Immunological Tolerance and Autoimmunity Flashcards
What is immunologic tolerance?
Immunologic tolerance is a SPECIFIC UNRESPONSIVENESS to an Antigen
What is self tolerance?
Immunologic unresponsiveness to self-antigens
Every individual exhibits self tolerance
What is the general explanation for the occurrence of Autoimmunity?
Autoimmunity is a result from breakdown of self-tolerance
NOTE: A ow level of physiologic auto-reactivity is necessary for normal immune function
What is central tolerance?
Central tolerance ensures that mature lymphocytes are not reactive to self antigens
Induced in immature self-reactive lymphocytes in primary lymphoid organs (Bone Marrow, Thymus)
Immature lymphocytes specific for self-antigens may encounter these antigens in the generative (central) lymphoid organs and are either:
- Deleted (apoptosis)
- Changed BCR specificity (B cells ONLY)
- Develop into Treg cells
What is peripheral tolerance?
Peripheral tolerance is needed to prevent activation of these dangerous self-reactive lymphocytes in tissues
Induced in mature self-reactive lymphocytes in peripheral sites (not primary lymphoid organs)
Mature self-reactive lymphocytes in the peripheral tissues may be either:
- Inactivated (ANERGY)
- Deleted (apoptosis)
- Suppressed by Treg cells
How does central tolerance work for T cells?
Thymus has a special mechanism for expressing many protein antigens that are present only in certain peripheral tissues
The dendritic cell presents self-circulating proteins (ie plasma proteins) to the immature CD8+and CD4+ T cells in the thymus
AIRE is present inside a medullary thymic epithelial cell that presents tissue restricted antigens to immature CD8+ and CD4+ T cells
Recognition of self-antigens/TCR signaling by immature T cells in the thymus leads to death of cells by negative selection (via mitochondrial pathway of apoptosis) or development of Treg cells that enter the peripheral tissues
Thymocytes that are STRONGLY reactive to self (determined by interactions with MHC-self peptide complexes) and nonfunctional thymocytes showing no affinity undergo apoptosis
Only thymocytes that are activated by MHC-self peptide complexes below a certain threshold are positively selected and migrate into the periphery as mature T cells
Most of these T cells develop into CD4+ or CD8+ T cells and mediate cell-mediated and humoral responses
A small percentage of T cells that emigrate from the thymus express FOXP3 and develop into natural CD4+ CD25+ CTLA4+ Treg Cells
How does anergy occur as a result of Peripheral T Cell Tolerance mechanisms?
Self-reactive T cells can also become functionally unresponsive (ANERGY)
Anergic cells survive but are incapable of responding to antigen
Antigen recognition without costimulation (No B7 by APC) induces anergy
T cells may engage inhibitory receptors CTLA4 or PD-1 after antigen stimulation which will block activation and make the T cell anergic
Cancer patients can be treated with anti-CTLA4 and anti-PD-1 drugs that block these receptors and enhance anti-tumor immune responses and tumor regression
- This is called checkpoint blockade
- Downside is that checkpoint blockade can lead to autoimmune reactions (T cells are overstimulated)
How do Treg Cells participate in Peripheral T cell Tolerance?
Cells with very high TCR self avidity will undergo negative selection
But cells that express FOXP3 (by chance) will survive cells even if they have relatively high avidity to self antigens (these become Treg cells)
Treg cells produce anti-apoptotic molecules which protect them from negative selection in the thymus
Treg cells express FOXP3 transcriptional factor and are CD4+ CD25+ and express high levels of CTLA4
The generation of some Treg cells requires TGF-beta
Treg cells also need IL-2 for survival and functional competence
Treg cells are endogenous long-lived populations of self-antigen-specific T cells that serve to prevent autoimmune reactions
Natural T reg cells are produced by self antigen recognition in they thymus
Inducible Treg cells are produced by antigen recognition in LNs and GI tract
The development and survival of these Treg cells require IL-2 and FOXP3
Self reactive T cells in the peripheral tissues can have activation suppressed by Treg cells
What are Inducible Treg cells?
