Kobayashi Masaru, Yasui Natsuo, Ishimaru Naozumi, Arakaki Rieko, Hayashi Yoshio
Tokushima University School of Dentistry, and The University of Tokushima School of Medicine, Tokushima, Japan.
Arthritis Rheum. 2004 Dec;50(12):3974-84. doi: 10.1002/art.20679.
A wide spectrum of extraglandular manifestations may occur in patients with Sjogren's syndrome (SS), but the mechanisms responsible for in vivo progression are still obscure. We undertook this study to evaluate the age-related changes during the development of extraglandular autoimmune lesions, including arthritis, in the murine model of primary SS, and to evaluate the possible relationship between age-related disturbance of activation-induced cell death and the in vivo kinetics against autoantigens.
A total of 126 NFS/sld mice were investigated at ages 2, 4, 6, 10, 12, 18, 20, and 24 months. Cytokine production was tested using culture supernatants from anti-CD3 monoclonal antibody-stimulated T cells. Anti-single-stranded DNA (anti-ssDNA) antibodies, Ig isotypes (IgG1, IgG2a), rheumatoid factor (RF), and anti-type II collagen (anti-CII) antibodies were detected by enzyme-linked immunosorbent assay. Proliferative T cell responses against each of 3 recombinant alpha-fodrin proteins and against CII were analyzed.
Autoimmune arthritis developed in SS model mice until age 24 months. Significant elevations in serum levels of RF, anti-ssDNA antibodies, and anti-CII antibodies were found in aging SS model mice. A high titer of serum autoantibodies against alpha-fodrin fragments (containing different epitopes that were originally identified in primary SS model mice) was frequently detected in young and aged SS model mice. Moreover, we found that alpha-fodrin autoantigen induced Th1 immune responses and accelerated disturbance of Fas-mediated T cell apoptosis in aged SS model mice.
These results indicate that age-related disturbance of activation-induced cell death via bystander T cell activation may play a crucial role in the development of autoimmune arthritis in a murine model of SS.
干燥综合征（SS）患者可能出现多种腺外表现，但其体内进展机制仍不清楚。我们开展本研究，以评估原发性SS小鼠模型中腺外自身免疫性病变（包括关节炎）发展过程中的年龄相关变化，并评估激活诱导细胞死亡的年龄相关紊乱与自身抗原体内动力学之间的可能关系。
共对126只NFS/sld小鼠在2、4、6、10、12、18、20和24月龄时进行研究。使用抗CD3单克隆抗体刺激的T细胞培养上清液检测细胞因子产生。通过酶联免疫吸附测定法检测抗单链DNA（抗ssDNA）抗体、Ig同种型（IgG1、IgG2a）、类风湿因子（RF）和抗II型胶原（抗CII）抗体。分析针对3种重组α- fodrin蛋白和CII的增殖性T细胞反应。
SS模型小鼠中自身免疫性关节炎发展至24月龄。在衰老的SS模型小鼠中，RF、抗ssDNA抗体和抗CII抗体的血清水平显著升高。在年轻和衰老的SS模型小鼠中经常检测到高滴度的针对α- fodrin片段（包含最初在原发性SS模型小鼠中鉴定的不同表位）的血清自身抗体。此外，我们发现α- fodrin自身抗原在衰老的SS模型小鼠中诱导Th1免疫反应并加速Fas介导的T细胞凋亡紊乱。
这些结果表明，通过旁观者T细胞激活导致的激活诱导细胞死亡的年龄相关紊乱可能在SS小鼠模型中自身免疫性关节炎的发展中起关键作用。
