Genome-wide association studies to advance our understanding of critical cell types and pathways in rheumatoid arthritis

Diogo, Dorothée; Okada, Yukinori; Plenge, Robert M.

doi:10.1097/bor.0000000000000012

Cited by 50 publications

(37 citation statements)

References 98 publications

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“…Multiple genes driving NF-kB pathway activation are associated with RA susceptibility (23). Furthermore, NF-kB subunits are overexpressed in RA synovial tissue (24,25).…”

Section: Introductionmentioning

confidence: 99%

Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype–positive rheumatoid arthritis patients

et al. 2015

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In animals, immunomodulatory dendritic cells (DCs) exposed to autoantigen can suppress experimental arthritis in an antigen-specific manner. In rheumatoid arthritis (RA), disease-specific anti-citrullinated peptide autoantibodies (ACPA or anti-CCP) are found in the serum of about 70% of RA patients and are strongly associated with HLA-DRB1 risk alleles. This study aimed to explore the safety and biological and clinical effects of autologous DCs modified with a nuclear factor κB (NF-κB) inhibitor exposed to four citrullinated peptide antigens, designated "Rheumavax," in a single-center, open-labeled, first-in-human phase 1 trial. Rheumavax was administered once intradermally at two progressive dose levels to 18 human leukocyte antigen (HLA) risk genotype-positive RA patients with citrullinated peptide-specific autoimmunity. Sixteen RA patients served as controls. Rheumavax was well tolerated: adverse events were grade 1 (of 4) severity. At 1 month after treatment, we observed a reduction in effector T cells and an increased ratio of regulatory to effector T cells; a reduction in serum interleukin-15 (IL-15), IL-29, CX3CL1, and CXCL11; and reduced T cell IL-6 responses to vimentin(447-455)-Cit450 relative to controls. Rheumavax did not induce disease flares in patients recruited with minimal disease activity, and DAS28 decreased within 1 month in Rheumavax-treated patients with active disease. This exploratory study demonstrates safety and biological activity of a single intradermal injection of autologous modified DCs exposed to citrullinated peptides, and provides rationale for further studies to assess clinical efficacy and antigen-specific effects of autoantigen immunomodulatory therapy in RA.

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“…Multiple genes driving NF-kB pathway activation are associated with RA susceptibility (23). Furthermore, NF-kB subunits are overexpressed in RA synovial tissue (24,25).…”

Section: Introductionmentioning

confidence: 99%

Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype–positive rheumatoid arthritis patients

et al. 2015

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“…There is ample evidence for genetic influences on RA and heritability is estimated to be about 60% [2]. It is estimated that risk alleles identified up to now explain about 17% of seropositive RA [3]. One hallmark of RA pathogenesis is infiltration of synovial fluid by autoreactive immune cells.…”

Section: Introductionmentioning

confidence: 99%

Cellular Adhesion Gene SELP Is Associated with Rheumatoid Arthritis and Displays Differential Allelic Expression

et al. 2014

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In rheumatoid arthritis (RA), a key event is infiltration of inflammatory immune cells into the synovial lining, possibly aggravated by dysregulation of cellular adhesion molecules. Therefore, single nucleotide polymorphisms of 14 genes involved in cellular adhesion processes (CAST, ITGA4, ITGB1, ITGB2, PECAM1, PTEN, PTPN11, PTPRC, PXN, SELE, SELP, SRC, TYK2, and VCAM1) were analyzed for association with RA. Association analysis was performed consecutively in three European RA family sample groups (Nfamilies = 407). Additionally, we investigated differential allelic expression, a possible functional consequence of genetic variants. SELP (selectin P, CD62P) SNP-allele rs6136-T was associated with risk for RA in two RA family sample groups as well as in global analysis of all three groups (ptotal = 0.003). This allele was also expressed preferentially (p<10−6) with a two- fold average increase in regulated samples. Differential expression is supported by data from Genevar MuTHER (p1 = 0.004; p2 = 0.0177). Evidence for influence of rs6136 on transcription factor binding was also found in silico and in public datasets reporting in vitro data. In summary, we found SELP rs6136-T to be associated with RA and with increased expression of SELP mRNA. SELP is located on the surface of endothelial cells and crucial for recruitment, adhesion, and migration of inflammatory cells into the joint. Genetically determined increased SELP expression levels might thus be a novel additional risk factor for RA.

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“…Получены данные о других генетических факторах риска, связанных в первую очередь со множественными однонуклеотидными полиморфизмами других генов, вы-явленными в процессе широкомасштабного скрининга ге-нома у пациентов с РА [178]. К ним в первую очередь отно-сится гены, участвующие в активации Т-клеток, -PTPN22 (Protein tyrosine phosphatase, non-receptor type 22), CTLA4 (cytotoxic T-lymphocyte-associated protein 4) и STAT4 (Signal transducer and activator of transcription 4) [23].…”

Section: генетические фак торыunclassified

Problems of Rheumatoid Arthritis Immunopathology: Evolution of the Disease

Насонов¹

2017

rsp

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Genome-wide association studies to advance our understanding of critical cell types and pathways in rheumatoid arthritis

Abstract: These findings highlight the promises and need of future studies investigating causal genes and underlined mechanisms in GWAS loci to advance our understanding of RA.

Cited by 50 publications

References 98 publications

Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype–positive rheumatoid arthritis patients

Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype–positive rheumatoid arthritis patients

Cellular Adhesion Gene SELP Is Associated with Rheumatoid Arthritis and Displays Differential Allelic Expression

Problems of Rheumatoid Arthritis Immunopathology: Evolution of the Disease

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