Lecture 18: Immunological Tolerance & Autoimmunity Flashcards
What is immunological tolerance? (IT)
What is self-tolerance?
What results from the BD of self-tolerance?
- Specific unresponsiveness to Ag
- all individuals are tolerant to self-Ags
- autoimmunity
___ tolerance is induced in immature self-reactive lymphoctes in _____ lymphoid organs.
- what would this ensure?
___ tolerance is induced in mature self-reactive lymphoctes in _____ sites.
- what would this ensure/prevent?
Central tolerance & primary are NOT REACTIVE to self Ags
Peripheral tolerance & in peripheral sites –> prevents activaiton of pot. dangerous lymphocytes in tissues
Describe central tolerance, where it’s located & the 3 fates
IMMATURE lymphocytes specific for self Ags –> may encounter self Ags in generative lymphoid organs (THYMUS and BM) –> either:
- apoptosis (deletion)
- change BCR specificity (B cells only)
- develop into Treg cells
Describe peripheral tolerance, where it’s located & the 3 fates
MATURE self reactive lymphocytes in PERIPHERAL TISSUES are either:
- inactivated via ANERGY
- deleted via APOPTOSIS
- suppressed by Treg cells
Central B cell Tolerance:
- What happens with high avidity self Ag recognition?
- What happens with low avidity self Ag recognition?
- They either die by apoptosis or remain in BM to undergo BCR receptor editing (rearranging IgL chain genes; this occurs until non-self recognizing receptors are produced or the cell dies)
- Ungergo anergy = funcitonal inactivation
Which pathway is used to for deletion of self-reactive lymphocytes in primary lymphoid organs?
Mitochondrial (intrinsic) pathway
- the death receptor (extrinsic) pathway does not operate in the thymus or BM
Central T Cell Tolerance:
What are the two outcomes of immature T cells that recognize self Ags in thymus?
- Undergo NEGATIVE SELECTION –> cell death/apoptosis
- Develop into Treg cells (if they express FOXP3)
- How are Treg cells POSITIVELY SELECTED for in the thymus?
- What do these Treg cells express?
- What cytokine is critical for survival and competence of Treg cells?
- Via strong TCR interactions with self Ags
- FOXP3, CD4+, CD25+ (IL-2aR) and CTLA-4
- IL-2
These are known as NATURAL Treg cells
Prevent AUTOIMMUNE rxns in tissues
- How are inducible Treg cells created? (iTreg)
- What cell formed w/ TGF-beta + IL-2?
- What cell is formed with TGF-β + IL-6??
- iTreg cells produced by Ag recogntion in LN* and GI tract (peripheral tissues)
- FOXP3 expression induced in naive CD4+ cells upon Ag regoc. in the presence of TGF-β
- iTreg cell is formed
- Th17 cell (TGF-β + IL-6 prevents FOXP3 expression, induces retinoic acid receptor (RAR), RORγt expression leading to Th17 cell differentiation)
What are the key cells/mediators of peripheral tolerance?
Treg cells
- inhibit T cell activaiton
- prevent T cell help to B cells in production of Abs
- immunosuppressive cytokines: IL-10, TGF-β, IL-35
- IL-2 consumption –> deprive effector T cells of IL-2
What are the major effects of TGF-β (transforming growth factor-β)?
- inhibit proliferation of & fxns of effector T cells
- inhibits development of Th1 & Th2 cells
- PROMOTES Th17 IF IL-6 and IL-1 present
- inhibits M1 macrophages (strong APC capacity)
- regulates differentiation of induced FOXP3 Treg cells
- Stimulates switch IgM–> IgA
- promotes tissue repair & collagen synthesis by production of fibroblasts
What are the 3 mechanisms of peripheral T cell tolerance?
-
anergy (functional unresponsiveness –> when APC presents Ag but with no costimulatory signal)
- without CD80:CD28 costimulation
- anergic cells survive but incapable of responding to Ag
-
suppression (block activation by Treg cells)
- T cell engages CTLA-4 or PD-1 inhibitory receptors causing suppression of T cell response
- these are both expressed on CD4+ and CD8+ T cells after Ag stimulation
-
deletion (apoptosis)
- mitochondrial/intrinsic pathway (caspase 8 and 3)
- Death receptor (extrinsic pathway)
- Fas (FasL on T cell) and TNF receptor
What are the 3 mechanisms of peripheral B cell tolerance?
- Anergy -
- occurs when matuer B cells recog. self Ags in absence of Th cells –> will be rendered unresponsive or die via apoptosis
- Deletion/apoptosis (explanation above)
- Regulation by inhibitory receptors
- CD22 inhibitory receptor –> phosphorylated by Lyn –> recruits SHP-1 Tyr phosphatases attenuating BCR signaling
What is essential for helping to maintain B cell tolerance to self Ags?
Defects in what can lead to autoimmunity??
CD22 = inhibitory B cell coreceptor
- Lyn-mediated phosphorylation of CD22
- Recruitment of Shp-1 phospatase
- Dephosphorylation of BCR signaling components
- Leads to inhibited BCR signaling
Defects in Lyn Tyr kinsae, SHP-1 Tyr phosphatase & CD22
What is the only mutation that breaks central tolerance??
AIRE (autoimmune regulator)
- AIRE regulates expression of tissue-restricted Ags (TRAs)
- peptides from TRAs are displayed on medullary thymic epithelial cells
- In absence/mutation of AIRE: self reactive T cells are not eliminated (failure of neg. selection) & they enter tissues where Ags continue to be produced & cause injury
- can cause Autoimmune polyendocrine syndrome (APS)
