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

Baumgart, Martin; Moos, Verena; Schuhbauer, Diana; Müller, Brigitte

doi:10.1073/pnas.95.12.6936

Cited by 46 publications

(32 citation statements)

References 42 publications

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“…Its H2E molecule is no longer expressed, as commonly occurs in mice (36,37). The promoter at its H2Ab locus gives its H2A molecule some of functions of the missing H2E, namely high expression (23,38), and a consequent effect on Th1͞Th2 balance that affects disease susceptibility (39,40). The wild-derived inbred strains that have this type of promoter at H2Ab are CZECH, LEWES, MOR, PERC, SK, SF, TIRANO, WSB, ZALENDE, and M. caroli.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

Patterned variation in murine MHC promoters

Mitchison¹,

Roes²

2002

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

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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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“…Likewise, the differential expression of murine class II MHC genes has been shown to be restricted to macrophages and to be associated with protective/suppressive effects via the T cell cytokine profile (5). One approach to addressing the impact of differential HLA-DRB4 expression on the T cell cytokine profile in human RA will involve the analysis of rheumatoid factor isotypes in correlation with the respective DRB4 promoters.…”

Section: Discussionmentioning

confidence: 99%

“…The DR4, DR1, and DR10 haplotypes have been found to be positively associated with the disease, while others, such as DR2 and DR7, have been reported to be neutral, if not protective (1)(2)(3). Several mechanisms have been proposed to explain the association, among them are epitope selection (4) and differential expression (5). The shared epitope hypothesis centers on epitope selection and is intriguingly simple.…”

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

Abstract: Protective͞suppressive major histocompatibility complex (

Cited by 46 publications

References 42 publications

Patterned variation in murine MHC promoters

Patterned variation in murine MHC promoters

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

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

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