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While the association of particular major histocompatibility complex (MHC) haplotypes with human diseases has been extensively reviewed, we felt that the area of modulation of MHC antigen expression and its association with human and animal diseases was less well explored. These ideas were initially exchanged between the editors and some of the authors of this book at a most interesting meeting organized by the British Society for Immunology in Warwick in 1991 entitled ‘Viruses, Cytokines and the MHC’. Following this meeting, we realised that there was a need for a broad, interdisciplinary treatment of the area of MHC modulation that would be useful for both basic medical researchers and clinicians.
Expression of MHC class I and class II antigens follows a complex pathway from gene transcription to plasma membrane insertion and many steps can be stimulated or repressed leading to altered levels of cell surface MHC molecules. Therefore, to provide basic background information on the MHC, the genomic organization, antigen structure, biosynthesis and function and control of transcription of class I and II are considered first along with the important effects which cytokines and other extracellular agents can have on MHC antigen expression. Infection and oncogenic transformation of mammalian cells by viruses have provided powerful systems for analysing precise mechanisms of MHC antigen modulation and the relationship of this process to disease.
The major histocompatibility complex (MHC) genes are involved in the immune system's response to tumour and infected cells and in generating an immune response. This book brings together basic aspects of the regulation of MHC antigens with important clinical applications (in viral infection, viral oncology, cancer biology and autoimmunity). There is a strong emphasis on situations where MHC expression is modulated (either stimulated or repressed). The book's major themes are: the mechanisms of MHC expression explored at several levels including the transcription and translation of MHC genes and the insertion of MHC protein molecules into plasma membranes; the effect of cytokines on MHC expression both in the aetiology of certain diseases and in possible immunotherapeutic approaches to disease; and the use of gene therapy to modify MHC expression in cancer cells, and thereby cause tumour rejection.
Many animal viruses have the property of being able to modulate the expression of the MHC antigens of infected host cells and sometimes of uninfected cells of the host animal. Since the MHC is central to the immune system, this may be beneficial to the virus in evading an immune response and, therefore, have consequences for disease. The significance of such modulation can be seen from how widespread it is, its effects on pathogenicity and its prevalence in common and important human (and animal) infections. It will be shown here and below (Chapters 7 to 12) that modulation of MHC by viruses (and, briefly, other pathogens) is indeed widespread, does affect pathogenicity and is present in common and important infections. It will, therefore, be possible to conclude that modulation of MHC antigens is a highly important characteristic of viruses in general.
This chapter describes the different viruses for which modulation of MHC has been observed. Different mechanisms involved in modulation, both potential and actual, are summarized with suitable examples where known. This information is related to the pathogenicity of the virus where data are available. In the overall context of infectious disease, a brief note is made of other infectious organisms (i.e. microorganisms other than viruses) that are known to affect expression of functional MHC antigens with immunological consequences. Conclusions are drawn from these data on the importance of the modulation of MHC expression and on suitable directions for further research.
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