Polymorphic MHC class II promoters exhibit distinct expression pattern in various antigen‐presenting cell lines

Janitz, Michael; Mitchison, Avrion; Reiners-Schramm, Luzie; Lauster, Roland

doi:10.1111/j.1399-0039.1997.tb02721.x

Cited by 27 publications

(26 citation statements)

References 31 publications

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“…Remarkably, this was specific to particular cell types, in macrophages, for example, altering the subsequent T-cell cytokine response. 82,83 In humans, quantitative differences in levels of DRB1 and DRB3 expression are also highly significant in determining the CD4 þ T-cell response. 84,85 An analysis illustrating the occurrence of sequence diversity in conserved SXY module motifs for the HLA-DRB1 promoter is shown in Figure 4.…”

Section: Mhc Haplotypes Sequence Variation and Class II Regulationmentioning

confidence: 99%

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

et al. 2009

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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.

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Section: Mhc Haplotypes Sequence Variation and Class II Regulationmentioning

confidence: 99%

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

et al. 2009

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“…The sequences, too bulky to be given here in full, are also deposited at Mouse Genome Informatics. Sequences from eight other strains, published (23) and unpublished from the same group (GenBank accession nos. Y13072-Y13083) are also included in the analysis.…”

Section: Methodsmentioning

confidence: 99%

Patterned variation in murine MHC promoters

Mitchison¹,

Roes²

2002

Proc. Natl. Acad. Sci. U.S.A.

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To compare variation in regulatory and coding DNA, promoter sequences have been obtained from wild-derived mice and laboratory rats. The sequences are from the proximal promoter of the H2Aa, H2Ab, H2Eb, and H2K genes of 24 wild-derived inbred strains and a sample of the corresponding exon 2 sequences and of the RT1.Ba gene of six strains of laboratory rat. They reveal a high level of variation in the mouse MHC class II promoters (H2A and H2E), a low level in MHC class I (H2K), and none in the rat. The variation is pronounced in and around the cAMP response element, a major binding site for modulating promoter activity in response to external stimulation. This finding, together with the different levels of variation in MHC classes I and II, is suggestive of natural selection. However, selection operating via the MHC coding sequences must also contribute, as indicated by the minimal variation in both the MHC class II promoter and coding sequences of the rat. Furthermore CIITA (trans-activator of class II) of the mouse has been reported to have minimal variation in its promoter and none in its coding sequence. Taken together these data suggest that the regulatory and coding sequences undergo coselection. Each of the mouse class II promoters has a pattern of variation that appears to be basically dimorphic, with further variation added by recombination͞mutation. The dimorphic allelic lineages are in marginally detectable linkage disequilibrium with the exon 2 sequences, particularly in H2Aa, thus lending further support to the coevolution hypothesis.

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“…In this context, differential expression of the various I-A genes has been correlated with a single mismatch in the X2 box of the promoter region (6). Interestingly, the structural requirements for class II MHC promoters (S, X1, and X2, as well as Y, CAAT, and TATA boxes) are well conserved over long evolutionary distances but allow for considerable intraspecies variability.…”

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confidence: 99%

Differential expression of HLA class II genes associated with disease susceptibility and progression in rheumatoid arthritis

Heldt

Listing

Sozeri

et al. 2003

Arthritis & Rheumatism

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Objective. Rheumatoid arthritis (RA)-associated HLA class II genes are assumed to promote susceptibility to and/or progression of the disease. Among the various modes of action proposed so far is the effect of the differential expression of HLA class II genes in different types of antigen-presenting cells on the Th1/ Th2 balance. The aim of this study was to investigate the differential expression of genes encoded within the RA-associated HLA-DR4 superhaplotype and within the neutral DR7 and DR9 superhaplotypes.Methods. The promoters encoded within these 3 haplotypes were first analyzed for sequence polymorphisms. To test for functional consequences, we assumed that the binding of nuclear factors to the promoter elements was correlated with the transcription activity, and we used surface plasmon resonance technology. To that end, oligonucleotides representing the polymorphic regulatory sequences and nuclear extracts from a monocyte cell line and a B cell line were used.Results. While the promoters of the highly polymorphic HLA-DRB1*04, *07, and *09 alleles showed comparable binding of nuclear factors, differential binding was observed for the 2 promoters that drive the relatively nonpolymorphic DRB4 alleles in linkage disequilibrium with DRB1. Interestingly, analysis of RA patients positive for DR4, DR7, and DR9 revealed the segregation of radiographic progression with the stronger of the 2 DRB4 promoters, independent of the DRB1 allele. Moreover, DRB1*04 alleles in RA patients showed a reduced association with the DRB4 splice variant, completely preventing DRB4 expression.Conclusion. Our findings represent the first evidence of a correlation between the differential expression of HLA class II genes and both the susceptibility and the progression of RA.

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Polymorphic MHC class II promoters exhibit distinct expression pattern in various antigen‐presenting cell lines

Cited by 27 publications

References 31 publications

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

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

Patterned variation in murine MHC promoters

Differential expression of HLA class II genes associated with disease susceptibility and progression in rheumatoid arthritis

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