Hu Yi-Ling, Metz Daniela P, Chung James, Siu Gerald, Zhang Ming
Department of Inflammation, Amgen, Inc., Thousand Oaks, CA 91320, USA.
J Immunol. 2009 Feb 1;182(3):1421-8. doi: 10.4049/jimmunol.182.3.1421.
Autoimmune diseases are marked by the presence of class-switched, high-affinity autoantibodies with pathogenic potential. Costimulation plays an important role in the activation of T cells and the development of T cell-dependent B cell responses. ICOS plays an indispensable role in the development of follicular helper T cells (T(FH) cells), which provide cognate help to germinal center (GC) B cells. We show that the levels of T(FH) cells and GC B cells in two different models of autoimmunity, the New Zealand Black/New Zealand White (NZB/NZW) F(1) mouse model of systemic lupus erythematosus and the collagen-induced arthritis model of rheumatoid arthritis, are dependent on the maintenance of the ICOS/B7RP-1 pathway. Treatment with an anti-B7RP-1 Ab ameliorates disease manifestations and leads to a decrease in T(FH) cells and GC B cells as well as an overall decrease in the frequency of ICOS(+) T cells. Coculture experiments of Ag-primed B cells with CXCR5(+) or CXCR5(-) T cells show that blocking B7RP-1 does not directly impact the production of IgG by B cells. These findings further support the role of ICOS in autoimmunity and suggest that the expansion of the T(FH) cell pool is an important mechanism by which ICOS regulates Ab production.
自身免疫性疾病的特征是存在具有致病潜力的类别转换、高亲和力自身抗体。共刺激在T细胞活化和T细胞依赖性B细胞反应的发展中起重要作用。诱导共刺激分子（ICOS）在滤泡辅助性T细胞（T(FH)细胞）的发育中起不可或缺的作用，T(FH)细胞为生发中心（GC）B细胞提供同源辅助。我们发现，在两种不同的自身免疫模型中，即系统性红斑狼疮的新西兰黑/新西兰白（NZB/NZW）F(1)小鼠模型和类风湿性关节炎的胶原诱导性关节炎模型中，T(FH)细胞和GC B细胞的水平依赖于ICOS/B7RP-1通路的维持。用抗B7RP-1抗体治疗可改善疾病表现，并导致T(FH)细胞和GC B细胞减少，以及ICOS(+) T细胞频率总体下降。用CXCR5(+)或CXCR5(-) T细胞对经抗原刺激的B细胞进行共培养实验表明，阻断B7RP-1不会直接影响B细胞产生IgG。这些发现进一步支持了ICOS在自身免疫中的作用，并表明T(FH)细胞库的扩大是ICOS调节抗体产生的重要机制。
