Central/Peripheral Tolerance Flashcards
Where does central tolerance occur
in the lymphoid generative organs
where does peripheral tolerance occur?
in the peripheral lymphoid tissue
how does central tolerance for T cells work?
thymic epithelial cells present self-Ags to immature T lymphocytes
if they do not recognize sellf-Ag —> they receive no survival signal, undergo apoptosis
if they recognize self-Ag too strongly —> they receive a death signal undergo apoptosis
what happens after central tolerance?
they mature and then migrate to the periphery where they can be activated
destruction of endocrine organs by antibodies
AutoImmune REgulator: failure of central tolerance
AIRE
AIRE
What is it, where is located etc
autoimmune regulator protein is suspected to be the mutation associated with failure of central tolerance to select viable lymphocytes
its located in medullary thymic epithelial cells
its associated with decreased expression of self-Ag
proposed as a transcription factor
what is the role of medullary thymic epithelial cells?
they present self-Ags to developing lymphocytes
AIRE’s regulate
tissue restricted antigens (TRAs)
these peptides are displayed by medullary thymic epithelial cells
who recognizes TRAs?
immature Ag-specific TCRs recognize tissue restricted antigens in the medulla
what is the central outcome of AIRE?
self-reactive lymphocytes fail to be eliminated
Strong recognition of self-Ags by immature T cells leads to
developing of either T(reg) cells that enter the peripheral tissues or apoptosis (negative selection)
T(reg) cell production
They are generated after strong interactions with self Ag in the thymus. After stimulation they produce strong anti-apoptotic molecules (in the thymus).
Their major cytokine requirement is TGF-beta.
Surface molecules expressed by T(reg) (both unique and common) + transcription factor + survival signal
CD4+, CD25+ (unique), FOXP3, IL-2 is the survival signal
What is the role of T(reg)?
Long lived endogenous cells that prevent autoimmune reactions
Natural/Inducible T(reg) cells
“natural” have been present in the absence of the non-immunized; generated by self-Ag recognition in the thymus
inducible T(Reg) are produced by Ag recognition in the LNs
what is their role in peripheral tissue?
they protect against self-reactive lymphocytes
What cells do T(reg) inhibit?
inhibit T cell responses, inhibit other cells like B cells and NK cells
What cytokine do the iT(regs) produce
IL-10, anti-inflammatory
T(reg) Immunosuppressive “acts”
contact inhibition
reduces APC expression of:
IL-12 (can not influence Th1 or activate phagocytes)
CD80/86
but T(reg) upregulates expression of:
IL-10
T(reg) Immunosuppressive “acts”
Immunosuppressive Cytokines
IL-4, IL-10, TGF-beta inhibit
CD40 expression on APC
TGF-beta: effects on T cells
inhibits proliferation of T cells
inhibits differentiation of Th1 and Th2 effector cells in cooperation with IL-6 and IL-1
TGF-beta: effects on phagocytes
inhibits macrophage activation
TFG-beta: effects on T(reg)
regulates differentiation of FOXP3 T(reg)s
TGF- beta on Abs
stimulates IgA by inducing isotype switching
TGF-beta effects on tissues
promotes tissue repairs by stimulating collagen synthesis by macrophagea and fibroblasts
Breaking peripheral tolerance
impaired production of T(regs)
FOXP3 deficiency —>
IPEX, impaired production of FOXP3
Impaired tolerance induction of apoptotic cells =
complement impairment of C1q and C4
Altered immune signaling
CTLA-4 polymorphisms
CTLA-4 polymorphisms produce what two effects
failure of T cells to undergo anargy: lymphoproliferation of T cells in multiple organs, especially the heart
lethal by 4-5 wks
IPEX
FOX03 deficiency: failure of T(reg) to develop
SLE
deficiency of C4. defective clearance of immune complexes
ALPS
autoimmune lympho-proliferative syndrome (ALPS)
problem with Fas/FasL
defection deletion of anergic self-reactive B cells
nephritis, arthritis, etc
problems with IL-2
inflammatory bowel disease
anti-erythrocyte and anti-DNA autoantibodies
defective development, survival or function of regulatory T cells
What do CTLA-4s do?
during self-Ag recognition, CTLA-4 inhibits CD28/B7 interactions by replacing CD28
terminate T cell response
THEY TERMINATE IMMUNE RESPONSE AND MAINTAIN SELF TOLERANCE
CLTA-4 KO would lead to
uncontrolled lymphocyte proliferation
CTLA-4 deficiency leads to
autoimmune illness such as type I diabetes (autoreactive T lymphocytes attacking pancreas?), Graves disease, etc.
Two important actions of CTLA-4 cells
1) expressed on low/resting T cells until Ag activation
2) once expressed, they terminate T cell activation
CTLA-4 is expressed on T(reg) and mediates suppressive function of these cells by inhibiting the activation of naive T cells
How CTLA-4 works on APCs
CTLA-4 can either directly prevent APCs from activating other cells by inhibiting CD80/86 expression (Cell intrinsic function of CTLA-4)
or
CTLA-4 can reduce B7 expression by binding to APC while it interacts with T cells, and in this way “blocking and removing” of B7’s costimulatory effects on T cells
(apparently cell extrinsic ctla-4)
Central B CELL tolerance
immature B cells that recognize Ag in bone marrow with high avidity die by apoptosis OR undergo receptor editing and change the specificity of their BCRs
weak recognition of self-Ags in the bone marrow may lead to anergy of the B cells
There are 3 outcomes for self-Ag recognition in B cell central tolerance
1) strong avidity —> apoptosis –> dead B cell
2) strong avidity —> receptor editing –> non-self reactive B cell
3) no avidity –> anergic B cells
Peripheral B cell tolerance
non-T cell assisted recognition of self-Ags may lead to apoptosis or anergy
defects in CD22 –>
no inhibitory signals, autoimmunity
defects in Lck phosphorylation
no inhibitory signals, autoimmunity
defects in SHP-1 tyrosine phosphatase
no inhibitory signals, autoimmunity
