Apr3 M1-Autoimmunity Flashcards
1st and most important level of tolerance + what happens
central tolerance in lymphoid organs where lymphocytes develop
-lymphocyte with an activated receptor (BCR or TCR) (=recognizes self) receives signal to turn off = apoptotic signal or signal to become T reg
how developing lymphocytes can see an Ag and receive an apoptotic signal bc they’re are not ‘‘self-tolerant’’
- AIR gene (autoimmune regulator) in the thymus expresses Ags from the body
- similar mechanism in the BM (+B reg cells in the BM)
why peripheral tolerance exists
can’t express all Ags in the central lymphoid organs
most important mechanism of peripheral tolerance
lymphocyte in the periphery becomes anergic or T reg cell or apoptose (if B cell) if encounters SELF Ag but DOESN’T HAVE:
- costimulation from APC (costimulatory molecules)
- stimulatory cytokines
anergy def
refractory type, mostly unreactive lymphocyte
(IMPORTANT) locations of T reg cells in the body
you have:
- central T reg cells (lymphoid organs)
- peripheral T reg cells
which lymphocytes have more autoreactivity (auto-immunity, self-reactivity)
B lymphocytes bc exposed to less stuff in the BM even through exposed to hematopoiesis (T cells have AIR gene in the thymus)
how intensity of a signal determines peripheral tolerance
- strong constant signal (self Ags) through naive TCR or BCR = get TOLERANCE
- sudden INCREASE in Ag-R signal in naive lymphocytes = they’re activated (no tolerance)
what is the function of T reg cells central and peripheral
repress effector T cells that recognize an Ag (especially self Ag)
(EXAM) 4 mechanisms of T reg cells action
- inhibitory cytokines
- metabolic disruption
- targeting dendritic cells
- cytolysis
(EXAM) inhibitory cytokines mech of T reg cells
TGF-beta and IL-10 turn off effector T cells
(EXAM) metabolic disruption mechanism of T reg cells
- T reg cells express IL-2 Rs to capture IL-2 so no more left in solution for effector T cells
- effector T cells don’t survive
(EXAM) targeting dendritic cells mechanism of T reg cells
- T reg cell shuts off the dendritic cells (inhibit their maturation and fct)
- dendritic cells express less coreceptors and interact less well with T effector cells
- T effector cells don’t work well
(EXAM) cytolysis mechanism of T reg cells
T reg cell kills the effector T cell that recognizes self with perforin and granzyme
(imp?) what’s clonal exhaustion? (one of the mechanisms of self-tolerance)
- after a massive adaptive immunity to a pathogen, like influenza, all pathogens are eliminated
- no more GFs or stiimuli are around for lymphocytes to divide
- lymphocytes are exhausted and apoptose
- good mechanism of regulation*
bad defect of central tolerance
- AIR gene mutation = get APECED (other defects often die in embryo)
- AIR gene not functional = get APECED bc self reactive T cells leak out in the body
APECED def
autoimmune polyendocrinopathy, candidiasis and ectodermal dysplasia
- bc AIR gene expresses lot of endocrine Ags
- immune deficiency so get candidiasis (for ex mounting self response against IL17, a T reg cytokine, so less good immunity)
(EXAM) 4 mechanisms of DEFECTIVE peripheral tolerance
- molecular mimickery
- epitope spreading
- bystander activation
- cryptic antigens
(EXAM) molecular mimickery (mech of defective peripheral tolerance)
autoimmunity after disease bc Ags produced to pathogens recognize self (transient, or chronic if lot of resemblance)
(EXAM) epitope spreading (mech of defective peripheral tolerance)
- initial self autoimmunity causes cells with that self surface Ag to lyse (bc attacked)
- they release histones and dsDNA that we’ve never seen
- B cells engulf all that, APC to T cells
- get auto-immunity to histones
(EXAM) bystander activation (mech of defective peripheral tolerance)
activation of the anergic lymphocytes in the periphery (remember became anergic bc no APC costim and no cytokines) because now see a LOT of inflam and cytokines
(EXAM) cryptic antigens (mech of defective peripheral tolerance)
- see Ags that the immune system never encounters normally
- for ex, breach in BBB, will see CNS Ags to which we have no tolerance
best example of genetic defect of T reg cells and cause
IPEX: defect in foxp3, a TF needed to turn on genes that transform naive T in to T reg
what’s IPEX (what’s the consequence of having no T reg)
autoimmunity, FTT, lymphadenopathy, anaphylaxis to everything, diarrhea, wasting
(EXAM) what is the strongest association with auto-immunity
- MHC genotype (certain genotypes can dx an auto-immune disease)
- bc certain MHC genotypes may cue T cells towards auto-immunity
types of genetic mutations that predispose to autoimmunity
- genes affecting auto-Ag availability and clearance (C1q,2,4 and SLE)
- genes of apoptosis (Fas, ALPS)
- signaling threshold genes (CTLA4)
- genes of cytokines expression and signaling
- genes of expression of co-stimulatory molecules
- genes of dev and fct of Treg (FoxP3 and IPEX)
genetic mutation associated with Crohn’s disease and fct
- NOD2 mutation
- NOD2 is a cell surface receptor that normally helps detect commensal gut bacteria to keep them in mucosa
- bacteria go in submucosa, get a lot of lymphocytes and reaction to the BACTERIA
- Crohn’s is NOT autoimmune*
