Anti-Ro/SSA antibodies are among the most frequently detected autoantibodies against extractable nuclear antigens and have been associated with systemic lupus erythematosus (SLE) and Sj？gren's syndrome (SS). Although the presence of these autoantibodies is one of the criteria for the diagnosis and classification of SS, they are also sometimes seen in other systemic autoimmune diseases. In the last few decades, the knowledge of the prevalence of anti-Ro/SSA antibodies in various autoimmune diseases and symptoms has been expanded, and the clinical importance of these antibodies is increasing. Nonetheless, the pathological role of the antibodies is still poorly understood. In this paper, we summarize the milestones of the anti-Ro/SSA autoantibody system and provide new insights into the association between the autoantibodies and the pathogenesis of autoimmune diseases. 1. Introduction Systemic autoimmune diseases, including systemic lupus erythematosus (SLE) and Sj？gren’s syndrome (SS), are a category of medical conditions that affects multiple organs and are related to autoimmune responses. These are commonly characterized by the development of autoantibodies against intracellular autoantigens. In fact, diagnosis, classification, and prognosis often rely on specificity and levels of the autoantibodies, in addition to clinical symptoms and other laboratory evaluations. Among autoantigens, extractable nuclear antigens (ENA) are soluble cytoplasmic and nuclear components with over 100 different antigens described. The main antigens used in immunological laboratories for detection are Ro, La, Sm, RNP, Scl-70, and Jo1 [1]. Anti-Ro/SSA and anti-La/SSB antibodies are among the most frequently detected autoantibodies against ENA and have traditionally been associated with SLE, SS, subacute cutaneous lupus erythematosus (SCLE), and neonatal lupus erythematosus (NLE) [2–5]. Anti-Ro/SSA and anti-La/SSB can be detected in 70–100% and 40–90%, respectively, of patients with SS [6], and the presence of these autoantibodies is one of the criteria for the diagnosis and classification of SS [7, 8]. Anti-Ro/SSA and anti-La/SSB antibodies were originally described in 1961 as two precipitating antibodies reacting with antigens contained in extracts from salivary and lacrimal glands of patients with SS, termed SjD, and SjT, respectively [9]. SjD antigen was reported to be insensitive to trypsin or heat, while SjT antigen could be destroyed by the same treatment. In 1969, Clark et al. described the presence of antibodies in the sera of patients with SLE that reacted with
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