Department of Medicine, Channing Laboratory, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Am J Pathol. 2011 May;178(5):2177-90. doi: 10.1016/j.ajpath.2011.01.031.
The mystery of why and how a small, seemingly disparate subset of all self molecules become functional autoantigens holds a key to understanding autoimmune diseases. Here and in a companion article in this issue, we show that affinity of self molecules to the glycosaminoglycan dermatan sulfate (DS) is a common property of autoantigens and leads to a specific autoreactive B-1a cell response. Autoimmune ANA/ENA reference sera react preferentially with DS affinity-fractionated cellular proteins. Studying patients with autoimmune diseases, we discovered patient-specific complex autoantigen patterns that are far richer and more diverse than previously thought, indicating significant pathological heterogeneity even within traditionally defined clinical entities, such as systemic lupus erythematosus. By shotgun sequencing of DS affinity-enriched proteomes extracted from cell lines, we identified approximately 200 autoantigens, both novel and previously linked to autoimmunity, including several well-known families of autoantigens related to the nucleosome, ribonucleoproteins, the cytoskeleton, and heat shock proteins. Using electron microscopy, we recognized direct interaction with dead cells as an origin of autoantigenic association of DS with self molecules. DS affinity may be a unifying property of the human autoantigen-ome (ie, totality of self molecules that can serve as functional autoantingens) and thus provides a promising tool for discovery of autoantigens, molecular diagnosis of autoimmune diseases, and development of cause-specific therapies.
为什么以及如何一小部分看似不同的所有自身分子成为功能性自身抗原的奥秘是理解自身免疫性疾病的关键。在这里和本期的一篇相关文章中，我们表明，自身分子与糖胺聚糖硫酸皮肤素 (DS) 的亲和力是自身抗原的共同特性，并导致特定的自身反应性 B-1a 细胞反应。自身免疫性抗核抗体/可提取性核抗原参考血清优先与 DS 亲和力分级的细胞蛋白反应。通过研究自身免疫性疾病患者，我们发现了患者特异性的复杂自身抗原模式，这些模式远比以前认为的更加丰富多样，表明即使在传统定义的临床实体（如系统性红斑狼疮）中，也存在显著的病理异质性。通过从细胞系中提取的 DS 亲和力富集蛋白质组的鸟枪法测序，我们鉴定了大约 200 种自身抗原，包括新的和以前与自身免疫相关的自身抗原，包括与核小体、核糖核蛋白、细胞骨架和热休克蛋白相关的几个著名的自身抗原家族。通过电子显微镜，我们发现与死细胞的直接相互作用是 DS 与自身分子形成自身抗原性关联的起源。DS 亲和力可能是人类自身抗原组（即可以作为功能性自身抗原的所有自身分子的总和）的统一特性，因此为发现自身抗原、自身免疫性疾病的分子诊断和开发针对病因的治疗方法提供了有前途的工具。
