Apr3 M1-Autoimmunity

Question 1

1st and most important level of tolerance + what happens

Answer 1

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

Question 2

how developing lymphocytes can see an Ag and receive an apoptotic signal bc they’re are not ‘‘self-tolerant’’

Answer 2

• AIR gene (autoimmune regulator) in the thymus expresses Ags from the body
• similar mechanism in the BM (+B reg cells in the BM)

Question 3

why peripheral tolerance exists

Answer 3

can’t express all Ags in the central lymphoid organs

Question 4

most important mechanism of peripheral tolerance

Answer 4

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

Question 5

anergy def

Answer 5

refractory type, mostly unreactive lymphocyte

Question 6

(IMPORTANT) locations of T reg cells in the body

Answer 6

you have:

• central T reg cells (lymphoid organs)
• peripheral T reg cells

Question 7

which lymphocytes have more autoreactivity (auto-immunity, self-reactivity)

Answer 7

B lymphocytes bc exposed to less stuff in the BM even through exposed to hematopoiesis (T cells have AIR gene in the thymus)

Question 8

how intensity of a signal determines peripheral tolerance

Answer 8

• 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)

Question 9

what is the function of T reg cells central and peripheral

Answer 9

repress effector T cells that recognize an Ag (especially self Ag)

Question 10

(EXAM) 4 mechanisms of T reg cells action

Answer 10

1. inhibitory cytokines
2. metabolic disruption
3. targeting dendritic cells
4. cytolysis

Question 11

(EXAM) inhibitory cytokines mech of T reg cells

Answer 11

TGF-beta and IL-10 turn off effector T cells

Question 12

(EXAM) metabolic disruption mechanism of T reg cells

Answer 12

• 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

Question 13

(EXAM) targeting dendritic cells mechanism of T reg cells

Answer 13

• 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

Question 14

(EXAM) cytolysis mechanism of T reg cells

Answer 14

T reg cell kills the effector T cell that recognizes self with perforin and granzyme

Question 15

(imp?) what’s clonal exhaustion? (one of the mechanisms of self-tolerance)

Answer 15

• 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*

Question 16

bad defect of central tolerance

Answer 16

• 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

Question 17

APECED def

Answer 17

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)

Question 18

(EXAM) 4 mechanisms of DEFECTIVE peripheral tolerance

Answer 18

1. molecular mimickery
2. epitope spreading
3. bystander activation
4. cryptic antigens

Question 19

(EXAM) molecular mimickery (mech of defective peripheral tolerance)

Answer 19

autoimmunity after disease bc Ags produced to pathogens recognize self (transient, or chronic if lot of resemblance)

Question 20

(EXAM) epitope spreading (mech of defective peripheral tolerance)

Answer 20

• 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

Question 21

(EXAM) bystander activation (mech of defective peripheral tolerance)

Answer 21

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

Question 22

(EXAM) cryptic antigens (mech of defective peripheral tolerance)

Answer 22

• see Ags that the immune system never encounters normally

- for ex, breach in BBB, will see CNS Ags to which we have no tolerance

Question 23

best example of genetic defect of T reg cells and cause

Answer 23

IPEX: defect in foxp3, a TF needed to turn on genes that transform naive T in to T reg

Question 24

what’s IPEX (what’s the consequence of having no T reg)

Answer 24

autoimmunity, FTT, lymphadenopathy, anaphylaxis to everything, diarrhea, wasting

Question 25

(EXAM) what is the strongest association with auto-immunity

Answer 25

• MHC genotype (certain genotypes can dx an auto-immune disease)
• bc certain MHC genotypes may cue T cells towards auto-immunity

Question 26

types of genetic mutations that predispose to autoimmunity

Answer 26

1. genes affecting auto-Ag availability and clearance (C1q,2,4 and SLE)
2. genes of apoptosis (Fas, ALPS)
3. signaling threshold genes (CTLA4)
4. genes of cytokines expression and signaling
5. genes of expression of co-stimulatory molecules
6. genes of dev and fct of Treg (FoxP3 and IPEX)

Question 27

genetic mutation associated with Crohn’s disease and fct

Answer 27

• 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*