Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Induction of Regulatory B Cells in Healthy Individuals and Patients with Systemic Lupus Erythematosus.
Ota, Shun-ichiro, Niiro, Hiroaki, Ueki, Naoko, Tsuzuki, Hirofumi, Jabbarzadeh-Tabrizi, Siamak, Inoue, Yasushi, Arinobu, Yojiro
Recent evidence from B-cell depletion studies highlights the importance of antibody-independent roles for B cells in autoimmune diseases. In this respect, B cells can negatively regulate the disease process via production of an anti-inflammatory cytokine, IL-10, and thus is termed regulatory B cells (Bregs). The nature of human Bregs, however, remains somewhat elusive, due to a few conflicting previous results.
IL-10 expression in B cells was evaluated using real-time quantitative PCR and ELISA.
We first determined IL-10 expression in CD19+ B cells from healthy controls following stimulation of surface receptors for BCR, CD40, and TLR9, and found that CpG, a TLR9 ligand, is the most potent for Breg induction. Combined stimulation with BCR and CpG exerted synergistic effects on IL-10 production in B cells. Both naïve and memory B cells exhibited comparable levels of CpG-induced IL-10 expression. We next evaluated the effects of various chemical inhibitors of signaling pathways on CpG-induced Bregs. Among them, the inhibitors of the ERK, p38 MAPK, PI3K and STAT3 pathways significantly abrogated Breg induction. Combined stimulation with CpG and STAT3-activating cytokines induced higher levels of IL-10 production in B cells. We finally determined Breg induction in patients with systemic lupus erythematosus (SLE), and found that CpG-induced IL-10 production is significantly impaired in memory B cell subsets as compared with healthy controls. Intriguingly, sustained calcium signaling in B cells from healthy controls abrogated Breg induction in particularly memory B cells, which is reminiscent of SLE memory B cells. We are currently working on further underlying mechanisms of impaired induction of Bregs in SLE patients.
Our current findings could help to better understand a role of human Bregs in the pathogenesis of autoimmune diseases as well as to provide a novel clue to manipulate the generation of human Bregs for therapeutic application in the future.
To cite this abstract, please use the following information:
Ota, Shun-ichiro, Niiro, Hiroaki, Ueki, Naoko, Tsuzuki, Hirofumi, Jabbarzadeh-Tabrizi, Siamak, Inoue, Yasushi, et al; Induction of Regulatory B Cells in Healthy Individuals and Patients with Systemic Lupus Erythematosus. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1766