Hayer Silvia, Tohidast-Akrad Makiyeh, Haralambous Silva, Jahn-Schmid Beatrice, Skriner Karl, Trembleau Sylvie, Dumortier Hélène, Pinol-Roma Serafin, Redlich Kurt, Schett Georg, Muller Sylviane, Kollias George, Smolen Josef, Steiner Günter
Department of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria;
J Immunol. 2005 Dec 15;175(12):8327-36. doi: 10.4049/jimmunol.175.12.8327.
Human TNF-alpha transgenic (hTNFtg) mice develop erosive arthritis closely resembling rheumatoid arthritis (RA). To investigate mechanisms leading to pathological autoimmune reactions in RA, we examined hTNFtg animals for the presence of RA-associated autoantibodies including Abs to citrullinated epitopes (anti-cyclic citrullinated peptide), heterogeneous nuclear ribonucleoprotein (hnRNP)-A2 (anti-RA33), and heat shock proteins (hsp) (anti-hsp). Although IgM anti-hsp Abs were detected in 40% of hTNFtg and control mice, IgG anti-hsp Abs were rarely seen, and anti-cyclic citrullinated peptide Abs were not seen at all. In contrast, >50% of hTNFtg mice showed IgG anti-RA33 autoantibodies, which became detectable shortly after the onset of arthritis. These Abs were predominantly directed to a short epitope, which was identical with an epitope previously described in MRL/lpr mice. Incidence of anti-RA33 was significantly decreased in mice treated with the osteoclast inhibitor osteoprotegerin and also in c-fos-deficient mice lacking osteoclasts. Pronounced expression of hnRNP-A2 and a smaller splice variant was seen in joints of hTNFtg mice, whereas expression was low in control animals. Although the closely related hnRNP-A1 was also overexpressed, autoantibodies to this protein were infrequently detected. Because expression of hnRNP-A2 in thymus, spleen, brain, and lung was similar in hTNFtg and control mice, aberrant expression appeared to be restricted to the inflamed joint. Finally, immunization of hTNFtg mice with recombinant hnRNP-A2 or a peptide harboring the major B cell epitope aggravated arthritis. These findings suggest that overproduction of TNF-alpha leads to aberrant expression of hnRNP-A2 in the rheumatoid joint and subsequently to autoimmune reactions, which may enhance the inflammatory and destructive process.
人肿瘤坏死因子-α转基因（hTNFtg）小鼠会发展出与类风湿性关节炎（RA）极为相似的侵蚀性关节炎。为了研究导致RA病理性自身免疫反应的机制，我们检测了hTNFtg动物体内是否存在与RA相关的自身抗体，包括针对瓜氨酸化表位的抗体（抗环瓜氨酸肽抗体）、异质性核糖核蛋白（hnRNP）-A2（抗RA33）以及热休克蛋白（hsp）（抗hsp）。虽然在40%的hTNFtg小鼠和对照小鼠中检测到了IgM抗hsp抗体，但很少见到IgG抗hsp抗体，且根本未检测到抗环瓜氨酸肽抗体。相比之下，超过50%的hTNFtg小鼠显示出IgG抗RA33自身抗体，这些抗体在关节炎发病后不久即可检测到。这些抗体主要针对一个短表位，该表位与先前在MRL/lpr小鼠中描述的一个表位相同。在用破骨细胞抑制剂骨保护素治疗的小鼠以及缺乏破骨细胞的c-fos缺陷小鼠中，抗RA33的发生率显著降低。在hTNFtg小鼠的关节中可见hnRNP-A2及其一个较小剪接变体的明显表达，而在对照动物中表达较低。虽然密切相关的hnRNP-A1也有过表达，但很少检测到针对该蛋白的自身抗体。由于hTNFtg小鼠和对照小鼠胸腺、脾脏、大脑和肺中hnRNP-A2的表达相似，异常表达似乎仅限于炎症关节。最后，用重组hnRNP-A2或含有主要B细胞表位的肽对hTNFtg小鼠进行免疫会加重关节炎。这些发现表明，肿瘤坏死因子-α的过量产生导致类风湿关节中hnRNP-A2的异常表达，进而引发自身免疫反应，这可能会增强炎症和破坏过程。
