Immunogenetics

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Immunogenetics

Immunogenetics is the study of the mechanisms of autoimmune diseases, tolerance in organ transplantation, and immunity to infectious diseaseswith a special emphasis on the role of the genetic make-up of an organism in these processes. The immune system evolved essentially to protect vertebrates from a myriad species of potentially harmful infectious agents such as bacteria , virus, fungi and various eukaryotic parasites . However, the growing understanding of the immune system has influenced a variety of different biomedical disciplines, and is playing an increasingly important role in the study and treatment of many human diseases such as cancer and autoimmune conditions.

There are two broad types of immune systems. The innate immune system of defense depends on invariant receptors that recognize common features of pathogens, but are not varied enough to recognize all types of pathogens, or specific enough to act effectively against re-infection by the same pathogen. Although effective, this system lacks both specificity and the ability to acquire better receptors to deal with the same infectious challenge in the future, a phenomenon called immunological memory. These two properties, specificity and memory, are the main characteristics of the second type of immune system, known as the specific or adaptive immune system, which is based on antigen specific receptors. Besides these two families of different receptors that help in immune recognition of foreign infectious agents, both the innate and the adaptive immune systems rely on soluble mediators like the different cytokines and kemokines that allow the different cells involved in an immune response to communicate with each other. The major focus of immunogeneticists is the identification, characterization, and sequencing of genes coding for the multiple receptors and mediators of immune responses.

Historically, the launch of immunogenetics could be traced back to the demonstration of Mendelian inheritance of the human ABO blood groups in 1910. The importance of this group of molecules is still highlighted by their important in blood transfusion and organ transplantation protocols. Major developments that contributed to the emergence of immunogenetics as an independent discipline in immunology were the rediscovery of allograft reactions during the Second World War and the formulation of an immunological theory of allograft reaction as well as the formulation of the clonal selection hypothesis by Burnett in 1959. This theory proposed that clones of immunocompetent cells with unique receptors exist prior to exposure to antigens, and only cells with specific receptors are selected by antigen for subsequent activation. The molecular understanding of how the diverse repertoire of these receptors is generated came with the discovery of somatic recombination of receptor genes, which is the paradigm for studying gene rearrangement during cell maturation.

The most important influence on the development of immunogenetics is, however, the studies of a gene family known as the MCH, or major histocompatibility complex . These highly polymorphic genes, first studied as white-cell antigens of the blood and therefore named human leukocyte antigens (HLA ), influence both donor choice in organ transplantation and the susceptibility of an organism to chronic diseases. The MHC is also linked with most of all the important autoimmune diseases such as rheumatoid arthritis and diabetes.

The discovery in 1972 that these MHC molecules are intimately associated with the specific immune response to viruses led to an explosion in immunogenetic studies of these molecules. This has led to the construction of very detailed genetic and physical maps of this complex and ultimately to its complete sequence in an early stage of the human genomesequencing project.

Other clusters of immune recognition molecules that are well established at the center of the immunogenetics discipline are the large arrays of rearranging gene segments that determine B-cell immunoglobulins and T-cell receptors. Immunoglobulins, which mediate the humoral immune response of the adaptive immune system, are the antibodies that circulate in the bloodstream and diffuse in other body fluids, where they bind specifically to the foreign antigen that induced them. This interaction with the antigen most often leads to its clearance. T cell receptors, which are involved in the cell-mediated immune response of the adaptive immune system, are the principle partners of the MHC molecules in mounting a specific immune response. An antigen that is taken up by specialized cells called antigen presenting cells is usually presented on the surface of this cell in complex with either MHC class I or class II to T cells that use specific receptors to recognize and react to the infectious agent. The reacting T cells can kill the host cells that bear the foreign antigen or secrete mediators (cytokines and lynphokines) that activate professional phagocytic cells of the immune system that eliminate the antigen. It is believed that during disease epidemics , some forms of class I and class II MHC molecules stimulate T-cell responses that better favor survival. Which MHC molecule is more favorable depends on the infectious agents encountered. Consequently, human populations that were geographically separated and have different disease histories differ in the sequences and frequencies of the HLA class I and class II alleles.

Other immune recognition molecules that were studied in great details in immunogenetics are two families of genes that encode receptors on the surface for natural killer (NK) cells. These large lymphocytes participate in the innate immune system and provide early defense from a pathogens attack, a response that distinguish them from B and T cells which become useful after days of infection. Some NK-cell receptors bind polymorphic determinants of MHC class I molecules and appear to be modulated by the effects that infectious agents have upon the conformation of these determinants.

One of the most important applications of immunogenetics in clinical medicine is HLA-typing in order to help match organ donors and recipients during transplantation surgery. Transplantation is a procedure in which an organ or tissue that is damaged and is no longer functioning is replaced with one obtained from another person. Because HLA antigens can be recognized as foreign by another person's immune system, surgeons and physicians try to match as many of the HLA antigens as possible, between the donated organ and the recipient. In order to do this, the HLA type of every potential organ recipient is determined. When a potential organ donor becomes available, the donor's HLA type is determined as well to make absolutely sure that the donor organ is suitable for the recipient.

See also Autoimmunity and autoimmune diseases; Immunity, active, passive and delayed; Immunity, cell mediated; Immunity, humoral regulation; Immunologic therapies; Immunosuppressant drugs; In vitro and in vivo research; Laboratory techniques in immunology; Major histocompatibility complex (MHC); Medical training and careers in immunology; Molecular biology and molecular genetics; Mutations and mutagenesis; Oncogenetic research; Transplantation genetics and immunology; Viral genetics

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Immunogenetics

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