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FRI0012 Pronounced SYK phosphorylation and TRAF6 overexpression in B cells correlating with the activity of systemic lupus erythematosus
  1. S. Iwata1,
  2. K. Yamaoka1,
  3. H. Niiro2,
  4. K. Nakano1,
  5. S.-P. Wang1,
  6. K. Akashi2,
  7. Y. Tanaka1
  1. 1The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu
  2. 2Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, Fukuoka, Japan

Abstract

Background B cells play a pivotal role in the pathological processes of SLE. We have reported that marked increase of activated memory B cells was observed in refractory SLE patients. Although the efficacy of B cell-targeted therapy such as rituximab has been undeartaken, clinical trials treating SLE with rituximab have failed and a novel strategy is prerequisite. Spleen tyrosine kinase (Syk) is a key molecule in B-cell receptor (BCR)-mediated signaling. We have recently reported that Syk-mediated BCR-signaling is prerequisite for optimal induction of TNF receptor-associated factor (TRAF)6, thereby allowing efficient propagation of CD40- and TLR9- signaling in human B cells in vitro. However, the underlying mechanism of Syk and TRAF6 in autoimmune diseases remains unclear.

Objectives The aim of this study was to clarify the molecular mechanism of Syk and TRAF6 in B cell activation, differentiation and its relevance to SLE pathology.

Methods PBMCs were isolated from healthy donors (n=27) and SLE patients (n=58). Phosphorylation and/or expression of Syk and TRAF6 in naïve (CD19+CD27-) and memory (CD19+CD27+) B cells were analysed by flow cytometry. A Syk specific inhibitor (BAY61-3606) was utilized for in vitro analysis and the disease activity of SLE was measured by SLEDAI.

Results Syk was pronouncedly expressed and phosphorylated in peripheral B cells from SLE patients, compared to those from healthy donors, even without in vitro stimulation. The levels of Syk phosphorylation and ratio of phospho-Syk/Syk were significantly correlated with SLEDAI. Recently, we have reported that TRAF-6 is a common key molecule activated at downstream of BCR-mediated signaling in vitro. The TRAF6 expression level was also increased in SLE patients with a positive correlation with disease activity. It is noteworthy that TRAF6 expression strongly correlated with the ratio of phospho-Syk/Syk, suggesting that unabated Syk phosphorylation up-regulated TRAF6 expression in patients with active disease. The expression level of TRAF6 was higher in memory B cells compared to those in naïve B cells and the percentage of TRAF6-positive B cells significantly correlated with the abundance of memory B cells among total B cells in SLE patients. In vitro culture of SLE B cells with a Syk inhibitor reduced the level of phosphorylated Syk as well as TRAF6 expression.

Conclusions Our current results suggest that Syk-mediated TRAF6 signal transduction is activated in SLE patients, in relation to the disease activity. In addition, we suggest that the Syk-mediated TRAF6 pathway leads to unabated activation and differentiation of pathogenic memory B cells in SLE. Therefore, we underscore the potential role of Syk in B-cell-mediated pathological processes in autoimmune disease such as SLE. Furthermore, inhibition of Syk has a potential to adequately control the disease activity of SLE by regulating pathogenic memory B cells.

Disclosure of Interest S. Iwata: None Declared, K. Yamaoka: None Declared, H. Niiro: None Declared, K. Nakano: None Declared, S.-P. Wang: None Declared, K. Akashi: None Declared, Y. Tanaka Consultant for: Dr. Tanaka has received consulting fees, speaking fees, and/or honoraria from Mitsubishi-Tanabe Pharma, Chugai Pharma, Eisai Pharma, Pfizer, Abbott Immunology Pharma, Daiichi-Sankyo, Janssen Pharma, Astra-Zeneca, Takeda Industrial Pharma, Astellas Pharma, Asahi-kasei Pharma and GlaxoSmithKline and has received research grant support from Mitsubishi-Tanabe Pharma, Bristol-Myers Squibb, Takeda Industrial Pharma, MSD, Astellas Pharma, Eisai Pharma, Chugai Pharma, Pfizer and Daiichi-Sankyo.

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