Functional significance of polymorphism among MHC class II gene promoters

Abstract

The functional significance of polymorphism among MHC class II promoters in man and mouse is here reviewed, mainly in terms of the hypothesis of differential expression. The hypothesis proposes that differences between antigen-presenting cells in MHC class II expression exert a co-dominant effect on the Th1-Th2 cytokine balance, such that class II molecules of one type come to control to a greater extent the production of one group of cytokines, and those of another type the production of the alternative group. The survey deals with the influence of signal strength and antigen-presenting cell type on T-cell subset differentiation; functional differences between MHC class II molecules not obviously related to determinant selection; disease protection mediated by HLA alleles; mechanisms possibly responsible for allotypic and isotypic bias; overdominance (heterozygous advantage) in selection for expression of class II alleles; MHC class II promoter structure and function; inter-locus and inter-allele variability within human MHC class II gene upstream regulatory regions; a comparison of these polymorphisms in mouse and man; read-out of class II promoter function; and a comparison with expression of MHC class I. We conclude that the evidence that this variation is functionally active (i.e. controls expression) is increasing, but is not yet compelling. The crucial test still to come, we suggest, is whether or not the biological effects attributable to this polymorphism will line up with molecular studies on expression.

Differential expression of major histocompatibility complex class II genes on murine macrophages associated with T cell cytokine profile and protective/suppressive effects

“…It suggests that differential expression may play a role in the control of disease susceptibility by MHC class II genes. Differential expression is also in line with the distribution of polymorphism across MHC class II genes, which is high not only in the peptide-binding domains but also in the promoter region (promoter polymorphism is less evident in MHC class I genes) (2,29). Significantly, this polymorphism in the mouse is highest in the region of the X and Y boxes, where transcription factors bind; it has been suggested that heterozygosity in this region may confer increased fitness through immunological flexibility (29).…”

“…Differential expression of protective MHC class II molecules in the various antigen-presenting cells (APCs) is one hypothesis that has been proposed to explain the protective effect (2,5,10,11), although other possibilities remain open (3,12). The findings leading to the present study are as follows.…”

Ancient polymorphism and functional variation in the primate MHC-DQA15′ cis-regulatory region

“…Of these, overdominant selection for multiple expression phenotypes has been a primary hypothesis for the maintenance of MHC class II promoter region diversity (22,61). This is based on the idea that functional cis-regulatory diversity within an individual confers additional range and f lexibility in important parameters of transcriptional output (e.g., site, timing, and responsiveness to cytokines), which facilitates a more precise, context-specific immune response.…”

“…The overall importance of proper immune regulation, the observed population genetic diversity of the DQA1 promoter in humans (19)(20)(21), and the demonstrated functional significance of this diversity make the proximal promoter region of DQA1 a likely target of natural selection (22). To explore this possibility, we investigated the evolutionary history of the DQA1 proximal promoter region in primates and characterized cis-regulatory variation at both the nucleotide and functional levels.…”

The importance of the back–signal from T cells into antigen–presenting cells in determining susceptibility to parasites

“…Some MHC class II promoters are highly polymorphic, to an extent that indicates that they must be under selective pressure (Guardiola et al 1996). In contrast, MHC class I promoters are relatively constant (Cereb & Yang 1994;Yao et al 1995).…”