Tamura Hiroaki, Hasegawa Kiminori
Department of Internal Medicine, Rheumatic diseases, Kin-ikyo-chuo Hospital.
Nihon Rinsho Meneki Gakkai Kaishi. 2009 Feb;32(1):35-42. doi: 10.2177/jsci.32.35.
AA amyloidosis is a life threatening clinical complication of chronic inflammatory diseases such as rheumatoid arthritis. It has been demonstrated biochemically that amyloidosis resulted from abnormal folding of proteins, which are deposited as insoluble fibrils in extracellular tissue, leading to the disruption of their normal function. In this regard, amyloidosis has been recognized as a conformation disorder. Interestingly, genetic polymorphisms of amyloid precursor protein (SAA) have been reported to associate with increased risk for AA amyloidosis. Also recent biochemical research revealed that SAA is synthesized under the influence of the proinflammatory cytokines, such as IL-6, TNF-alpha, IL-1. Additionally, it was suggested that amyloid deposits in extracellular tissue could reflect to the serum level of SAA in the reversible fashion, leading to the hypothesis that the control of the SAA synthesis could be beneficial to the treatment of amyloidosis. In this context, anti-cytokine therapies may be most effective. Especially the inhibition of IL-6 is critical to suppression of SAA production, so treatment with a humanized monoclonal antibody against human IL-6 receptor may not only ameliorate RA disease activity but also pave the way for the treatment of AA amyloidosis.
AA淀粉样变性是类风湿关节炎等慢性炎症性疾病的一种危及生命的临床并发症。生化研究表明，淀粉样变性是由蛋白质异常折叠所致，这些蛋白质以不溶性纤维的形式沉积在细胞外组织中，导致其正常功能受到破坏。就此而言，淀粉样变性已被视为一种构象障碍。有趣的是，已有报道称淀粉样前体蛋白（SAA）的基因多态性与AA淀粉样变性风险增加有关。此外，最近的生化研究表明，SAA是在促炎细胞因子如IL-6、TNF-α、IL-1的影响下合成的。另外，有人提出细胞外组织中的淀粉样沉积物可能以可逆的方式反映SAA的血清水平，从而产生了控制SAA合成可能有利于治疗淀粉样变性的假说。在这种情况下，抗细胞因子疗法可能最为有效。尤其是抑制IL-6对于抑制SAA的产生至关重要，因此用人源化抗人IL-6受体单克隆抗体进行治疗不仅可以改善类风湿关节炎的疾病活动度，还可为AA淀粉样变性的治疗铺平道路。
