Genes, B Cells, and Antibodies (Genetics & Inherited Conditions)
The fundamental question that led to the development of immunogenetics relates to how scientists are able to make the thousands of specific antibodies that protect people from the thousands of organisms with which they come in contact. Macfarlane Burnet proposed the clonal selection theory, which states that an antigen (that is, anything not self, such as an invading microorganism) selects, from the thousands of different B cells, the receptor on a particular B cell that fits it like a key fitting a lock. That cell is activated to make a clone of plasma cells, producing millions of soluble antibodies with attachment sites identical to the receptor on that B-cell surface. The problem facing scientists who were interested in a genetic explanation for this capability was the need for more genes than the number that was believed to make up the entire human genome.
It was Susumu Tonegawa who first recognized that a number of antibodies produced in the lifetime of a human did not have to have the equivalent number of physical genes on their chromosomes. From his work, it was determined that the genes responsible for antibody synthesis are arranged in tandem segments on specific chromosomes relating to specific parts of antibody structure. The amino acids that form the two light polypeptide chains and the two heavy polypeptide chains making up the IgG class of antibody are programmed by nucleotide sequences of DNA...
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Major Histocompatibility Genes (Genetics & Inherited Conditions)
In humans, the major histocompatibility genes encoding “self antigens” are also called the HLA complex and are located on chromosome 6. The nucleotides that compose this DNA complex encode for two sets of cell surface molecules designated MHC Class I and MHC Class II antigens. The Class I region contains loci A, B, and C, which encode for MHC Class I A, B, and C glycoproteins on every nucleated cell in the body. Because the A, B, and C loci comprise highly variable nucleotide sequences, numerous kinds of A, B, and C glycoproteins characterize humans. All people inherit MHC Class I A, B, and C genes as a haplotype from each of their parents. Children will have tissues with half of their Class I A, B, and C antigens like those of their mother and half like those of their father. Siblings could have tissue antigens that are identical or totally dissimilar based on their MHC I glycoproteins. Body surveillance by T lymphocytes involves T cells recognizing self glycoproteins. Cellular invasion by a virus or any other parasite results in the processing of an antigen and its display in the cleft of the MHC Class I glycoprotein. T cytotoxic lymphocytes with T-cell receptors specific for the antigen-MHC I complex will attach to the antigen and become activated to clonal selection. Infected host cells are killed when activated cytotoxic T cells...
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Genes, T Helper Cells, and T Cytotoxic Cells (Genetics & Inherited Conditions)
The thousands of specific T-cell receptors (TCR) available to any specific antigen one might encounter in a lifetime are formed in the human embryonic thymus from progenitor T cells. The TCR comprises two dissimilar polypeptide chains designated α and β or γ and δ. They are similar in structure to immunoglobulins and MHC molecules, having regions of variable amino acid sequences and constant amino acid sequences arranged in loops called domains. This basic structural configuration places all three types of molecules in a chemically similar grouping designated the immunoglobulin superfamily. The genes of these molecules are believed to be derived from a primordial supergene that encoded the basic domain structure.
The exons encoding the α and γ polypeptides are designated V, J, and C gene segments in sequence and associate with recombination signal sequences similar to the immunoglobulin light-chain gene. The β and δ polypeptide genes are designated VDJ and C exon segments in sequence associating with recombination signal sequences similar to the immunoglobulin heavy-chain genes. Just as there are multiple forms for each of the immunoglobulin variable gene segments, so there are multiple forms for the variable TCR gene segments. Thymocytes, T-cell precursors in the thymus, undergo chance recombinations of gene segments. These genetic recombinations, as well as the chance combination of a...
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Immunogenetic Disease (Genetics & Inherited Conditions)
The HLA genes of the major histocompatibility complex identify every human being as distinct from all other things, including other human beings, because of the MHC Class I and Class II antigens. Surveillance of self involves B- and T-cell antigen recognition because of MHC self-recognition. How well individual human beings recognize self and their response to antigen in an adaptive immune response are determined by MHC haplotypes as well as the genes that make immunoglobulins and T-cell receptors. These same genes can explain a variety of disease states, such as autoimmunity, allergy, and immunodeficiency.
