Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
The Role of BAFF in Promoting the Development of IL-17-Producing Cells and Th17-Mediated Disease.
Zhou2, Xiaohui, Wang4, Julie, Liu1, Zhongmin, Stohl3, William, Zheng4, Song Guo
B cell-activating factor belonging to the TNF family (BAFF; BLyS) plays a critical role in promoting B cell maturation and survival and the development of autoimmune disorders. BAFF also affects T cell function through binding to one of the BAFF receptors, BAFF-R. BAFF arguments the Th1- but suppresses Th2-mediated inflammatory responses. It is less clear whether BAFF affects the development and Th17 cells-mediated autoimmune diseases.
Freshly isolated splenocytes and lymph node cells in BAFF knock out (KO), BAFF transgenic and wild type mice were analyzed ex vivo for the surface staining of CD19, CD4, CD8, CD69, CD44, CD62L, CCR-6, CD25 and intracellular staining of ROR-gt, IL-17, IFN-g, IL-4 and Foxp3. IL-17A and IL-17F mRNA was determined by qPCR. The effect of BAFF on in vitro differentiation of naïve CD4+ T cells into Th17 cells was assessed through stimulation with soluble anti-CD3/CD28 in the presence of IL-6 and TGF-b plus irradiated APC. We further detected the frequencies of Th1, Th2 and Treg cells in these mice. In addition, we evaluated the role of BAFF in the Th17 development in vivo using a Th17-mediated disease model, EAE.
In comparison to WT mice, the frequencies and total numbers of Th1 and Th17 cells in BAFF KO mice decreased, while that of these cells increased significantly in BAFF Tg mice. IL-17A and IL-17F mRNA in BAFF KO mice decreased compared to WT and Tg mice. In vitro induction of Th17 cells was also down regulated significantly in BAFF KO T cells. In addition, different origins of APC do not affect the induction of Th17 cells. There is no significant difference of Treg induction in these mice. Lack of BAFF delayed the appearance and attenuated the severity of Th17-mediated EAE symptoms. Conversely, the excessive expression of BAFF promoted Th17 cell development and persistent EAE symptoms. Increased IL-6R expression and function by CD4+ cells in BAFF Tg may be responsible for the increased Th17 cell production.
This study suggests that BAFF may promote the development of autoimmune diseases through Th17 cell development and function in addition to its direct effect on B cell maturation and survival. These results implicate that manipulation of BAFF pathways has a beneficial role in treating Th17- and/or Th1-mediated inflammatory diseases.
To cite this abstract, please use the following information:
Zhou, Xiaohui, Wang, Julie, Liu, Zhongmin, Stohl, William, Zheng, Song Guo; The Role of BAFF in Promoting the Development of IL-17-Producing Cells and Th17-Mediated Disease. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2129