lecture 6- autoimmunity

Question 1

autoimmune diseases result from ___ or ___

Answer 1

genetic factors or infection

Question 2

name 8 genetic/environmental factors that predispose to autoimmunity

Answer 2

1- break in T cell tolerance
2- incomplete deletion of T cells in thymus- AIRE deficiency
3- insufficient control of costimulation- CTLA4 deficiency
4- Treg cell dysfunction- FoxP3 deficiency
5- Fas/FasL
6- injury of privileged sites- eyes
7- infections leading to molecular mimicry- rheumatic fever
8- MHC haplotype

Question 3

describe tolerance

Answer 3

central tolerance happens during selection to avoid emergence of lymphocytes that are auto-reactive
- may try receptor editing in B cells to become less auto-reactive
- development of regulatory T lymphocytes (CD4)
- if autoreactive cell escapes to periphery, another layer should stop this…if T cell gets signal 1 and not 2 – anergy and death
- suppression- Treg inhibits autoreactive cell

Question 4

what is AIRE

Answer 4

TF expressed in medullary thymic epithelial cells- these cell involved in selection for T cells
- AIRE regulates expression of a wide variety of self-antigens
- if no AIRE, antigens cannot be displayed by thymic epithelial cells – failure of negative selection

Question 5

what is APECED

Answer 5

autoimmune syndrome in absence of AIRE

Question 6

CTLA4

Answer 6

naive T cell needs 2 signals- 2nd is interaction of B7 and CD28
- CTLA-4 is structurally similar to CD28, binds B7 with much higher affinity, it has the opposite activity of CD28
- negative regulator- can compete with CD28 for B7 and bind B7, inhibiting signal - dampens T cell responses and reduces their proliferation
- deficiencies in CTLA-4 cause widespread autoimmunity

Question 7

Tregs

Answer 7

• CD4 CD25 Treg
  in absence of Treg - widespread autoimmunity
• in absence of its TF FoxP3, no inhibitory signals produced by Tregs
• FoxP3 deficiency in humans called IPEX

Question 8

Fas-FasL

Answer 8

• first apoptosis signal receptor
• cells that express Fas are susceptible to death
• cells that express FasL are capable of inducing death of cells expressing Fas
• many T cells upregulate Fas expression after activation as part of contraction phase
• activates caspases - apoptosis cascade
• in absence of Fas-FasL, autoimmune disease because cannot properly facilitate the apoptotic cascade
• absence results in ALPS

Question 9

damage to privileged sites- eyes

Answer 9

results in sympathetic opthalmia
- trauma in one eye results in release of sequestered intraocular protein antigens

Question 10

infections can cause molecular mimicry

Answer 10

the same MHC molecule presents both a pathogen peptide and a self peptide that mimics it
- effector Th1 cell responds to the self-peptide mimic and activates the macrophage, causing inflammation