1 Immunological tolerance and regulating immune responses Shiv Pillai, MD PhD Massachusetts General Hospital 2 Lecture outline • Mechanisms of central and peripheral immune tolerance B cell tolerance T cell tolerance • Regulatory T cells • Lymphocyte Exhaustion • Autoimmunity • Integration and Summary GOD Self Non-Self Recognition 4 CENTRAL LYMPHOID ORGANS PERIPHERY Y Y Receptor Mature Central Naïve assembly Tolerance Cells EDIT OR ELIMINATE SELF- REACTIVE CELLS Pos. and Neg. Selection of Lymphocytes Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint of Elsevier Inc. Germline Organization of Human Ig Loci Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint of Elsevier Inc. Checkpoints during B cell development 7 8 Distant segments are recombined during receptor assembly 9 Receptor editing is the major mechanism of central B cell tolerance Multivalent high Oligovalent high affinity Low affinity self reactive B cells affinity self induces may persist - potentially dangerous self induces receptor editing anergy (and maybe deletion) Y Y Y BONE PERIPHERY: MARROW ANERGIZED B CELLS NEED BAFF Self-antigen Self-reactive B Edited B cell cell Receptor editing occurs in the bone marrow 11 ONE STEP L-CHAIN REARRANGEMENT DRIVES RECEPTOR EDITING Anergy Clonal Ignorance Deletion Tregs Mature B cell Somatically mutated Pathogenic IgG memory B cell MULTIPLE MECHANISMS OF PERIPHERAL B CELL TOLERANCE An overview of T cell development 13 14 Selection Events in Double and Single Positive Thymocytes 15 Consequences of self antigen recognition in thymus From: Abbas. Pillai & Lichtman, Cellular & Molecular Immunology 8th ed 2014 Deletion of self-reactive T cells in the thymus: 16 how are self antigens expressed in the thymus? AIRE (autoimmune regulator) is a regulator of transcription that stimulates expression of many self antigens in the medullary epithelial cells of the thymus, required for deletion of self-reactive thymocytes Mechanisms of peripheral T cell tolerance 17 T cell anergy- no Signal Two and role for CTLA-4 18 Inhibitory Receptors Dampen Immune Responses 19 They help mediate: 1.Peripheral Tolerance 2.Lymphocyte Exhaustion 3.Activation Induced Cell Death CTLA-4, PD-1, TIM-3 etc 20 Balancing lymphocyte activation and control Activation Inhibition Effector T cells Regulatory T cells, Anergy, AICD, Exhausted T cells Normal: reactions against pathogens No response to self Pathologic: inflammatory Controlled response to disease, e.g. caused by pathogens reactions against self or pathogens 21 Properties of regulatory T cells • Phenotype: CD4+, high IL-2 receptor (CD25), low IL-7 receptor, Foxp3 transcription factor; other markers • Significance: Foxp3 mutations --> autoimmune disease (IPEX); many autoimmune diseases may be associated with defects in or resistance to Tregs • Mechanisms of action: multiple – secretion of immune-suppressive cytokines (TGF, IL-10; IL-35?) – inhibition of APC function (role of CTLA-4?) 22 Regulatory T cells Inhibition of Self-reactive Peipheral B cells 23 Autoimmune diseases: failure of control Failure of tolerance Tolerance Lymphocyte activation Effector T cells Normal Inflammatory disease, e.g. reactions against self tissues Pathogenesis of autoimmunity Genetic defects Epigenetic Changes Break in tolerance and in immune Enhanced inflammation cells Microbes, microbial metabolites Availability of B and T cell clones in IgG4-RD subjects may facilitate studies on epigenetic alterations Pathogenesis of organ-specific autoimmunity 25 Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011 c Elsevier Model for the Pathogenesis of SLE Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011Copyright by © Saunders,2011 by Saunders, an an imprint imprint of ofElsevier Elsevier Inc. Inc. 27 A game of dice…......