Genetic Regulation of T Regulatory, CD4, and CD8 Cell Numbers by the Arthritis Severity Loci Cia5a, Cia5d, and the MHC/Cia1 in the Rat

Laragione, Teresina; Yarlett, Nigel; Gulko, Pércío S.

doi:10.2119/2007-00003.brenner

Cited by 9 publications

(5 citation statements)

References 74 publications

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“…The locus on chromosome 10 regulating frequency of CD25+ CD4 T cells, and the frequencies of CD4 and CD8 T cells, has previously been shown to control CD4 and CD8 frequencies in a cross between ACI and F344 29 , both represented in the NIH-HS rats. The amino acid substitution at position 175 (p.Gly175Arg) of the TBX21 protein is a very strong causal candidate at this QTL since this domain is important for DNA interactions.…”

Section: Discussionmentioning

confidence: 99%

Combined sequence-based and genetic mapping analysis of complex traits in outbred rats

2013

Nat Genet

178

200

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Genetic mapping on fully sequenced individuals is transforming our understanding of the relationship between molecular variation and variation in complex traits. Here we report a combined sequence and genetic mapping analysis in outbred rats that maps 355 quantitative trait loci for 122 phenotypes. We identify 35 causal genes involved in 31 phenotypes, implicating novel genes in models of anxiety, heart disease and multiple sclerosis. The relation between sequence and genetic variation is unexpectedly complex: at approximately 40% of quantitative trait loci a single sequence variant cannot account for the phenotypic effect. Using comparable sequence and mapping data from mice, we show the extent and spatial pattern of variation in inbred rats differ significantly from those of inbred mice, and that the genetic variants in orthologous genes rarely contribute to the same phenotype in both species.

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Section: Discussionmentioning

confidence: 99%

Combined sequence-based and genetic mapping analysis of complex traits in outbred rats

2013

Nat Genet

178

200

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“…CD4 T cells may be required for the induction of CIA, and CD8 T cells may play a suppressive role in the etiology of CIA [26]. CD4 T cells contribute to autoantibody production, inflammation, synovial angiogenesis, hyperplasia and cartilage and bone destruction in CIA and RA [27]. RA patients exhibit significantly reduced numbers of CD8 T cells and greater CD4/CD8 ratios in peripheral blood and a greater number of CD4 T cells and lower CD4/CD8 ratios in synovial fluid [28]–[32].…”

Section: Discussionmentioning

confidence: 99%

Investigate Pathogenic Mechanism of TXNDC5 in Rheumatoid Arthritis

Wang

Zheng

et al. 2013

PLoS ONE

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Hypoxia stimulates synovial hypoperfusion in rheumatoid arthritis (RA). TXNDC5 stimulates cellular proliferation in hypoxic conditions. We previously detected increased TXNDC5 expression in synovial tissues and blood from RA patients and demonstrated that the gene encoding TXNDC5 increased RA risk. The present study investigated the pathogenic roles of TXNDC5 in RA. Transgenic mice that over-expressed TXNDC5 (TXNDC5-Tg) were generated using C57BL/6J mice and treated with bovine collagen II to induce arthritis (CIA). Synovial fibroblasts from RA patients (RASFs) were cultured and incubated with TXNDC5-siRNA or CoCl2, a chemical that induces hypoxia. CIA was observed in 80% of the TXNDC5-Tg, but only 20% of the wild-type mice (WT) developed CIA. The clinical arthritis scores reached 5 in the TXNDC5-Tg, but this index only reached 2 in the control mice. CIA TXNDC5-Tg exhibited clear pannus proliferation and bone erosion in joint tissues. A significant increase in CD4 T cells was observed in the thymus and spleen of TXNDC5-Tg during CIA. Serum levels of anti-collagen II IgG, IgG1 and IgG2a antibodies were significantly elevated in the mice. Increased cell proliferation, cell migration and TXNDC5 expression were observed in RASFs following incubation with 1 µM CoCl2. However, this effect was diminished when TXNDC5 expression was inhibited with 100 nM siRNA. TNF-alpha, IL-1α, IL-1β and IL-17 levels were significantly increased in the blood of TXNDC5-Tg mice, but the levels of these cytokines declined in the supernatant of RASFs that were treated with TXNDC5 siRNA. The expression of adiponectin, a cytokine-like mediator, decreased significantly in RASFs following TXNDC5 siRNA treatment. These results suggest that TXNDC5-over-expressing mice were susceptible to CIA. This study also suggests that hypoxia induced TXCNDC5 expression, which contributed to adiponectin expression, cytokine production and the cellular proliferation and migration of fibroblasts in RA.

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“…Previous studies have shown that antigen‐specific CD4 + T cells and CD8 + T cells play a pivotal role in autoimmune diseases such as RA. CD8 + T cells and NK cells are closely related to the MHC class I pathway, while CD4 + T cells are related to the MHC class II pathway in RA (Brenner, Laragione, Yarlett, & Gulko, ; Wilson et al., ). In terms of antigen‐presenting cells (APCs), B cells are recognized as professional APCs that can present MHC complex to T cells, then receive secondary signals from costimulatory molecules on T cells (Nakken et al., ).…”

Section: Discussionmentioning

confidence: 99%

Integrative analysis of genome‐wide association study and expression quantitative trait loci datasets identified various immune cell‐related pathways for rheumatoid arthritis

Wang

Guo

et al. 2019

Annals of Human Genetics

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Rheumatoid arthritis (RA) is an autoimmune chronic disorder manifesting as warm, swollen, and painful joints. Multiple immune cells are implicated in the development of RA. Previous studies demonstrated that integrating the genetic information of genome-wide association studies (GWAS) and expression quantitative trait loci (eQTLs) is capable of identifying new disease-risk loci and providing novel insights into the etiology of complex human disease. In this study, we conducted an integrative pathway association analysis of RA by using GWAS summary data and five immune cell types related to eQTL datasets of RA. After combining the cell-specific eQTLs and GWAS summary of RA and performing a pathway-enrichment analysis, we detected a group of RA-associated pathways with common or cell-specific enriched in the five immune cell types. 41 pathways for B cells, 33 pathways for CD4 +

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Genetic Regulation of T Regulatory, CD4, and CD8 Cell Numbers by the Arthritis Severity Loci Cia5a, Cia5d, and the MHC/Cia1 in the Rat

Cited by 9 publications

References 74 publications

Combined sequence-based and genetic mapping analysis of complex traits in outbred rats

Combined sequence-based and genetic mapping analysis of complex traits in outbred rats

Investigate Pathogenic Mechanism of TXNDC5 in Rheumatoid Arthritis

Integrative analysis of genome‐wide association study and expression quantitative trait loci datasets identified various immune cell‐related pathways for rheumatoid arthritis

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