Tolerance & Autoimmunity

Two major aspects to regulation of the immune response 1. Developmental pathways of immunocompetence 2. Response of mature lymphocytes to antigen Breakdown of control mechanisms Autoimmunity

Tolerance State of unresponsiveness to a particular antigenic epitope occurred by inactivation (turn off) of an antigen-specific lymphocyte antigen lymphocyte (immature or mature) interaction deletion anergy

Mutually tolerant of skin grafts The earliest experiment demonstrating tolerance by Ray Owens in 1945 Dizygotic cattle twins shared a common vacscular system in utero Mutually tolerant of skin grafts one another as adults

Neonatal tolerance demonstrated by Peter Medawar in the 1950s Figure 11.1 Rejection or acceptance of a skin graft from an MHC-distinct mouse. Line 1: Adult recipient of strain A mouse rejects skin graft from MHC-distinct strain B donor. Line 2: Adult strain A mouse which was injected within 24 hours after birth with spleen cells from strain B or from an (A X B)F1 accepts a strain B skin graft. The neonatally-injected mouse is tolerant to B-strain MHC molecules.

Induction of tolerance in immature T and B lymphocytes (central tolerance) If immature T and B cells are exposed to foreign antigens, the result is inactivation rather than activation (negative selection). Mechanisms Anergy, receptor editing, deletion and clonal ignorance

Anergy : the functional inactivation of a cell, resulting in Anergy : the functional inactivation of a cell, resulting in nonresponsiveness upon contact with self antigen Fig. 12.1 Lack of co-stimulation leads to B cell anergy. Two signals are required for B cell activation by a T-dependent antigen. Signal 1 is provided by antigen binding to and cross-linking the BCR. Signal 2 is provided by the interaction of CD40L expressed on the T cell with CD40 on the B cell.

Fig. 12.2 Antigen recognition in the absence of costimulation leads to T cell anergy. Two signals are required for T cell activation to secrete IL-2. Signal 1 is provided by the recognition of peptide + MHC. Signal 2 is provided by the interaction of a co-stimulatory molecule (B7) expressed on the surface of an APC (mature dendritic cell) and a receptor (CD28) on the surface of T cell. If a T cell receives signal 1 in the absence of signal 2, it is anergized.

Receptor editing Reactivation of RAG-1 and RAG-2 genes --- V1 + J5 --- Clonal ignorance : a state whereby autoreactive lymphocytes are neither anergized, deleted, nor receptor edited; yet, co-existed with antigen and remain in an unactivated state because of their weak affinity for the autoantigen or a low concentration of autoantigen. Unlike anergic cells, they can be activated under certain conditions.

Induction of tolerance in mature T and B lymphocytes (peripheral tolerance) 1. Inhibition of T and B cell activation (Anergy) - Inhibition of T cell activation: MHC-TCR interaction without IL-2 and costimulatory signals(CD28-B7) Inhibition of B cell activation: absence of T cell help 2. Activation-induced cell death 3. Active suppression via T cells : suppressor T cells

Fig. 12.3. The life span of an autoreactive T cells is directly related to the extent of receptor cross-linking, which depends on the avidity of interaction between the T cells and APC. Fig. 12.4 Fas mediated apoptosis of T cells

Two other types of T cells having suppressor activity: or CD4+ T cells or CD4+ T cells (10% of peripheral CD4+ T cells) Two other types of T cells having suppressor activity: - type 1 T regulatory cells (Tr1): CD25- or CD25low produce high level of IL-10 and TGF-b, but no IL-2 & IL-4 - TH3 cells: primarily produce TGF-b, variable level of IL-4 & IL-10 involved in oral tolerance

Regulation of the response in the individual Age Nutrition MHC molecules Effects of cytokines Effects of antigens 1) Dosage 2) Antigen sequestration 3) Nature of antigen 4) Form of the antigen: soluble or aggregated 5) Metabolism of the antigen Regulation of antibody

Immunosuppression by drugs or radiation Immunosuppressive drugs Methotrexate & cyclophophamide: kill rapidly dividing cells Corticosteroids: affect wide range of cells and inhibit inflammatory responses Cyclosporine & FK506: prevent T cell acitivation by inhibition of the synthesis of IL-2 and other cytokines Rapamycin: blocks the signal pathway of the IL-2/IL-2R Radiation: affects hematopoietic and lymphoid systems