
what are two examples of diseases that people with APECED suffer?
- alopecia
- vitiligo
what occurs in the loss or lack of peripheral tolerance?
soluble CTLA-4 binds B7 preventing CD28 interactions
what are the 2 molecules that bind T cell activation?
- normally CD28
- CTLA-4
what does CTLA-4 do?
dampens T cell activation by competing with CD28 for B7
Patients with which diseases have an increased expression of CTLA-4?(3)
Graves
Hashimoto
IDDM
which cytokines are responsible for CD4 cell regulation?
IL4
IL10
TGF -beta
what is the transcriptional repressor expressed by CD4+ T regs?
FoxP3
how does cross reacting antigens or molecular mimicry allow for controls to be bypassed?
- provide help for B cells to produce antibodies
- microbial antigens share amino acid sequences wth mamalian proteins
revisit effector mechanisms
…
what are some consequences of cross reacting microbes associated with autoimmunity?
- strep = rheumatic fever
- chlamydia = arthritis
- shigella = reactive arthritis
- Borrelia burgdorferi = chronic arthritis in Lyme disease
- Coxsackie = Type 1 diabetes
Reiter’s syndrome and Reactive arthritis
- both autoimmune infections linked to infections
Reiter’s syndrome causes
- genital infection with chlamydia trachomatis or gastroenteritis caused by enteric pathogens (Yersinia enerocolitica)
- form or arthritis similar to ankylosis spondylitis
Reactive Arthritis causes
- a number of pathogens that cause gastrointestinal infection from food poisoning are implicated
possible mechanisms of induction of autoimmunity (3)
- chemical modification of antigen
- polyclonal activation
- viral factors
- abnormal expression of MHC 2
- deficiency in complement components
- breach of central tolerance
- loss of peripheral tolerance
Type 2 Hypersensitivity and autoimmunity
autoimmune diseases caused by antibodies against a cell surface or tissue marker
Type 2 autoimmunity list
1- Autoimmune Hemolytic Anemia 2- Autoimmune thrombocytopenia purpura 3- Goodpasture's syndrome 4- Pemphigus vulgaris 5- Pemphigus foliaceus 6- Acute rheumatic fever 7- Graves disease 8- Myasthenia Gravis AA-GPP-AGM
Type 2- Autoimmune hemolytic anemia
- warm antibodies (some IgG against antigen) initiate immune adherence and phagocytosis (identified by direct Coombs test)
- cold antibodies- IgM binds to I or I antigens on glyphorin RBC ( activates complement and hemolysis occurs when patients are exposed to cold)
Type 2- autoimmune thrombocytopenia purpura
- anti platelets antibodies
- accelerated removal by phagocytes in spleen and liver
Type 2 -Goodpasture’s syndrome
- antibodies against the alpha-3 chain of type 4 collagen found in the basement membrane of kidney and lung
- LINEAR pattern of immunofluorescence
Type 2- Pemphigus vulgaris
- blisters and rash caused by antibodies against epithelium
- desmogleins: adhesion molecules in the desmosomes that bind keratinocytes together
Type 2- Pemphigus foliaceus
…
Type 2- acute rheumatic fever
- antibodies against Streptoccal M proteins that cross react with myocardium (anti-myosin and sarcolemmal proteins)
Type 2 - Graves disease
- abnormal class 2 expression by thyroid cells
- IgG against TSH receptors leading to hypersensitivity
- transient Grave’s disease in newborns
Type 2- Myasthenia Gravis
- anti-acetylcholine receptor antibodies
- block Ach binding to neuromuscular junctions
- muscle weakness: ptosis, swallowing, breathing
- thymoma
pernicious anemia? Type 2?
- antibodies to intrinsic factor
- antiparallel cell antibodies
- no vitamin B12 uptake
Type 3 HyperSensitivity and Autoimmunity
Autoimmune diseases caused by immune complex deposition
Type 3 HyperSensitivity and Autoimmunity List
1- Subacute bacterial endocarditis
2- Mixed essential cryoglobulinemia
3- Systemic lupus erythematosus
Subacute bacterial endocarditis
- autoantigen: bacterial antigen
- consequence: causes Glomerulonephritis
Mixed essential cryoglobulinemia
- autoantigen: Rheumatoid factor IgG complexes (with or without hepatitis C antigens)
- consequence: Systemic vasculitis
Systemic lupus erythematosus
- autoantigen: DNA, histones, ribosomes, snRNP, scRNP
- consequence: Glomerulonephritis, vasculitis, arthritis
what type of sensitivity is rheumatoid arthritis?
Type 4
in SLE, what class of antibodies against ds DNA correlate best with the disease?
IgG
In SLE Aside from antibodies against ds DNA, what targets exist?
- ss denatured DNA
- nucleus
- histone
- RNP and Sm proteins
In SLE, which toll like receptor recognizes unmethylated CpG nucleotide sequences found on bacterial DNA but also human DNA?
TLR-9
In SLE, what is the second signal generated via?
NFkB
what type of test is used to test for SLE?
- anti-nuclear antibodies
- patient serum is reacted with rat liver cells
How is the anti-nuclear antibody reaction detected?
- with FITC- conjugated anti-human Ig antibodies
- POSITIVE TEST - fluorescent nucleus
the butterfly rash present in SLE is similar in appearance to patients with ____
serum sickness
immune complex deposition in the skin
what is the pattern of fluorescence in SLE?
LUMPY BUMPY
- immune complexes deposit on kidney, activate C, PMNs
what pathologies are caused by SLE?
glomerulonephritis
proteinuria
hematuria
Type 4 Hypersensitivity & Autoimmunity
T-cell mediated diseases
Type 4 Hypersensitivity & Autoimmunity List
1- multiple sclerosis 2- IDDM -insulin dependent diabetes mellitis 3- Hashimoto thyroiditis 4- Rheumatoid arthritis 5- Celiac disease 6- Sjogren's Syndrome?
Multiple sclerosis
demyelination of CNS and sclerotic plaque replacement leading to relapsing or chronic progressive paralytic course
- evidence of link to viral infection due to antigenic mimicry
Multiple sclerosis mechanism
1- TH1 secreting IFNgamma together with macrophages penetrate the blood-brain barrier
2- Macrophages then secrete proteases and cytokines induce inflammation along the myelin sheath (leads to loss of myelin and sclerotic plaques)
- Fas induction - apoptosis of neuronal cells
What experimental model has been used as evidence that MS is autoimmune?
EAE - Experimental Allergic Encephalitis
- inject myelin basic protein (MBP) into mice with adjuvant induces MS symptoms
IDDM
chronic inflammatory destruction of the insulin producing b-islet cells of the pancreas
IDDM
…
IDDM
…
Hashimoto Thyroiditis
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Hashimoto Thyroiditis
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Rheumatoid Arthritis
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Rheumatoid Arthritis
hypersenitivity to food that has much in common with autoimmune disease)
Rheumatoid Arthritis
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Celiac Disease
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Celiac Disease
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Celiac Disease
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Sjogren’s Syndrome
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