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

Abstract

Major histocompatibility complex (MHC) class II molecules are central to adaptive immune responses and maintenance of selftolerance. 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 haplotypespecific 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.

Characterization of the mononuclear phagocyte system in zebrafish

“…In mammals, mhc2 expression is regulated at the transcriptional level by the class II transactivator, which is recruited to the mhc2 promoter by proteins selectively bound to the X1, X2, and Y promoter sequences that are required for optimal constitutive and cytokine-induced expression in both humans and mice. 27 Analysis of the zebrafish mhc2dab proximal promoter revealed the presence of these conserved elements within a 4-kb fragment upstream of the transcriptional start site (data not shown). This 4-kb regulatory domain of the mhc2dab gene was cloned upstream of GFP-LT and flanked by Tol2 recombination sequences.…”

Immunogenicity and Immune-Modulating Properties of Human Stem Cells

“…MHC class II consists of three classes of HLA-II antigens: HLA-DP, -DQ and -DR presenting peptide antigens derived from extracellular proteins to CD4+ T helper cells to elicit an immune response. Because MHC class II expression is cell-type specific and mainly restricted to thymic epithelial cells and bone marrow-derived antigen presenting cells it is not expected to be a problem in many stem cell applications (Handunnetthi et al, 2010). Natural killer (NK) cells participate in the innate immune response as they are capable of killing tumor cells and virally-infected cells.…”

Genetic Factors that Influence HIV Infection: The Role of the Major Histocompatibility Complex System

“…Their promoter contains regulatory elements collectively called the "SXY module", to which various proteins bind, including regulatory factor X (RFX) and the class II transactivator (CIITA) (Handunnetthi et al, 2010). Induction of CIITA and subsequent expression of the MHC class II isotype HLA-DR are hallmarks of CD4 + T cell activation which, paradoxically, favors HIV replication.…”