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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= don’t 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 can’t 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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- Spring '11
- Pathology, cells