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Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

Genes & Immunity volume 11, pages 99–112 (2010)Cite this article

Abstract

Major histocompatibility complex (MHC) class II molecules are central to adaptive immune responses and maintenance of self-tolerance. Since the early 1970s, the MHC class II region at chromosome 6p21 has been shown to be associated with a remarkable number of autoimmune, inflammatory and infectious diseases. Given that a full explanation for most MHC class II disease associations has not been reached through analysis of structural variation alone, in this review we examine the role of genetic variation in modulating gene expression. We describe the intricate architecture of the MHC class II regulatory system, indicating how its unique characteristics may relate to observed associations with disease. There is evidence that haplotype-specific variation involving proximal promoter sequences can alter the level of gene expression, potentially modifying the emergence and expression of key phenotypic traits. Although much emphasis has been placed on cis-regulatory elements, we also examine the role of more distant enhancer elements together with the evidence of dynamic inter- and intra-chromosomal interactions and epigenetic processes. The role of genetic variation in such mechanisms may hold profound implications for susceptibility to common disease.

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Acknowledgements

We thank all members of the Ebers and Knight laboratories together with members of Canadian Collaborative Project on the Genetic Susceptibility to Multiple Sclerosis. Funding: JCK is a Wellcome Trust Senior Research Fellow in Clinical Science. GCE is the Action Research Professor of Clinical Neurology at University of Oxford. The Medical Research Council of the United Kingdom funds LH This research is also funded by the Multiple Sclerosis Society.

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  1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    L Handunnetthi, S V Ramagopalan, G C Ebers & J C Knight

  2. Department of Clinical Neurology, University of Oxford, Oxford, UK

    L Handunnetthi, S V Ramagopalan & G C Ebers

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  1. L Handunnetthi
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Handunnetthi, L., Ramagopalan, S., Ebers, G. et al. Regulation of major histocompatibility complex class II gene expression, genetic variation and disease. Genes Immun 11, 99–112 (2010). https://doi.org/10.1038/gene.2009.83

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