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The Major Histocompatibility Complex on chromosome 6 encodes a diverse array of genes involved in the immune and inflammatory response. The region is remarkably polymorphic and has been associated with susceptibility to autoimmune and infectious disease. The approaches to defining and understanding the nature and consequences of genetic diversity in the MHC are reviewed in terms of the biology of encoded molecules, evolutionary selective pressures and relationship to disease. Progress in haplotypic analysis of the MHC, resequencing and fine mapping are discussed together with insights from structural biology and detailed functional characterisation of the consequences of genetic diversity. The role of genetic variation in the MHC for a number of specific diseases are reviewed including rheumatoid arthritis, haemochromatosis, type 1 diabetes, coeliac disease, narcolepsy and sarcoidosis with emphasis on progress in defining the functional basis of disease associations, for example modulation of alternative splicing by genetic variation associated with sarcoidosis.

This chapter surveys connections between the nervous system and the immune system, and suggests that their connections mediate many significant health outcomes. The nervous and immune systems are intimately connected by shared developmental, functional and biochemical pathways. The extraordinary diversity and remarkable evolution of MHC genes have been influenced by several distinct forces, including pathogen-mediated selection, and sexual and reproductive selection. MHC diversity influences the risk and progression of infectious, reproductive, autoimmune, and inflammatory diseases. MHC genes play a significant role in olfactory communication, behavior, and mate choice in vertebrates, including humans. The unique evolution of MHC genes contributed to the prevalence of autoimmune and inflammatory diseases in modern human populations.

Females choose mating partners for three main reasons: direct benefits, indirect benefits, and compatibility, either genetic or social. In this chapter I am not trying to look at all angles of mate choice, but to give a short overview of female choice to provide a basis for a comparison with male choice. This will highlight what studies are needed to reach a more complete picture of sexual selection. I would summarize the chapter like this: it’s the ecology, stupid.

The initiation and maintenance of an immune response to pathogens requires the interactions of cells and proteins that together are able to distinguish appropriate non-self targets from the myriadof self-proteins (Janeway and Bottomly, 1994). This discrimination between self and non-self is in part accomplished by three groups of proteins of the immune system that have direct and specific interactions with antigens: antibodies, T cell receptors (TcR) and major histocompatibility complex (MHC) proteins. Antibodies and TcR molecules are clonally expressed by the B and T cells of the immune system, respectively, defining each progenitor cell with a unique specificity for antigen. In these cell types both antibodies and TcR proteins undergo similar recombination events to generate a variable antigen combining site and thus produce a nearly unlimited number of proteins of different specificities. TcR molecules are further selected to recognize antigenic peptides bound to MHC proteins, during a process known as thymic selection, restricting the repertoire of T cells to the recognition of antigens presented by cells that express MHC proteins at their surface. Thymic selection of TcR and the subsequent restricted recognition of peptide-MHC complexes by peripheral T cells provides a fundamental molecular basis for the discrimination of self from non-sell and the regulation of the immune response (Allen, 1994; Nossal, 1994; von Boehmer, 1994). For example, different classes of T cells are used to recognize and kill infected cells (cytotoxic T cells) arid to provide lymphokiries that induce the niajority of soluble antibody responses of B cells (helper T cells). In contrast to the vast combinatorial and clonal diversity of antibodies and TcRs, a small set of MHC molecules is used to recognize a potentially unlimited universe of foreign peptide antigens for antigen presentation to T cells (Germain, 1994). This poses the problem of how each MHC molecule is capable of recognizing enough peptides to insure an immune response to pathogens. In addition, the specificity of the TcR interaction with MHC-peptide complexes is clearly crucial to the problem of self :non-self discrimination, with implications for both protective immunity and auto-immune disease.