6.3.2 Self Tolerance
Normal individuals are tolerant of their own antigens(self-antigen):
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6.3.2.1 Central tolerance
Central T cell tolerance
Positive and negative selection:
The key factor determining the choice between positive and negative selection is the strength of antigen recognition.
  • low-avidity recognition leading to positive selection
  • high-avidity recognition inducing negative selection
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Positive selection
Positive selection of thymocytes is to develop the self MHC-Restricted T cell repertoire.
  • positive selection works by promoting the selective survival and expansion of thymocytes with self MHC- restricted TCRs and by permitting thymocytres whose TCRs are not self MHC- restricted to die by apoptosis.
  • positive selection of T cells requires the recognition of self MHC molecules in the thymus by the TCRs of immature(double-positive) thymocytes.
  • During the trransition from double-positive to single-positive cells, thymocytes with class I- restricted TCRs become CD8+CD4-, and cells with Class II-restricted TCRs become CD4+CD8- .
  • Peptides bound to MHC molecules on theymic epithelial cells play an essential role in positive selection.
NOTE:
  • One consequence of self-peptide-induced positive selection is that the T cells that mature have some capacity to recognize self peptides. The survival of naive lymphocytes before encounter with foreign antigens requires survival signals that are apparently generated by recognition of self antigens.
  • How does positive selection drive by self antigens produce a repertoire of mature T cells specific for foreign antigens? The likely answer is that T cells that recognize self peptides with low affinity will, after maturing, fortuitously recognize foreign peptides with  high enough affinity to be activated and to generate immune responses.
Negative selection
  • Negative selection of thymocytes works by inducing apoptotic death of cells whose receptors recognize abundant peptide-MHC complexes in the thymus with high avidity.
  • this process is responsible for tolerance to many self antigens.
Central B cell tolerance
  • Tolerance in B lymphocytes is necessary for maintaining unresponsiveness to thymus- independent self antigens, such as polysaccharides and lipids. B cell tolerance may also play a role in preventing antibody responses to protein antigens.
  • Immature B lymphocytes that recognize self antigens in the bone marrow with high affinity either are deleted or change their specificity.
Mechanism:
  • Deletion by apoptotic death.
    • similar to the mechanism of negative selection of immature T cells in the thymus
    • Depends on the nature and concentration of self antigens as well as the affinity of the B cell receptor for that Ag.
    • Multivalent self antigens that can crosslink the B cell receptor and deliver a strong signal.
  • change in receptor specificity(receptor editing)
  • down-regulation of antigen receptor
Experimental model:
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6.3.2.2 Peripheral tolerance
From central to peripheral:
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In the case B or T cells, they have a receptor that recognizes self…
How do they escape negative selection?
  • Over-expression of low-affinity receptors
  • Availability of antigen for negative selection
    • Medullary Epithelial cells of the thymus can express a diverse selection of tissue- specific genes
    • Clearly, not all self antigens are available for negative selection
Peripheral T cell tolerance
Potential mechanism:
  • Lack of Co-stimulation
  • Failure to Encounter Self Antigens
  • Receipt of Death Signals
  • Control by Regulatory T Cells
Anergy
Anergy:
  • Lack of co-stimulators
  • Inhibitory receptor engagement
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induced by lack of costimulation
Co-stimulatory molecules…
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induced by inhibitory receptors
CTLA-4 receptor bind to B7 molecules
Deletion
Types and pathways of Apoptosis (Program Cell death):
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Deletion by program cell death in T lymphocytes:
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  • Deletion by activation-induced program cell death(AIPCD)
    • extrinsic death receptor pathway
      • repeated stimulation of T cells by persistent antigens leads to the coexpression of the two molecules, a death- inducing receptor called Fas(CD95) and its ligand, Fas ligand(FasL).
      • activation of caspase-8
    • intrinsic mitochondrial pathway
      • An important family of proteins called Bcl family proteins has two members: anti- apoptotic member(such as Bcl-2, Bcl-x) and pro-apoptotic member(such as Bim,Bax and Bak ). Anti-apoptotic member inhibit apoptosis by blocking the release of pro-apoptotic proteins like cytochrome c form mitochondria and by inhibiting the activation of caspase- 9. Pro-apoptotic member promote apoptosis by blocking the protective function of anti- apoptotic members.
      • repeated stimulation may trigger mitochondrial translocation of pro- apoptotic members of Bcl family(such as Bim,Bax, and Bak), which block the protective actions of the anti-apoptotic memers of Bcl family(such as Bcl- 2,Bcl-x) ,resulting cell death.
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  • Deletion by passive program cell death(death by neglect): more important for maintaining homeostasis than for self- tolerance
    • intrinsic mitochondrial pathway1
      • depletion of survival stimuli including antigens and growth factor leads to increased permeability of mitochondrial memberane and release of the pro- apoptotic protein:cytochrome c.
      • cytochrome c function as a cofactor of apoptosis activating factor-1(Apaf-1) to activate caspase-9
    • intrinsic mitochondrial pathway2
      • survival stimuli for lymphocytes function mainly by inducing the expression of anti- apoptotic protein of Bcl family.
      • the clones of lymphocytes that were activated by antigen are deprived of the essential survival simuli and die by apoptosis.
activation-induced cell death(fas-mediated)
  • activation-induced cell death: Repeated stimulation of T lymphocytes by persistent antigens results in death of the activated cells by process of apoptosis.
"passive cell death (fail to encounter self-antigen)
  • "passive" cell death (death by  neglect): elimination of antigen and other signals
  • Anatomic barriers that generally prevent T cell access.So called "privileged sites“
    • Eye
    • CNS – blood-brain barrier
Terminal signaling
Some tissues express signaling molecules that will initiate apoptosis in T cells.
  • FasL expression on target cells interacts with Fas on the T cell, inducing apoptosis
  • Many cell types in the eye express FasL constitutively
Inhibited by Regulatory T cells
Regulatory T cells (T regs):
Regulatory T cells inhibit immune responses by blocking activation and function of effector T cells
  • Suppress T cell activity
  • Release immunomodulatory cytokines
    • Interleukin 9 (IL-9)
    • Interleukin 10 (IL-10)
Transforming growth factor-beta (TGF-β)
Characteristics:
  • CD4 positive
  • High levels of CD25
  • Generated in thymus/LN
  • Activity depends on TxFr, Foxp3(intracellular)
Mechansim:
  • not well established
  • possibly by cytokine secretion (IL10, TGF-b)
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Perpheral B cell tolerance
  • Potentially self-reactive B cells in the periphery are kept in check by the general requirement for CD4+ T cell co-stimulation.
  • So, peripheral B cell tolerance is synonymous with peripheral T cell tolerance.
  • necessity
    • To maintain unresponsiveness to the CHO & lipid TI self Ags
  • To prevent Ab responses to some protein antigens
Mechanism(not well known):
  • Anergy
    • incapable of activating tyrosine kinases
    • lose the capacity to migrate into lymphoid follicles
  • Tolerance of helper T cells
Experimental model:
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