Autoimmunity Flashcards
3 ways autoimmunity can occur
- immune regulation dysfunction: loss of Treg activity
- normal self-antigens become modified by drugs, environmental chemicals, viruses, mutations
- molecular mimicry: exposure to antigen very similar to self antigen
what are the 3 possible outcomes for immature lymphocytes that recognize self-antigen in central and peripheral tolerance, respectively?
central tolerance: either apoptosis, receptor editing (B cells), or development of Treg (T cells)
peripheral tolerance: either anergy, apoptosis, or suppression
how does anergy of T cells occur?
when TCR binds MHC on DC, but there is no signal 2 (B7 on DC binds CD28 on T cell)
natural vs induced Tregs
natural Tregs exist in the thymus already (most Tregs)
induced Tregs are a subset of immature T cells that recognized self-antigen, so are converted to Tregs
_____ is a transcriptional activator that is turned on only in Tregs
Foxp3+
key marker of Tregs
Foxp3+
transcriptional activator turned on only in Tregs, key marker of Tregs
you find a cell that expresses the following:
- CD4+
- IL-2 R
- IL-7 R
- Foxp3+
- GITR+
what kind of cell is it?
Treg
in particular, Foxp3+ is a key marker
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)
caused by Foxp3+ mutation —> nonfunctional Treg cells
- early onset T1 diabetes (insulin dependent)
- watery diarrhea
- failure to thrive - most affected children die within 2 years
mutation in Foxp3 causes what autoimmune disease
Foxp3 is critical transcriptional activator for Tregs
mutation —> IPEX
(immune dysregulation, polyendocrinopathy, enteropathy, X-linked)
APC or APECED
APC = autoimmune polyglandular syndrome
APECED = autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy
AR autoimmune disease
- yeast infections
- hypoparathyroidism
- Addison’s disease
mutation in AIRE gene (AutoImmune REgulator), which turns on expression of tissue-specific proteins in the thymus so immature T cells are exposed to them during negative selection
what occurs from a mutation in AIRE gene?
AIRE = AutoImmune REgulator
mutation —>
APC = autoimmune polyglandular syndrome
APECED = autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy
AR autoimmune disease
- yeast infections
- hypoparathyroidism
- Addison’s disease
[remember that AIRE is responsible for turning on expression of tissue-specific proteins in thymus so immature T cells are exposed to them, and won’t react to them when they are released throughout the body]
how does negative selection of T cells ensure that developing T cells don’t react to proteins found in other body systems/organs?
AIRE (AutoImmune REgulator) transcription regulator turns on expression of tissue-specific proteins/ antigens (TRAs) from all over the body in the thymus, so immature T cells are exposed to them
it is more common for MHC [I/II] genes to be associated with autoimmune disease
more autoimmune diseases are associated with specific MHC II alleles, because most autoimmune diseases are driven by antibodies, and CD4+ T cells are required to induce B cell class switching
citrullination and its relevance to autoimmunity
arginine is modified to have an oxygen, which makes it become citrulline (via PAD/ peptidyl-arginine-deiminase)
citrullinated proteins are recognized by HLA
*note that PAD is upregulated by cigarette smoking
T/F: most human autoimmune diseases are polygenic
TRUE
how does molecular mimicry play a role (potentially) in rheumatic fever? (hint - requires a specific infection)
molecular mimicry: autoimmune response triggered by an antigen that looks like self antigen
group A streptococcal M protein is similar to antigen found in cardiac muscle —> rheumatic fever
(potentially - no definitive evidence yet)
by-stander immune activation
infection induces an environment that promotes lymphocyte activation
a DC carrying a pathogen, but also expressing its own antigens, may by chance run into a self-reactive T cell and induce autoimmunity
[remember that autoimmune diseases are often associated with/triggered by infection]
2 types of drug-induced autoimmunity (DIA)
- immunological response (majority of cases) - drug hypersensitivity, usually reversible on drug withdrawal
- true autoimmune process - requires immunosuppressive treatment, progresses independently of drug withdrawal
2 factors that contribute to chronic nature of autoimmune diseases
- immune system has amplification mechanisms to proliferate “useful” cells for combatting infection (in autoimmunity, though, these are self-reactive cells)
- epitope spreading: immune response starts with one antigen but quickly spreads to others
*both of these processes lead to increased number of self-reactive clones
epitope spreading
immune response starts with one antigen but quickly spreads to others
2 major patterns of autoimmune diseases
- organ-specific (ex- Type 1 diabetes, Hashimoto’s thyroiditis, Graves’ disease, Addison’s disease)
- systemic (ex - Rheumatoid arthritis, systemic lupus erythematosus, scleroderma)
what organs are affected in the following organ-specific autoimmune diseases?
a. Type 1 diabetes
b. Hashimoto’s
c. Graves’
d. Addison’s
a. Type I diabetes - pancreas (insulin, beta cells)
b. Hashimoto’s - thyroid
c. Graves’ - thyroid (autoantibodies activate thyrotropin receptor)
d. Addison’s - adrenal
Rheumatoid arthritis, systemic lupus erythematosus, and scleroderma are common in that they are all examples of _____ autoimmune disease
systemic
what occurs in SLE and what are the treatment strategies that currently exist?
SLE = systemic lupus erythematosus
immune complex mediated systemic autoimmune disease —> too much Type I IFN production leads to high-level anti-nuclear IgG production
treatment:
- anti-IFNa antibody (Type I IFN) - Sifalimumab
- TLR inhibition
- B cell deletion (Rituximab)
- anti-BAFF anitbody (Tabalumab)
Sifalimumab, Rituximab, and Tabalumab are all used in treatment against SLE
what do they do
(note they can also be indicated for treatment of other diseases)
remember that SLE is due to too much Type I IFN that leads to high levels of anti-nuclear IgG (systemic autoimmune disease)
Sifalimumab: anti-IFNa (Type I IFN) antibody
Rituximab: B cell depletion (also used in treatment for non Hodgkin lymphoma)
Tabalumab: anti-BAFF antibody
what occurs in rheumatoid arthritis
citrillination (altered arginine) of self protein leads to
T and B cell response to self antigens in joint tissues —> synoviocyte activation, cytokine production, inflammation —> destruction of cartilage and bone
what are current treatments for rheumatoid arthritis?
remember that rheumatoid arthritis is destruction of cartilage and bone due to T/B cells recognizing citrullinated arginines in self-antigens
- TNF inhibitors, anti-TNF antibodies (Etanercept, Infliximab, Adalimumab, Golimumab, Centolizumab)
- IL-1 antagonist (Anakinra)
- anti-IL-6 receptor antibody (Tocilizumab)
- CTLA-4 fusion protein (binds B7, prevents it binding to CD28)
- anti IL-17 antibodies (Secukinumab)
- B cell deletion (Rituximab)
