Seyler Thorsten M, Park Yong W, Takemura Seisuke, Bram Richard J, Kurtin Paul J, Goronzy Jörg J, Weyand Cornelia M
Department of Medicine, Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
J Clin Invest. 2005 Nov;115(11):3083-92. doi: 10.1172/JCI25265. Epub 2005 Oct 20.
The cytokines B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) enhance autoimmune disease by sustaining B cell activation. In RA, B cells contribute to the formation of 3 functionally distinct types of lymphoid microarchitectures in the inflamed synovium: ectopic GCs; T cell-B cell aggregates lacking GC reactions; and unorganized, diffuse infiltrates. We examined 72 tissues representing the 3 types of synovitis for BLyS and APRIL production and for expression of APRIL/BLyS receptors. Biologic effects of BLyS and APRIL were explored by treating human synovium-SCID mouse chimeras with the APRIL and BLyS decoy receptor transmembrane activator and CAML interactor:Fc (TACI:Fc). GC+ synovitis had the highest levels of APRIL, produced exclusively by CD83+ DCs. BLyS was present in similar levels in all tissue types and derived exclusively from CD68+ macrophages. In GC+ synovitis, treatment with TACI:Fc resulted in GC destruction and marked inhibition of IFN-gamma and Ig transcription. In contrast, inhibition of APRIL and BLyS in aggregate and diffuse synovitis left Ig levels unaffected and enhanced IFN-gamma production. These differential immunomodulatory effects correlated with the presence of TACI+ T cells in aggregate and diffuse synovitis and their absence in GC+ synovitis. We propose that BLyS and APRIL regulate B cell as well as T cell function and have pro- and antiinflammatory activities in RA.
细胞因子B淋巴细胞刺激因子（BLyS）和增殖诱导配体（APRIL）通过维持B细胞活化来加重自身免疫性疾病。在类风湿关节炎（RA）中，B细胞在炎症滑膜中促成3种功能不同的淋巴微结构的形成：异位生发中心（GC）；缺乏GC反应的T细胞 - B细胞聚集体；以及无组织的弥漫性浸润。我们检查了代表3种滑膜炎类型的72个组织，以检测BLyS和APRIL的产生以及APRIL/BLyS受体的表达。通过用APRIL和BLyS诱饵受体跨膜激活剂和CAML相互作用分子：Fc（TACI:Fc）处理人滑膜 - SCID小鼠嵌合体，探索了BLyS和APRIL的生物学效应。GC +滑膜炎中APRIL水平最高，仅由CD83 +树突状细胞（DC）产生。BLyS在所有组织类型中的水平相似，且仅来源于CD68 +巨噬细胞。在GC +滑膜炎中，用TACI:Fc处理导致GC破坏，并显著抑制干扰素 - γ（IFN - γ）和免疫球蛋白（Ig）转录。相比之下，在聚集体和弥漫性滑膜炎中抑制APRIL和BLyS对Ig水平没有影响，但增强了IFN - γ的产生。这些不同的免疫调节作用与聚集体和弥漫性滑膜炎中TACI + T细胞的存在以及GC +滑膜炎中TACI + T细胞的缺失相关。我们提出，BLyS和APRIL调节B细胞以及T细胞功能，并在RA中具有促炎和抗炎活性。
