immune tolerance and autoimmunity

Question 1

what is the purpose of central tolerance and when/where does it occur?

Answer 1

• purpose: ensure that lymphocytes in periphery do not respond to self antigens
• place: occurs in bone marrow and thymus during t/b cell maturation

Question 2

T cell positive and negative selection

Answer 2

• occurs in the thymus
• positive selection:
• thymic cortical epitherial cells express MHC
• immature double positive (CD4+/CD8+) thymocytes must recognize self to proceed
• negative selection:
• transcriptional regulator AIRE expressed by medullary thymic epithelial cells
• AIRE induces expression of peripheral tissue restricted antigens in the thymus (ex: insulin)
• bone marrow APC’s in the medulla present these self-antigens to the double positive T cells
• self-reactivity => apoptosis and low self-affinity => maturation

Question 3

B cell negative selection

Answer 3

• occurs in bone marrow
• if a B cell recongizes self antigen => receptor editing:
• induction of a second VJ recombination event to replace the self reactive light chain
• new light chain pairs with old heavy chain to make a new BCR
• if new BCR still recognizes self => apoptosis

Question 4

what are the three mechanisms of peripheral tolerance?

Answer 4

1. clonal anergy
2. clonal deletion
3. suppression by Tregs

Question 5

clonal anergy

Answer 5

• functional inactivation of a self reactive T cell (or B cell)
• process
• T cell recognizes antigen-MHC on the surface of a cell lacking expression of co-stimulatory molecules
• Instead of T cell CD28 binding APC B7, inhibitory CTLA-4 (on an activated T cell or Treg) binds B7
• B7 is removed from APC
• CTLA4 is in the secondary lymphoid organs; PD-1 plays a similar role in the periphery
• anergized cells cannot produce IL-2; anergy may be overcome with high levels of IL-2

Question 6

clonal deletion

Answer 6

• activation induced cell death = induction of apoptosis when T cells repeatedly encounter high levels of self antigen in the periphery
• process:
• continual TCR stimulation => FasL expression
• FasL on T cell interacts with Fas receptor on T/B cells
• Fas/FasL interaction => caspase cascade => apoptosis
• lack of Fas/FasL => autoimmune disease

Question 7

regulation/suppression

Answer 7

• Tregs (CD4+CD25+Foxp3+) cells mediate antigen specific suppression via cell/cell contact and secreted cytokines (IL-10 and TGF-b)
• activated by IL-2 from activated T cells => inhibited T cells in a negative feedback loop
• other T cells subsets also secrete cytokines to inhibit other subsets
• Th1 cells produce IFN-g which inhibits Th2
• Th2 cells produce IL-4 which inhibits Th1
• B cells can be inhibited by inhibitory receptor CD22

Question 8

factors that determine immunogenicity/tolerance of an antigen

Answer 8

• immunogenicity:
• short lived
• subcutaneous or intradermal
• antigens with adjuvants that stimulate helper T cells
• mature dendreitic cells have high levels of costimulators
• tolerance:
• persistent antigen receptor engagement
• IV, mucosal, in organs
• antigens lack adjuvants; no costimulation
• immature dendritic cells; low levels of costimulators

Question 9

what leads to autoimmunity?

Answer 9

1. genetic susceptibility
   - different MHC alleles, polymorphisms in non-HLA genes, single gene abnormalities
2. second hit: infection or trauma
   - molecular mimicry => costimulation for self-reactive T cell
   - inflammation, ischemic injury, trauma => tissue changes => epitope spreading: reveal new self antigens to immune system

* role of hormones: more prevalent in women

Question 10

gold standard treatment for autoimmune disease

Answer 10

• induced antigen-specific tolerance = specifically target only autoreactive T or B cells
• non specific immunosuppresion => side effects of infection and cancer
• administration of autoantigens can prevent/treat autoimmunity by directly targeting these antigens to APC’s in the spleen that induce tolerance