Wengner Antje M, Höpken Uta E, Petrow Peter K, Hartmann Sven, Schurigt Uta, Bräuer Rolf, Lipp Martin
Max Delbrück Center of Molecular Medicine, Berlin, Germany.
Arthritis Rheum. 2007 Oct;56(10):3271-83. doi: 10.1002/art.22939.
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease with unknown etiology and only partially defined pathogenesis. The aim of this study was to establish a murine model of chronic arthritis in which the development of tertiary lymphoid tissue, a hallmark of human RA, is locally induced, and to characterize the roles of the homeostatic chemokine receptors CXCR5 and CCR7 in this process.
We developed a modified model of chronic antigen-induced arthritis (AIA) in mice with a strong bias toward inflammation. Disease pathology was assessed up to 9 months in wild-type, CXCR5-deficient, and CCR7-deficient mice by determination of knee joint swelling and cellular and humoral immune responses, as well as by histologic analysis of arthritic knee joints.
In this novel model of AIA, mice developed organized ectopic lymphoid follicles with topologically segregated B cell and T cell areas, high endothelial venules, and germinal center formation within the chronically inflamed synovial tissue. Analysis of the initiation and progression of AIA in wild-type, CXCR5-/-, and CCR7-/- mice revealed a reduction of acute inflammatory parameters in both knockout strains as well as significantly reduced joint destruction in CXCR5-/- mice. Most importantly, the development and organization of tertiary lymphoid tissue were significantly impaired in CXCR5-deficient and CCR7-deficient mice.
Our results suggest that an inflammatory microenvironment efficiently triggers lymphoid neogenesis in autoimmune diseases such as RA. Moreover, the generation of autoreactive tertiary lymphoid tissues, which is entirely dependent on homeostatic chemokines, may in turn maintain local aberrant chronic immune responses.
类风湿性关节炎（RA）是一种病因不明、发病机制仅部分明确的慢性炎症性自身免疫疾病。本研究的目的是建立一种慢性关节炎小鼠模型，在该模型中局部诱导三级淋巴组织的形成，这是人类RA的一个标志，并确定稳态趋化因子受体CXCR5和CCR7在此过程中的作用。
我们开发了一种改良的慢性抗原诱导性关节炎（AIA）小鼠模型，该模型具有强烈的炎症倾向。通过测定膝关节肿胀、细胞和体液免疫反应以及对关节炎膝关节进行组织学分析，在野生型、CXCR5缺陷型和CCR7缺陷型小鼠中评估疾病病理长达9个月。
在这个新的AIA模型中，小鼠在慢性炎症的滑膜组织内形成了有组织的异位淋巴滤泡，其中B细胞和T细胞区域拓扑分离，有高内皮微静脉和生发中心形成。对野生型、CXCR5-/-和CCR7-/-小鼠中AIA的起始和进展分析显示，两个敲除品系的急性炎症参数均降低，CXCR5-/-小鼠的关节破坏也显著减少。最重要的是，CXCR5缺陷型和CCR7缺陷型小鼠中三级淋巴组织的发育和组织化明显受损。
我们的结果表明，炎症微环境可有效触发自身免疫疾病（如RA）中的淋巴新生。此外，完全依赖稳态趋化因子的自身反应性三级淋巴组织的生成可能反过来维持局部异常的慢性免疫反应。
