Rosengren Sanna, Wei Nathan, Kalunian Kenneth C, Zvaifler Nathan J, Kavanaugh Arthur, Boyle David L
Division of Rheumatology, Allergy and Immunology, University of California at San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Arthritis Res Ther. 2008;10(5):R105. doi: 10.1186/ar2497. Epub 2008 Sep 1.
The purpose of this study was to quantitatively evaluate the contribution of synovial lymphoid aggregates to autoantibody (rheumatoid factor [RF] and anti-cyclic citrullinated peptide [anti-CCP]) and total immunoglobulin (IgG and IgM) production in rheumatoid arthritis (RA) patients and the effect thereon of the B-cell-depleting antibody, rituximab, in the ARISE (Assessment of Rituximab's Immunomodulatory Synovial Effects) trial.
Autoantibodies as well as total IgM and IgG were quantified by enzyme-linked immunosorbent assay in extracts of synovial tissues and matched serum from patients with RA or osteoarthritis (OA). Synovial biopsies and serum were obtained at baseline and 8 weeks following rituximab therapy in 14 RA patients. A synovial/serum index (SSI) was calculated as the ratio of synovial to serum antibody/albumin, with values above 1 representing synovial enrichment. Lymphoid aggregates were evaluated histologically.
Anti-CCP IgG, but not RF-IgM, was significantly enriched in RA synovia compared with serum. Total IgM and IgG were also enriched in RA, but not in OA. SSI correlated significantly with mRNA content for both IgM and IgG, demonstrating that it reflected synovial immunoglobulin production. RA synovia with lymphocyte aggregates contained significantly elevated RF-IgM and anti-CCP IgG compared with tissues with diffuse lymphoid infiltration. Rituximab treatment did not affect synovial autoantibody or total immunoglobulin SSI overall. However, in aggregate-containing tissues, rituximab significantly reduced total IgM and IgG SSI as well as IgM and IgG1 mRNA. Surprisingly, RF-IgM and anti-CCP IgG SSIs were unchanged by rituximab in aggregate-containing synovia.
Combined with earlier observations that synovial lymphoid aggregates are unaltered by rituximab treatment, these data suggest that lymphoid aggregates may provide a protective niche for autoantibody-producing cells.
本研究的目的是定量评估类风湿关节炎（RA）患者滑膜淋巴样聚集物对自身抗体（类风湿因子[RF]和抗环瓜氨酸肽[抗CCP]）及总免疫球蛋白（IgG和IgM）产生的贡献，以及在ARISE（利妥昔单抗免疫调节滑膜效应评估）试验中B细胞耗竭抗体利妥昔单抗对其的影响。
通过酶联免疫吸附测定法对RA患者或骨关节炎（OA）患者的滑膜组织提取物和配对血清中的自身抗体以及总IgM和IgG进行定量。在14例RA患者中，于基线时及利妥昔单抗治疗8周后获取滑膜活检组织和血清。计算滑膜/血清指数（SSI），即滑膜与血清抗体/白蛋白的比值，该值大于1表示滑膜富集。对淋巴样聚集物进行组织学评估。
与血清相比，RA滑膜中抗CCP IgG显著富集，但RF-IgM未富集。总IgM和IgG在RA中也有富集，但在OA中未富集。SSI与IgM和IgG的mRNA含量显著相关，表明其反映了滑膜免疫球蛋白的产生。与弥漫性淋巴细胞浸润的组织相比，有淋巴细胞聚集的RA滑膜中RF-IgM和抗CCP IgG显著升高。利妥昔单抗治疗总体上不影响滑膜自身抗体或总免疫球蛋白SSI。然而，在含有聚集物的组织中，利妥昔单抗显著降低了总IgM和IgG SSI以及IgM和IgG1 mRNA。令人惊讶的是，在含有聚集物的滑膜中，利妥昔单抗未改变RF-IgM和抗CCP IgG SSI。
结合早期关于利妥昔单抗治疗不改变滑膜淋巴样聚集物的观察结果，这些数据表明淋巴样聚集物可能为自身抗体产生细胞提供一个保护性微环境。
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