Contribution of inherited factors to rheumatoid arthritis.

Deighton, Chris; Wentzel, J.; Cavanagh, G.; Roberts, D. F.; Walker, David

doi:10.1136/ard.51.2.182

Cited by 47 publications

(27 citation statements)

References 4 publications

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“…Recent studies in RA patients have emphasized that HLA-DR molecules function as progression factors and may not be involved in the initiation of the disease [17]. Genotyping of large cohorts of RA patients as well as concordance studies in RA families indicated that disease associated HLA-DRB 1 alleles were frequently inherited on both haplotypes [18][19][20]. In a peptide binding model, heterozygosity for the relevant MHC molecule should be sufficient to ascertain antigen selection and presentation.…”

Section: Hla Genes and Disease Risk In Ramentioning

confidence: 99%

HLA Polymorphisms and T Cells in Rheumatoid Arthritis

Weyand

Goronzy

1999

International Reviews of Immunology

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A dense infiltrate of activated T cells, macrophages, and B cells in the synovial membrane is the cardinal pathological feature of rheumatoid arthritis (RA). Frequently, tissue infiltrating cells acquire a morphological organization reminiscent of secondary lymphoid tissue. The composition of the inflammatory lesions, the production of autoantibodies, and the association of disease risk with genes related to the HLA-D region have all been cited as evidence for a critical role of T cells in disease pathogenesis. Investigations on the precise role of HLA genes in RA have confirmed the importance of this genetic risk factor and have identified a consensus sequence within the HLA-DRBI genes. The observation that HLA polymorphisms are mostly associated with disease progression and severity and that a gene dose effect for HLA-DR genes is operational has challenged the simple model that HLA molecules select and present an arthritogenic antigen. Studies analyzing the repertoire of tissue infiltrating T cells have not been able to identify a dominant and common disease relevant T cell. The infiltrate is diverse in terms of T cell receptor gene usage but consistently includes clonally expanded populations. Recent evidence indicates that RA patients carry expanded CD4 clonotypes which are characterized by deficient CD28 expression and autoreactivity. These autoreactive CD4 T cells are not restricted to the joint, raising the possibility that rheumatoid synovitis is a manifestation of a systemic autoimmune disease. Support for this model has come from studies in T cell receptor (TCR) transgenic animals which develop inflammation of the synovial membrane stimulated by a T cell response to ubiquitously expressed self-MHC molecules. Antigens driving the chronic persistent immune response in RA may not be restricted to the joint but rather may be widely distributed, providing an explanation for the difficulties in identifying arthritogenic antigens directly or indirectly through the selection of joint infiltrating T cells.

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Section: Hla Genes and Disease Risk In Ramentioning

confidence: 99%

HLA Polymorphisms and T Cells in Rheumatoid Arthritis

Weyand

Goronzy

1999

International Reviews of Immunology

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“…Findings from genetically identical twins, where the concordance rate is far less than complete, are indicative for a major role of an environmental factor in the risk of developing RA. 9,10 From animal models it is clear that an exogenous challenge, like infectious agents may induce arthritis. In man, microbial infections are known to contribute to arthritis.…”

Section: Introductionmentioning

confidence: 99%

Expression of a pathogen-response program in peripheral blood cells defines a subgroup of Rheumatoid Arthritis patients

et al. 2007

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Rheumatoid arthritis (RA) is a heterogeneous disease with unknown etiology. Here we aimed to distinguish RA subtypes based on peripheral blood (PB) gene expression profiles in comparison with a pathogen-response transcriptional program. PB was obtained from 35 RA patients and 15 healthy individuals. For expression profiling we used DNA microarrays. A combined cluster analysis of RA and control samples together with samples from a viral infection model revealed that the gene expression profile of a subgroup of RA patients (RA A ) was reminiscent to that of poxvirus-infected macaques. Statistical analysis, followed by Gene Ontology analysis of the RA A patients confirmed that these patients form a distinct group, with activation of several host defense mechanisms that resemble a common host-pathogen response. Analysis of the promoter region of genes that were overexpressed in the RA A patients, revealed an enrichment of transcription factor binding sites for NFkB and interferon-activated transcription factors. Moreover, this subgroup of RA patients expressed significantly increased titers of anti-cyclic citrullinated peptide antibodies. We conclude that activation of a host-pathogen response defines a subgroup of RA patients characterized by increased autoreactivity against citrullinated proteins.

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“…The healthy control group consisted of 116 unrelated Caucasian women without autoimmune disease from the same geographic regions in Northern California. The study subjects were restricted to Caucasian females to minimize heterogeneity in allelic frequencies across populations, and because RA risk and disease expression are likely to differ between males and females [Deighton et al, 1992;Weyand et al, 1992a;Hasstedt et al, 1994;Meyer et al, 1996].…”

Section: Subjects and Methods Patientsmentioning

confidence: 99%