Casciola-Rosen L, Wigley F, Rosen A
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
J Exp Med. 1997 Jan 6;185(1):71-9. doi: 10.1084/jem.185.1.71.
The observation that revelation of immunocryptic epitopes in self antigens may initiate the autoimmune response has prompted the search for processes which induce novel fragmentation of autoantigens as potential initiators of autoimmunity. The reversible ischemia reperfusion which characterizes scleroderma has focused attention on reactive oxygen species as molecules which might induce autoantigen fragmentation. We demonstrate that several of the autoantigens targeted in diffuse scleroderma are uniquely susceptible to cleavage by reactive oxygen species, in a metal-dependent manner. Multiple features of the fragmentation reaction and its inhibition indicate that these autoantigens possess metal-binding sites, which focus metal-catalyzed oxidation reactions (and consequent fragmentation) to specific regions of the antigens. These data suggest that the autoantibody response in scleroderma is the immune marker of unique protein fragmentation, induced by ischemia reperfusion in the presence of appropriate metals, and focus attention on abnormal metal status as a potential pathogenic principle in this disease.
自身抗原中免疫隐匿表位的暴露可能引发自身免疫反应这一观察结果，促使人们寻找诱导自身抗原产生新片段化的过程，将其作为自身免疫的潜在引发因素。硬皮病所特有的可逆性缺血再灌注，使人们将注意力集中在活性氧物种上，认为它们可能是诱导自身抗原片段化的分子。我们证明，弥漫性硬皮病中几种靶向自身抗原对活性氧物种的切割具有独特的敏感性，且呈金属依赖性。片段化反应及其抑制的多个特征表明，这些自身抗原具有金属结合位点，可将金属催化的氧化反应（以及随之而来的片段化）集中到抗原的特定区域。这些数据表明，硬皮病中的自身抗体反应是独特蛋白质片段化的免疫标志，这种片段化是在适当金属存在的情况下由缺血再灌注诱导产生的，并将注意力集中在异常金属状态作为该疾病潜在致病机制这一点上。
