Autoimmunity I Flashcards
road to autoimmunity
Genetic factors + infection and environemntal exposure ..
immune regulation –> autoimmunity
AIRE deficiency
incomplete deletion of T cells in the thymus
CTLA4 deficiency
insufficient control of costimulation
FoxP3 deficiency
Treg cell dysfunction
eyes
immune priviledged site
autoimmunity results when tolerance fails
central tolerance
happens primarily during selection in primary lymphoid organs
Recognition of self antigen
- apoptosis (deletion)
- change in receptors (receptor editing by B cells)
- Development of regulatory T lymphocytes (CD4+ T cells only)
if an autoreactive cell escapes the central tolerance, the cell goes into
peripheral tolerance
- anergy
- apoptosis (deletion)
- suppression
AIRE promotes
central tolerance in the thymus
AIRE present
- negative selection of self reactive T cells: deletion
AIRE absent
- failure of negative selection , T cell would move into the periphery and react to self antigens - Autoimmunity
what is AIRE?
transcription factor found in medullary thymic epithelial cell
AIRE stands for
auto immune regulator, that is a transcriptional factor involved in transcriptional activation
mutations in AIRE
results in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED OR APS1) a syndrome charaterized by autoantibodies to multiple self antigens and lymphocytic infiltration of exocrine glands.
AIRE drives transcription of
some, but not all peripheral antigens in medullary thymic epithelal cells (mTECs)
AIRE may have other roles in negative selection
AIRE deficient mice develop autoimmune responses against antigens AIRE doesn’t regulate. Several genes associated with chemokine expression and antigen presentation are also downregulated in these animals
AIRE may have other roles in negative selection
AIRE deficient mice develop autoimmune responses against antigens AIRE doesn’t regulate. Several genes associated with chemokine expression and antigen presentation are also downregulated in these animals
if T cell recieves signal 1, without signal 2
signaling block –> unresponsive T cell (anergic T cell)
CTLA-4 structure
similar to CD28
upregulated on activated T cells
CTLA4 binds B7
with 20x the affinity of CD28
CTLA4 antagonizes the actvity of CD28
CTLA4 effect on T cell
dampens T cell responses on reduces their proliferation
- deficiency in CTLA4, causes widespread autoimmunity
CTLA4 and CD28 binding on T cell
signal block - inactivation of T cell activation
Blocking and removing b7 on APC
Reduced B7 costimulation - inhibition of T cell activation
core regulator of Treg cells
FoxP3
FoxP3 deficiency in humans
IPEX
present early in life, treated by bone marrow transplant
Fas-FasL
- 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 the contraction phase.
caspase 3 and caspace 9
induce apoptosis
immunologically priviliged sites
- brain
- eye
- testis
- uterus (fetus)
- hamster cheek pouch
Damage to a privilieged site result sin sympathetic opthalmia
- Trauma to one eye results in the release of sequestered intraocular protein antigens
- Released intraocular antigen is carried to lymph nodes and activates T cells
- Effector T cells return via bloodstream and encounter antigen in both eyes
molecular mimicry
- the same MHC molecule presents both a pathogen peptide and a self made peptide that mimics it
- Naive T cells is activated by the pathogen peptide presented by the particular MHC molecule
- Effector Th1 cell responds to the self-peptide mimic and activates the macrophage, causing inflammation.
influence of genetics on autoimmunity - monozygotic twins
Strong, but not complete. In SLE monozygotic twins 25% of both twins develop disease.
MHC on autoimmunity
DR3/4 correlated with diabetes
DR2
low representation in diabetic community
chronic nature of autoimmune disease
- normally during an acute immune responswe the antigen is cleared
- in autoimmune syndromes, for most part, antigen persists and the disease enters a chronic phase.
- during this time due to inflammation and tissue damage, more self antigens are exposed to the immune system leading to amplification of the response
in absence of AIRE patient would develop
APECED
