Immunophenotyping of Rheumatoid Arthritis Reveals the Linkage Between HLA-DRB1 Genotype, CXCR4 Expressions on Memory CD4+ T Cells, and Disease Activity

Yasuo Nagafuchi¹, Hirofumi Shoda¹, Shuji Sumitomo¹, Shinichiro Nakachi¹, Rika Kato², Yumi Tsuchida², Haruka Tsuchiya², Keiichi Sakurai², Norio Hanata², Shoko Tateishi², Hiroko Kanda², Keishi Fujio¹ and Kazuhiko Yamamoto¹, ¹Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, ²Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: Chemokine Receptors, genetics, immunology and rheumatoid arthritis (RA)

Session Information

Date: Tuesday, November 10, 2015

Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis Poster III

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: The HLA-DRB1 is the strongest genetic risk factor for rheumatoid arthritis (RA). Although this fact suggests a pivotal role for adaptive immunity in RA, the linkage between HLA-DRB1 genotype and lymphocytes activation remains unclear.

Methods: We analyzed 91 HLA-DRB1 genotyped RA patients and 110 healthy donors by 24-subset immunophenotyping of peripheral blood mononuclear cells (PBMC) combined with CXCR4 expression analysis, HLA-DR quantification, and multiplex serum cytokine analysis. The correlation between these biomarkers and clinical parameters, such as the titer of anti-citrullinated peptide antibody (ACPA) and DAS28esr, was examined. 20 RA patients were analyzed at the initiation of CTLA4-Ig treatment and after 6-months of treatment. PBMC of healthy donors were cultured for 5 days with IL-21 and anti-HLA-DR antibody to assess CXCR4 expression on CD4⁺ T cells.

Results: The frequency of CXCR4-expressing memory CD4⁺ T cells, not that of classical Th1 or Th17 cells, was significantly associated with DAS28esr and the titer of ACPA. RA patients with susceptible haplotype of HLA-DR (shared epitope: SE) displayed significantly higher frequency of memory CD4⁺ T cells and higher positivity for CXCR4 on memory CD4⁺ T cells than healthy donors and RA patients without SE. Moreover, the frequency of CXCR4-expressing memory CD4⁺ T cells displayed a significant correlation to the expression level of HLA-DR on B cells, which was elevated in RA patients with SE. In vitro experiments indicated that the increased CXCR4 expression on RA memory CD4+ T cells was dependent both on IL-21 and HLA-DR expression on antigen presenting cells. In clinic, higher frequency of CXCR4-expressing memory CD4⁺ T cells predicted better therapeutic effects of CTLA4-Ig.

Conclusion: These findings demonstrate a potential contribution of HLA-DR on B cells to the development of memory CD4⁺ T cells which is associated with disease activity. Identification of CXCR4 on memory T cells as a biomarker may promote the understanding of the linkage between genetic risk factor and adaptive immunity in RA.

Disclosure: Y. Nagafuchi, None; H. Shoda, None; S. Sumitomo, None; S. Nakachi, None; R. Kato, None; Y. Tsuchida, None; H. Tsuchiya, None; K. Sakurai, None; N. Hanata, None; S. Tateishi, None; H. Kanda, None; K. Fujio, Astellas, BMS, Daiichi-Sankyo, MitsubishiTanabe, Pfizer, Santen, Takeda, Chugai, Eisai, Taisho Toyama, UCB, and Janssen., 2; K. Yamamoto, UCB Pharma, Pfizer, Abbott, Santen, Mitsubish-Tanabe, Eisai, 2,UCB Pharma, Pfizer, Abbott, Bristol-Myers Squibb, Roche, Chugai, Mitsubish-Tanabe, Eisai, 5.

To cite this abstract in AMA style:

Nagafuchi Y, Shoda H, Sumitomo S, Nakachi S, Kato R, Tsuchida Y, Tsuchiya H, Sakurai K, Hanata N, Tateishi S, Kanda H, Fujio K, Yamamoto K. Immunophenotyping of Rheumatoid Arthritis Reveals the Linkage Between HLA-DRB1 Genotype, CXCR4 Expressions on Memory CD4+ T Cells, and Disease Activity [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/immunophenotyping-of-rheumatoid-arthritis-reveals-the-linkage-between-hla-drb1-genotype-cxcr4-expressions-on-memory-cd4-t-cells-and-disease-activity/. Accessed .

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