Elsevier

Autoimmunity Reviews

Volume 8, Issue 7, June 2009, Pages 632-637
Autoimmunity Reviews

Latest update on the Ro/SS-A autoantibody system

https://doi.org/10.1016/j.autrev.2009.02.010Get rights and content

Abstract

Anti-SS-A (Ro52/Ro60) autoantibodies have been described as serological marker for Sjögren's syndrome but are also found in patients with other systemic autoimmune diseases. Historically, these autoantibodies were considered as a uniform autoantibody-system. However, recent studies provided evidence that Ro60 and Ro52 are not part of a stable macromolecular complex and that anti-Ro52 and anti-Ro60 (SS-A) antibodies have different clinical associations. The prevalence of anti-Ro52 in systemic sclerosis and myositis is significantly higher than anti-Ro60 (SS-A) and isolated anti-Ro52 can be found in up to 37% of myositis patients, often correlated with anti-Jo-1 reactivity (p = 0.0002). Furthermore, recent developments have made significant improvements in the quality of recombinant Ro60 showing excellent performance in Ro60 (SS-A) ELISA (Dr. Fooke Laboratorien). Of note, single reactivity to either Ro52 or Ro60 (SS-A) can be missed when measured with a classical SS-A ELISA based on a mixture of both antigens. Approximately 20% of anti-Ro52 or Ro60 (SS-A) positive samples may remain undetected using a mixture of both antigens. Moreover, the international reference sera from the Centers for Disease Control and Prevention (CDC 2, 3, 7, 10) were further characterized. It was concluded that Ro60 (SS-A) and Ro52 represent two distinct autoantibody systems and that separate detection is desirable in a clinical diagnostic setting.

Introduction

SS-A/Ro autoantibodies (aab) are among the most frequently detected autoantibodies (aab) and have traditionally been associated with systemic lupus erythematosus (SLE), Sjögren's syndrome (SjS), subacute cutaneous lupus and neonatal lupus syndrome [1], [2], [3], [4]. Anti-SS-A/Ro aab have also been reported in systemic sclerosis (SSc) and myositis [5]. Anti-SS-A/Ro aab temporally precede other SLE associated aab such as anti-dsDNA, anti-ribonucleoprotein (RNP) and anti-Sm and are present on average 3.4 years before the diagnosis of SLE [6]. The target antigen, originally called “SjD”, was first described in 1962 by Anderson et al. [7]. The subsequent double name Ro and SS-A derives from the description of this aab system by two research groups: one part of the nomenclature relating to the name of a SLE patient (“Ro”) [8] and the other nomenclature related to its association with SjS (“SS”), the latter designation first published by Alspaugh and Tan in 1975 [9]. Eventually, after some of the molecular characteristics of target antigens were identified, the nomenclature became SS-A/Ro60 and SS-A/Ro52 to include the molecular masses of the respective antigens. In this manuscript we will refer to the antigens as Ro60 (SS-A) and Ro52. The primary target antigen for anti-Ro-aab was identified as a 60 kDa protein component of small cytoplasmic ribonucleoprotein complexes (hY-RNA complexes) in 1988 by Deutscher et al. [10] and shortly after by Ben Chetrit et al. [11], but only in 1991, it was confirmed by Chan et al. [12] that the Ro52 and the Ro60 (SS-A) antigens indeed consisted of two different proteins coded by different cDNAs. This review summarizes the historical milestones of the so-called Ro (SS-A) aab system and provides new insights into the association between anti-Ro52 and anti-Ro60 (SS-A) aab. Moreover, recent data on the detection of anti-Ro60 (SS-A) aab using recombinant Ro60 (rRo60) is presented and discussed. Finally, novel data of the anti-nuclear antibody (ANA) reference sera provided by the Centers for Disease Control and Prevention (CDC) is presented.

Section snippets

Ro52 is a biochemically and immunologically independent aab system

Although Ro52 and Ro60 (SS-A), which are encoded by different genes [12], were initially suggested to be closely related, a direct interaction of the proteins could never be conclusively proven. Their biological functions remained elusive for some time, but more recent studies indicate that they are localized to different cell compartments and they perform rather different functions. It was recently reported that the Ro60 (SS-A) protein, having a shape that resembles a doughnut, binds to

Association between anti-Ro52 and anti-Ro60 (SS-A) antibodies in different connective tissue diseases

Testing for anti-Ro60 (SS-A) and anti-Ro52 in different disease entities using three independent methods, namely line immunoassay (LIA), ALBIA and ELISA, revealed differing prevalence distribution (Fig. 1 a). The frequency of anti-Ro52 aab was similar to the frequency of anti-Ro60 (SS-A) in all groups except the myositis (35.4% vs. 0.0%, p < 0.001) and SSc (19.0% vs. 6.0%, p < 0.005) cohorts using the consensus of three methods. The percentages of anti-Ro52 aab that occur without anti-Ro60 (SS-A)

Conclusion

In summary, differing anti-Ro52 and anti-Ro60 (SS-A) reactivities were found in a panel of various systemic autoimmune rheumatic diseases. We conclude that anti-Ro52 clearly differs in reactivity from anti-Ro60 (SS-A): Anti-Ro52 is seen in more frequently in myositis and SSc and anti-Ro60 (SS-A) in SjS and SLE compared to the respective other aab. Anti-Ro52 has a prevalence of up to 35% in myositis and in this disease group co-occurs in up to 72% of anti-Jo-1 positive sera. Based on the results

Take-home messages

  • Ro52 is biochemically and immunologically distinct from Ro60 (SS-A).

  • Anti-Ro52 co-occurs in up to 72% of anti-Jo-1 positive sera from myositis patients.

  • Anti-Ro52 and anti-Ro60 (SS-A) reactivities can mask each other, thus more than 20% Ro positive samples can remain undetected in assays that utilize blended antigens.

  • Further characterization of CDC ANA reference sera (for CDC serum 2, 3, 7 and 10) showed anti-Ro52 reactivity in sera previously defined as anti-Ro (SS-A) negative.

  • Anti-Ro52 and

Acknowledgements

We thank M. Petschinka (Dr. Fooke Laboratorien GmbH) for technical assistance and support with the preparation of the data. Also we would like to thank Prof. Edward K. L. Chan (University of Florida) for his critical review of the manuscript.

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