Because immunoglobulin structure and T-cell receptor formation are based on a mechanism of chance, problems involving self-recognition may occur. It is currently believed that thymocytes with completed T-cell receptors are protected from apoptosis when they demonstrate self-MHC molecule recognition. Alternatively, it is believed that thymocytes are also presented with self-antigens processed by specialized macrophages bearing MHC Class I and Class II molecules. Thymocytes reacting with high-affinity receptors to processed self-antigens undergo apoptosis. There also appears to be a negative selection process within the bone marrow that actively eliminates immature B cells with membrane-bound autoantibodies that react with self-antigens. In spite of these selective activities, it is believed that autoreactive T cells...
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Impact (Genetics & Inherited Conditions)
Understanding the genetic basis for immune reactions is resulting in novel approaches to protection against disease and improvements in health. Researchers are pursuing the development of therapeutics aimed at controlling B cell responses in autoimmune diseases and IgE responses in allergic reactions. Clinical laboratories are providing detailed histocompatibility and immunogenetics testing for solid organ and stem cell transplantation and blood and platelet transfusions to reduce the incidence and severity of graft-versus-host disease.
Immunotherapy is increasingly used to capitalize on a person’s immune system to fight cancers or infectious diseases, either by actively stimulating the production of natural antibodies or by passively introducing antibodies specifically engineered in a laboratory. With active stimulation, specific immunity may be induced with vaccines or nonspecific immunity may be induced with interferons or interleukins. Passive stimulation is achieved with monoclonal antibodies that target specific cell-surface antigens. Several therapeutic monoclonal antibodies have been approved for use in humans by the U.S. Food and Drug Administration (FDA), particularly in the treatment of colorectal cancer, non-Hodgkin’s lymphoma, and some types of leukemia. Conversely, other therapeutic monoclonal antibodies have been produced and marketed to suppress immune responses in diseases such as rheumatoid arthritis and allergic...
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Further Reading (Genetics & Inherited Conditions)
Abbas, Abul K., and Andrew H. Lichtman. Basic Immunology: Functions and Disorders of the Immune System. 3d ed. Philadelphia: Elsevier Health Sciences, 2008. Written for college students, this book presents a complete overview of the field in a readable and easily digested manner, with a view to clinical applications. Available with STUDENT CONSULT Online Access.
Goldsby, Richard A., Thomas J. Kindt, Barbara A. Osborne, and Janis Kuby. Immunology. New York: W. H. Freeman, 2003. A very complete text dealing with the biological basis of immunity, including immunogenetics.
Oksenberg, Jorge R., and David Brassat, eds. Immunogenetics of Autoimmune Disease. New York: Springer-Verlag, 2006. Summaries of the current understandings of various autoimmune diseases presented clearly by leading researchers.
Paul, William E. Fundamental Immunology. 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2008. The most recent edition of a classic textbook that is both comprehensive and up-to-date on advanced research and applications, including immunogenetics.
Pines, Maya, ed. Arousing the Fury of the Immune System. Chevy Chase, Md.: Howard Hughes Medical Institute, 1998. Informative, well-done report relating different immunological concepts in an entertaining, readable format.
Roitt, Ivan, Jonathan Brostoff, and David Male. Immunology. New York:...
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Web Sites of Interest (Genetics & Inherited Conditions)
American Society for Histocompatibility and Immunogenetics. http://www.ashi-hla.org. A nonprofit professional organization for immunologists, geneticists, molecular biologists, transplant surgeons, and pathologists, devoted to advancing the science and exchanging information.
ImMunoGeneTics (IMGT) Database. http://imgt.cines.fr:8104. A database focusing on immunoglobulins, T-cell receptors, and MHC molecules of all vertebrates, including interactive tools.
Laboratory of Immunogenetics at the National Institute of Allergy and Infectious Diseases. http://www3.niaid.nih.gov/labs/aboutlabs/lig. The research in this government laboratory encompasses seven sections of immunogenetics using structural, molecular, and cellular biology approaches.
UCLA Immunogenetics Center. http://www.hla.ucla.edu. This laboratory conducts basic and clinical research and provides clinical testing services as a leading facility for human leukocyte antigen (HLA) typing.
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Immunogenetics (World of Microbiology and Immunology)
Immunogenetics is the study of the mechanisms of autoimmune diseases, tolerance in organ transplantation, and immunity to infectious diseasesith 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