lecture 21 - Immunology 21-Immunological Tolerance...

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Unformatted text preview: Immunology 21-Immunological Tolerance Immunological Tolerance Tolerance= non-responsiveness to an antigen: A) self tolerance= non-responsiveness to self-antigens B) acquired (induced) tolerance= the suppression of a specific, systemic immune response to foreign antigens induced by the specific actions of lymphocytes Ex. Fetal tolerance= the suppression of a specific, systemic immune response to foreign antigens found within a developing fetus Ex. Oral tolerance= the suppression of a specific immune response against antigens encountered via the enteric (oral) route; tolerance to food and gut flora Layers of Self Tolerance Types of tolerance Mechanism Site of Action Central tolerance Deletion; editing Thymus; bone marrow Antigen segregation Physical barrier to self-antigen access to lymphoid system Peripheral organs ( thyroid, pancreas etc) Peripheral anergy Cellular inactivation by weak signalling without co-stimulation Secondary lymphoid tissue Regulatory T cells Suppression by cytokines, intercellular signals Secondary lymphoid tissue and sites of inflammation Functional deviation Differentiation of regulatory T cells that limit inflammatory cytokine secretion Secondary lymphoid tissue and sites of inflammation Activation-induced cell death apoptosis Secondary lymphoid tissue and sites of inflammation Antigen Segregation Most self antigens are retained outside of the lymphoid spleen by physical barriers (cell membranes, endothelium etc) In the absence of tissue damage (allows proteins to leak), these antigens are not encountered by immune cells Most self proteins are found in cells (sequestered) Immune Privileged Sites Brain, testes, eyes and placenta/fetus Immune system actively excluded; very tight barriers to blood; keep immune system out Sites capable of tolerating the introduction of an antigen without eliciting a damaging immune response Tissue grafts into these tissues often can survive without immunosuppressive drugs Ex. Cataracts; not affected by mismatched MHC haplotypes Mechanisms: Restricted entry of immune cells= tight vasculature, no adhesion molecules Expression of class Ib MHC (non classical) in preference to classical MHC I= dont present too many antigens to CD8 T cells; sufficient for NK cell activation High expression of complement inhibitors Local production of TGF-B (suppressive) Minimal/no draining lymphatics Constitutive expression of apoptosis-inducing ligands (FASL, TRAIL)=activate pro-apoptotic receptors on leukocytes Tissue specific immunomodulation; ex. Placenta= expression of indolamine 2, 3 dioxygenase (IDO) removes tryptophan, preventing T cells from proliferating; we cant synthesize our own Tryp FAS/FASL Trimeric Fas ligand binds to and trimerizes Fas (active form) clustering of the death domains in the Fas cytoplasmic domains allows Fas to recruit FADD via its death domain the clustered death effector domains (DED) of FADD recruit pro-...
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lecture 21 - Immunology 21-Immunological Tolerance...

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