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)