Mature T cells outside of the thymus can also acquire Treg phenotype and function (these are called induced Treg cells and they differentiate in the periphery)
FOXP3 can be induced in naive CD4+ cells in vitro by antigen recognition in the presence of TGF-beta
Close relathionship between iTregs and Th17 cells
iTreg differentiation caused by antigen recognition with:
- IL-2
- TGF-beta
- Retinoic Acid
Retinoic acid produced by DCs facilitates de novo generation of FOXP3+ Treg cells from CD4+ CD25+ T cells
Antigen recognition in the presence of TGF beta induces FOXP3 expression only if IL-6 is not present (leading to Th17 cell differentiation)
What is the mechanism of Treg Cells?
Treg cells may inhibit T cell activation by APCs and inhibit T cell differentiation into CTLs
When a Treg cell interacts with an APC via cell contact it secretes IL-4, IL-10, and TGF-beta
- This causes APC to downregulate CD40, B7, and IL-12 while upregulating IL-10
- Inhibits effector T cells
Treg cells may also prevent Th cells from helping B cells produce antibodies
Treg cells release inhibitory cytokines like IL-10 and TGF -beta
Treg cells are also involved in cytolysis via granzyme A and granzyme B dependent and perforin dependent killing mechanisms
Treg cells can also cause metabolic disruption
- High affinity CD25 (IL-2 receptor) deprives cells from IL-2, causing apoptosis
- cAMP-mediated inhibition through gap junctions
- Adenosine receptor 2A (A2AR)-mediated immunosuppression
Treg cells can target dendritic cells by expressing CTLA4 that binds B7 (CD80/CD86) on the dendritic cell (inhibitory receptor) and induction of IDO which degrades essential amino acid Tryptophan
How does peripheral T Cell Tolerance lead to apoptosis of mature lymphocytes?
Self-reactive T cell in the periphery can be deleted via apoptosis (deletion)
Cell death can be caused in 2 ways:
- Mitochondrial (Intrinsic) Pathway
- Death receptor (extrinsic) pathway
What is the Mitochondrial (intrinsic) pathway of apoptosis?
Antigen recognition without costimulation leads to apoptotic proteins being released from mitochondria
Signal for apoptosis:
- Bcl2 and Bcl-xL are anti-apoptotic factors that inactivate pro-apoptotic factors Bax and Bak
- Bcl2 and Bcl-xL require co-stimulation in order to be produced
- Without Bcl2 and Bcl-xL, Bax and Bak are free to induce apoptosis
- Bax and Bak promote the release of Cytochrome C from the mitochondria
- Cytochrome C activates Caspase 9
- Caspase 9 activates Caspase 3
- Caspase 3 causes DNA breakdown and cell apoptosis
What is the Death Receptor (extrinsic) pathway of apoptosis?
The extrinsic signal for apoptosis is the binding of the FasL ligand (on activated T cells) to Fas receptor on the target cell
The binding of the ligand and the receptor causes Caspase 8 in the target cell to become activated
Activates Caspase 8 activates Caspase 3
Caspase 3 causes DNA breakdown and apoptosis of the target cell
What is the mechanism responsible for Central B Cell Tolerance?
Immature B cells that recognize self-antigens in the bone marrow with HIGH avidity have two options:
- Death by apoptosis within 2-3 days (clonal deletion)
- Receptor editing
Weak recognition of self antigens in the bone marrow leads to anergy of the B cells
Anergic B cells are unresponsive to subsequent stimulation but are allowed to migrate into the peripheral compartment but cannot enter a follicle in lymph nodes/spleen and have low life span
How does Central B cell Tolerance lead to Receptor Editing?
If B cell has strong affinity for self antigens, it may undergo Receptor Editing and change the specificity of their BCRs to become a non-self reactive B cell
Receptor editing involves further rearrangement and replacement of the Ig Light-chain genes (since there is lambda and kappa available) until non-self recognizing receptors are produced or the cell dies
Pre-BCR light chain pairs with the existing Heavy chain to form a non-autoreactive BCR that promotes the selection of these edited B cells into the periphery
This process uses RAG1 and RAG2
