Lecture 5 - MHC & Immunological Tolerance PDF

The Immune System Major Histocompatibility Complex & Immunological Tolerance Histocompatibility Antigens Nucleated cells such as leukocytes and tissues possess many cell surface–protein antigens that readily provoke an immune response if transferred into a genetically different (all...

The Immune System Major Histocompatibility Complex & Immunological Tolerance Histocompatibility Antigens Nucleated cells such as leukocytes and tissues possess many cell surface–protein antigens that readily provoke an immune response if transferred into a genetically different (allogenic) individual of the same species. Some of these antigens constitute the major histocompatibility complex (MHC) referred to as the human leukocyte antigen (HLA) system in humans because its gene products were originally identified on white blood cells (WBCs, leukocytes). Very potent immunogens Play significant role in organ transplant rejection Histocompatibility Antigens The major histocompatibility complex (MHC) is a cluster of genes found on the short arm of chromosome 6 at band 2. These genes code for proteins that have a role in immune recognition. The MHC encodes the human leukocyte antigens (HLAs), which are the molecular basis for T cell discrimination of self from nonself. Transplanted tissue may trigger a destructive mechanism, rejection, if the recipient’s cells recognize the MHC protein products on the surface of the transplanted tissue as foreign, or if immunocompetent cells transplanted on the donor tissue target the foreign cells of the recipient for elimination. MHC MCH occurs as three classes Two classes function in antigen presentation  MHC I on virtually all tissue cells  MHC II only on PM some immune system cells Interacts with two major types of T cells  MHC I – CD8 (Cytotoxic)  MHC II - CD4 (Helper T cells) MHC III genes code for products that include secreted proteins that have immune functions eg. complement components, and inflammatory cytokines Cell Mediated: MHC display properties Figure 21.16a MHC I on virtually all tissue cells  Display only proteins produced inside the cell  Endogenous antigens = foreign proteins produced by the cell (viral / cancer)  Stimulate the CD8* cell population form cytotoxic T-cells (Killer T, TC) *formerly T8 cells Cell Mediated: MHC display properties Figure 21.16b MHC II found only on PM of B-cells, some T-cells & APCs  Display proteins derived from a phagocytized target  Exogenous antigen: foreign protein from outside the cell – presented to PM surface  Stimulates the CD4* cell population form Helper T-cells (T ) H *formerly T4 cells Histocompatibility Antigens Transplanted tissue may trigger a destructive mechanism, rejection, if the recipient’s cells recognize the MHC protein products on the surface of the transplanted tissue as foreign, or if immunocompetent cells transplanted on the donor tissue target the foreign cells of the recipient for elimination. HLA Genotypes and Risk of Disease HLA testing has increasingly been used as a diagnostic and genetic counseling tool. Knowledge of HLA antigens and their linkage has become important because of the recognized association of certain antigens (Box 31-1) with distinct immunologic- mediated reactions, autoimmune diseases, some neoplasms, and other disorders;  these disorders, although nonimmunologic, are influenced by non-HLA genes also located within the major MHC region. HLA Genotypes and Risk of Disease HLA and Organ Transplant The MHC gene products have an important role in clinical immunology. For example, transplants are rejected if performed against MHC barriers; thus, immunosuppressive therapy is required. These antigens are of primary importance and are second only to the ABO antigens in influencing the genetic basis of survival or rejection of transplanted organs. HLA and Organ Transplant HLA matching is of value in organ transplantation, as well as in the transplantation of bone marrow. There are 6 main HLA markers that the immune system uses to target foreign cells.  (Class I) HLA-A, HLA-B, HLA-C  (Class II) HLA-DR, HLA-DP, HLA-DQ The most important HLA antigens are HLA-A, and HLA- B. The best possible match is 6/6; the worst possible match is 0/6. Testing is done primarily by PCR. Immunological Tolerance Immunological tolerance is the state of unresponsiveness of T- and B-lymphocytes to a particular antigen. The clonal antigen receptors of lymphocytes are generated by random recombination of the many genes that code for the antigen binding regions. This creates the need to sort out dangerous receptors that could recognize and destroy self tissues. The breakdown of immunological tolerance to self- antigens is the cause of autoimmune diseases. Immunological Tolerance Since the specificity of the antigen receptors of T cells and B cells is the result of random shuffling of the many genes, theoretically, this process could generate more than 1015 different T-cell receptors, including some that can bind to autoantigens. The immune system, then, has to fulfill two contradictory requirements:  on the one hand the repertoire of different antigen receptors needs to be as large as possible to recognize all possible pathogens that attempt to evade immune detection.  On the other hand, the receptor repertoire must be shaped to prevent the immune system from attacking the host. Any disturbance in this delicately balanced system can have pathogenic or even lethal consequences, either from infections or from the unwanted reaction with autoantigens or harmless external antigens as in allergy. Immunological Tolerance Natural or "self" tolerance  This is the failure (a good thing) to attack the body's own proteins and other antigens. Induced tolerance  This is tolerance to external antigens.  Involves deliberately manipulating the immune system to protect us from unpleasant, even dangerous, allergic reactions to such things as food (e.g. peanuts), insect stings, grass pollen (hay fever). T-Cell Tolerance T cell tolerance is established at two levels:  Central tolerance: immature thymocytes undergo harsh selection processes in the thymus resulting in the deletion of most T cells with high affinity for self antigens.  Peripheral tolerance: mechanisms that reinforce and regulate mature T cell tolerance outside the thymus to avoid self- reactivity. Central Tolerance Central tolerance refers to the selection processes which T cell precursors undergo in the thymus before they are released as mature naive T cells. Thymic epithelial cells and dendritic cells present self-antigens to the immature T cell precursors. A specialized population of thymic epithelial cells is capable of expressing genes which are expressed in a strictly organ specific manner (e.g. insulin, which is expressed only in the pancreas and the thymus). Those T cell precursors that respond strongly to the self-antigens presented in the thymus undergo apoptosis; this is called negative selection. Those that recognize a peptide/MHC complex via the T cell receptor (but do not respond) receive a survival signal; this is called positive selection. Less than 5% of the T cell precursors survive these selection events and are allowed to exit the thymus as naive mature T cells. Central Tolerance Peripheral T-cell Tolerance Despite the intricate mechanisms of central tolerance induction in the thymus, approximately one third of the autoreactive clones are not deleted. Thus, a large number of low-avidity self-reactive T cells escapes into the periphery; thus, autoreactive T cells are part of the normal repertoire. Peripheral tolerance refers to mechanism that enforce and maintain T-cell tolerance outside the thymus. These include:  Immunological ignorance - the prevention of contact between auto- reactive T-cells and their target antigens  Anergy - the incapacity of T cells to mount effector responses upon recognizing their target antigen  the peripheral deletion of auto-reactive T-cells by activation-induced cell death or cytokine withdrawal  the suppression of immune responses by regulatory T cells. B cell Tolerance B cell tolerance is established by several mechanisms including:  clonal deletion of autoreactive B cells, mostly in the bone marrow  receptor editing - the rearrangement of autoreactive B cell receptors  B cell anergy - the incapacity of B cells to mount responses upon recognizing their target antigen B-cell tolerance is maintained by tolerant T cells. Therefore, if tolerance to a particular antigen is firmly established in the T-cell compartment, B-cells that recognize this antigen will usually remain tolerant. B cell Tolerance