Date: Monday, November 9, 2015
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: B cells play a pivotal role in the pathogenesis of autoimmune diseases. Although Syk function as a key molecule in BCR signaling, the pathological role of Syk in B cells in RA remains unclear. The purpose of this study was to assess the relevance of activation of Syk in B cells to RA pathology and responsiveness to treatment with biologics.
Methods: Healthy subjects (n=36) and patients with moderate or severe RA disease activity (n=70) were studied. The phosphorylation of Syk in peripheral blood B cells was measured by flow cytometry, and the correlation with clinical characteristics and changes after administration of biological products were evaluated.
Results: Syk phosphorylation in B cells was significantly higher in RA patients compared with the control (p-Syk-positive CD19+ B cells (%): control, 11.9±8.2; RA, 27.7±23.2, p=0.0019). The expression levels of p-Syk in all different treatment groups of RA patients were significantly higher than the control (control; 10.7±1.3%, treatment-naïve RA (n=12); 21.6±7.7%, MTX-treated (n=36); 24.8±3.3%, MTX+biologics-treated (n=9); 30.8±10.0%, p=0.0036). Although Btk is well-known as downstream of Syk, Btk phosphorylation in B cells was also higher in patients with RA compared with the control (mean MFI of p-Btk in CD19+ B cells: control, 144±73.4; RA, 224±171, p=0.031). Syk phosphorylation was significantly higher in B cells of patients strongly positive for ACPA (p-Syk-staining among CD19+ B cells (%): negative for ACPA, 22.2±24.9; positive, 19.5±21.5; strongly positive, 32.6±23.5; p=0.0335), but not correlated with indexes of RA disease activity, such as tender joints, swollen joints, CRP, ESR, MMP-3, DAS28-CRP, DAS28-ESR, CDAI, and SDAI. Autoantibody production by B cells requires the involvement of T cells and abatacept can inhibit T cell activation. Based on this background, we hypothesized that abatacept inhibits Syk phosphorylation in B cells. Interestingly, the rate p-Syk-positive cells among CD19+ B cells diminished from 21.4±30.9 to 3.3±3.8 (from week 0 to week 24, p=0.0341) in the abatacept group, and from 30.0±23.1 to 42.0±34.8 (p=0.1255) in the TNF inhibitors group. Although Th1 cells (CD4+CXCR3+ cells) were not changed, abatacept significantly reduced the proportion of Tfh cells (CD4+CXCR5+PD-1+ cells) from 5.7±5.7 at week 0 to 3.4±4.7 % at week 4 (p=0.0206).
Conclusion: Our results demonstrated that significantly high levels of Syk phosphorylation in B cells were strongly related to ACPA in RA patients. Our data suggested that abatacept seems to inhibit Syk-Btk signal in B cells as well as development of T follicular helper cells, highlighting the relevance of B-T cell interaction as a potential target of abatacept therapy in RA.
To cite this abstract in AMA style:Iwata S, Nakayamada S, Fukuyo S, Wang SP, Kubo S, Yoshikawa M, Saito K, Tanaka Y. Activation of Syk-Btk Signal in Peripheral Blood B Cells in Patients with Rheumatoid Arthritis: A Potential Target for Abatacept Therapy [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/activation-of-syk-btk-signal-in-peripheral-blood-b-cells-in-patients-with-rheumatoid-arthritis-a-potential-target-for-abatacept-therapy/. Accessed October 22, 2017.
« Back to 2015 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - http://acrabstracts.org/abstract/activation-of-syk-btk-signal-in-peripheral-blood-b-cells-in-patients-with-rheumatoid-arthritis-a-potential-target-for-abatacept-therapy/