Tan F K, Arnett F C, Reveille J D, Ahn C, Antohi S, Sasaki T, Nishioka K, Bona C A
University of Texas-Houston Health Science Center, USA.
Arthritis Rheum. 2000 Nov;43(11):2464-71. doi: 10.1002/1529-0131(200011)43:11<2464::AID-ANR13>3.0.CO;2-F.
We previously reported the presence of autoantibodies to the extracellular matrix protein, fibrillin 1, in sera from patients with systemic sclerosis (SSc). These autoantibodies appeared to be highly disease-specific but had significantly different frequencies among ethnic groups. The aims of this study were 3-fold: 1) to determine whether sera from SSc patients of different ethnic backgrounds recognized different antigenic epitopes of fibrillin 1, 2) to determine whether sera from patients with polymyositis/dermatomyositis (PM/DM) with or without interstitial lung disease (ILD) also produced these antibodies, and 3) to determine any correlation of anti-fibrillin 1 antibodies with specific clinical features of SSc, other autoantibodies, or HLA class II alleles in a prospectively studied cohort of SSc patients with early (<5 years' duration) disease (the Genetics versus Environment In Scleroderma Outcome Study [GENISOS] cohort).
Three recombinant peptides accounting for the N-terminal end, proline-rich C region, and epidermal growth factor-like calcium-binding (EGF-cb) domains of fibrillin 1 were used in a radioimmunoassay to screen sera from a large group of SSc and PM/DM patients and ethnically matched controls.
The majority of Choctaw American Indians, Japanese, and African Americans with SSc produced IgM and/or IgG autoantibodies to one or more recombinant fibrillin 1 proteins, while <50% of Caucasians with SSc showed seroreactivity. There were striking ethnic differences in fibrillin 1 antigenic epitope recognition among these ethnic groups. African American SSc sera recognized primarily the N-terminal end, and Caucasian sera mostly recognized the EGF-cb repeats and the proline-rich C region. In contrast, most Choctaw American Indian and Japanese SSc sera appeared to recognize 2 or 3 epitopes, respectively. PM/DM patient sera did not recognize any of the fibrillin 1 epitopes regardless of the presence of ILD. In the prospective, multiethnic GENISOS cohort, the presence of anti-fibrillin 1 antibodies did not correlate with any major clinical manifestations, other autoantibodies, or HLA class II alleles.
There are striking ethnic differences in antigenic epitope specificity of anti-fibrillin 1 antibodies in patients with SSc, and the majority of SSc patients, except for Caucasians, produce antibodies to fibrillin 1. The antifibrillin response thus far remains specific for scleroderma syndromes, but it does not correlate with any major clinical features, other autoantibodies, or HLA class II alleles.
我们之前报道过，系统性硬化症（SSc）患者血清中存在针对细胞外基质蛋白原纤维蛋白1的自身抗体。这些自身抗体似乎具有高度疾病特异性，但在不同种族群体中的出现频率有显著差异。本研究的目的有三个：1）确定来自不同种族背景的SSc患者血清是否识别原纤维蛋白1的不同抗原表位；2）确定伴或不伴间质性肺病（ILD）的多发性肌炎/皮肌炎（PM/DM）患者血清是否也产生这些抗体；3）在一项对病程早期（<5年）的SSc患者进行前瞻性研究的队列（硬皮病结局研究中的遗传学与环境[GENISOS]队列）中，确定抗原纤维蛋白1抗体与SSc的特定临床特征、其他自身抗体或HLA II类等位基因之间是否存在相关性。
使用三种重组肽，分别对应原纤维蛋白1的N末端、富含脯氨酸的C区域和表皮生长因子样钙结合（EGF-cb）结构域，通过放射免疫测定法筛选一大组SSc和PM/DM患者以及种族匹配的对照的血清。
大多数患有SSc的乔克托族美国印第安人、日本人及非裔美国人产生针对一种或多种重组原纤维蛋白1蛋白的IgM和/或IgG自身抗体，而患有SSc的高加索人中只有不到50%表现出血清反应性。这些种族群体在原纤维蛋白1抗原表位识别方面存在显著的种族差异。非裔美国SSc患者血清主要识别N末端，而高加索人血清大多识别EGF-cb重复序列和富含脯氨酸的C区域。相比之下，大多数乔克托族美国印第安人和日本SSc患者血清似乎分别识别2个或3个表位。无论是否存在ILD，PM/DM患者血清均不识别任何原纤维蛋白1表位。在多民族的前瞻性GENISOS队列中，抗原纤维蛋白1抗体的存在与任何主要临床表现、其他自身抗体或HLA II类等位基因均无相关性。
SSc患者抗原纤维蛋白1抗体的抗原表位特异性存在显著的种族差异，除高加索人外，大多数SSc患者会产生针对原纤维蛋白1的抗体。迄今为止，抗原纤维蛋白反应仍对硬皮病综合征具有特异性，但与任何主要临床特征、其他自身抗体或HLA II类等位基因均无相关性。
