Immunologic Tolerance Lecture 18 Immunologic Tolerance

Importance of Regulation Inappropriate immune responses can have life-threatening consequences! Immune Response to self Ags Tolerance to pathogens Mechanisms of regulation are not very well understood.

Tolerance State of immune system unresponsiveness to an antigen. Failure to Respond to an antigen Tolerance to self antigens-Essential feature of the immune system Loss of tolerance to self: Destruction of self tissues-Autoimmune disease

Postulated Mechanisms of Autoimmunity

General Features of Immunologic Tolerance Tolerance is immunologically specific Induced by inxs. of antigen with antigen receptors Tolerance to self is learned/acquired Immature or developing lymphocytes are more susceptible to tolerance induction Tolerance to foreign antigens is induced even in mature lymphocytes

Tolerance Central Tolerance Peripheral Tolerance Tolerance established in lymphocytes developing in central lymphoid organs Peripheral Tolerance Tolerance acquired by mature lymphocytes in the peripheral tissues.

Basic Mechanisms of Tolerance Clonal Deletion Immature lymphocytes eliminated by apoptosis during T or B cell maturation. Clonal Anergy Naive T and B cells exposed to foreign /self Ag are inactivated or rendered unresponsive to restimulation-Functional Inactivation-Tolerogens

T Cell Tolerance

Mechanisms of T Cell Tolerance Clonal Deletion Deletion of self-reactive clones of CD4+ and CD8+ T cells in the thymus by Negative Selection Clonal Anergy-Peripheral lymphoid organs Regulatory Lymphocytes-Suppress T Cell Activation Clonal Ignorance

Peripheral T Cell Tolerance THYMUS Escape from Clonal Deletion Suppression by Regulatory T Cells PERIPHERY Autoreactive T cell (Naïve) MHC/Ag No Costim. Antigen Sequestered MHC/Ag + Costim. Clonal Ignorance Autoimmunity Clonal Anergy

Clonal/Immunological Ignorance

Immunologically Privileged Sites Tissue grafts placed in these sites are not rejected Antigens are sequestered in immunologically privileged sites Brain Anterior chamber of Eye Cornea Testis FasL Hamster Cheek Pouch

T cells specific to Myelin Transgenic Mouse has T cells specific to Myelin Basic protein (MBP) All the T cells carry the autoreactive TCR Brain autoantigen, MBP is sequestered in the CNS Normal, No Autoimmune Disease Immunological Ignorance

is sequestered in the CNS Transgenic Mouse TCR specific to Myelin Basic protein (MBP) All the T cells carry the autoreactive TCR Brain autoantigen, MBP is sequestered in the CNS Inject MBP With adjuvant No Autoimmune Disease Activation of Autoreactive T Cells Immunological Ignorance Migrate to tissues Including CNS Encephalitis and Death Activated T cells cross BBB and cause CNS disease

Trauma to one eye results in the release of sequestered intraocular antigens Released intraocular antigens carried to L. nodes and activates T cells Effector T cells return via blood stream and encounter antigen in both eyes SYMPATHETIC OPTHALMIA

Sequestered Antigens DO NOT induce a response by themselves Sequestered Antigens DO NOT induce a response by themselves. If a response is induced elsewhere they can serve as targets for attack.

Tolerance Induction in the Absence of Costimulation

Antigen recognition by T cells in the absence of costimulation leads to T cell Tolerance Naïve T cells recognizing self peptides on tissue cells are not activated, instead they enter a state of anergy/unresponsiveness.

T Cell-Mediated Suppression-Regulatory T Cells

Suppression of T Cell Responses by Regulatory T Cells

Oral Tolerance

Experimental allergic Dominant Immune Suppression Mouse develops Experimental allergic Encephalomyelitis Brain has TH1 CD4 cells Making IFNg Injected with adjuvant Spinal Cord Homogenate Brain has CD4 cells Making TGFb Healthy Mouse TGF-b suppresses the function of inflammatory TH1 Cells-Regulatory T Cells Feed Myelin Basic Protein Oral admn. of ag. can lead to protection against autoimmunity

B Cell Tolerance Deletion of Antigen-specific cells may occur as B cells arise in the bone marrow and encounter self antigens before they become functionally competent (immature). Clonal Anergy

Negative Selection and Receptor Editing in Immature B Lymphocytes

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