Clinical and laboratory aspects of Ro/SSA-52 autoantibodies

doi:10.1016/j.autrev.2010.09.005

Autoimmunity Reviews

Volume 10, Issue 3, January 2011, Pages 150-154

https://doi.org/10.1016/j.autrev.2010.09.005 Get rights and content

Abstract

Anti-Ro/SSA antibodies, which were described for the first time in systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS), are the most prevalent extractable nuclear antigen (ENA) specificity identified in laboratories. Two types of anti-Ro/SSA antibodies have been described, anti-SSA-52 kDa (aSSA52) and anti-SSA-60 kDa (aSSA60), each specific to different antigens.

Anti-Ro/SSA52 autoantibodies are more frequent than other autoantibodies possibly because of the antigen's accessible and ubiquitous nature. The sites involved and the symptoms associated with these autoantibodies depend on the antigen's structural variability.

Isolated congenital complete atrioventricular block (CAVB) shows a close association with maternal anti-Ro/SSA and anti-La/SSB antibodies; the highest relative risks of CAVB are seen in offspring of mothers with antibodies against 52-kDa Ro and 48-kDa La proteins. Anti-Ro/SSA52 antibodies have little impact on adult rheumatic autoimmune diseases or adult cardiac arrhythmias, but the course of autoimmune liver diseases is greatly worsened by their presence, and solid tumours tend to relapse. Their diagnostic role in rheumatic diseases is controversial, although a significant association between isolated anti-Ro/SSA52-kDa positivity and myositis and to a lesser extent with systemic sclerosis (SSc) has been described. However, the majority of the specific diagnosis is mostly based on the simultaneous presence of other autoantibodies that seems diagnostically more relevant.

Introduction

Systemic autoimmune diseases are commonly characterized by the presence of autoantibodies against intracellular autoantigens. In fact diagnosis, classification and prognosis of autoimmune diseases mostly rely on clinical symptoms and laboratory evaluation, in particular on specificity and levels of one or more autoantibodies. A recent study has found that 42.6% of 6422 consecutive patients were antinuclear antibodies (ANA) positive, and 13.0% showed reactivity to more than one extractable nuclear antigen (ENA), the most prevalent being anti-Ro/SSA (5.5%), anti-La/SSB (2.9%), anti-CENP-B (2.5%) and anti-histone antibodies (2.2%) [1]. Among a variety of autoantibodies, the Ro/SSA autoantibody-system (Ro60 and Ro52) is the most prevalent ENA specificity identified in laboratories. 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 antibodies have different clinical associations [2]. The Ro/SSA antigen was first described in 1962 by Anderson et al. [3]. The double name Ro and SS-A derives from the description of this system by two research groups: one part of the nomenclature relating to the name of a systemic lupus erythematosus (SLE) patient (“Ro”) [4] and the other nomenclature related to its association with Sjögren's syndrome (SS), the latter designation first published by Alspaugh and Tan in 1975 [5].

SSA/Ro antigen consists of two polypeptide components of 52 and 60 kDa. In humans, the 60-kDa Ro protein has an RNA binding domain, whereas the 52-kDa protein (Ro52) has zinc finger and leucine zipper domains but does not directly bind RNA. Molecular interactions between the leucine zipper region or Ro52 and three peptides of the 60-kDa Ro show that Ro52 binds the Ro-RNP complex as a result of an amino acid interaction [6].

Unlike Ro60 kDa and SSB proteins, the Ro52 kDa molecule is specific to humans and monkeys and cytoplasmic ribonucleoprotein particles (hYRNPs) can be found on the cytoplasmic membrane or in small blebs during apoptosis as a reaction to stimuli such as ultraviolet light B (UVB), 17-beta-estradiol, viral infection, tumour necrosis factor (TNF)-alpha and other cell apoptosis-inducing molecules.

In 2002, Fukada [7] found that serum from SS patients reacted heterogeneously to poly-ubiquinated Ro52 kDa, probably because of their different antigenic determinants, and this may be associated with different clinical features. Dorner [8] showed that the central AA 153–245 region is the main immunogenic region of the 52-kDa Ro(SSA) antigen and contains a strong antigenic epitope between AA 197 and AA 245. Antibody responses are directed against this region regardless of the underlying autoimmune disease, although the strikingly different antibody levels and the recognition of epitopes on AA 153–196 may be associated with different disease expressions.

The clinical associations of antibodies to the 60-kDa SSA/Ro protein are well documented and include SS, SLE and fetal–maternal autoimmune syndromes.

Autoantibodies against the 52-kDa Ro(SSA) protein are specific laboratory variables, and can exist without the presence of concomitant 60-kDa SSA/Ro antibodies in autoimmune diseases [9]. They have also been found in 2.7% of about 2000 asymptomatic residents in a small Japanese town [10].

Several laboratory methods can be used to detect antibodies to a-SSA/Ro52, including indirect immunofluorescence (IIF), counter-current immunoelectrophoresis (CIEP), ELISA, line immunoassay (LIA), Western blot and addressable laser bead assay (ALBIA). These differ widely in their sensitivity and specificity. The detection of SSA/Ro52 antibodies during standard testing will be determined by the choice of method for detecting antibodies against extractable nuclear antigens (anti-ENAs) [2].

This review summarizes the milestones of the Ro/SS-A52 autoantibodies and provides new insights into the association between SSA/Ro52 antibodies and autoimmune and non-autoimmune diseases.

Section snippets

Isolated anti-Ro/SSA52 antibody positivity

Peene [11] found that anti-Ro/SSA52 kDa-positive serum without anti-Ro/SSA-60 kDa or anti-La/SSB reactivity should be considered separately. The expression of anti-Ro/SSA52 antibodies is mainly associated with connective tissue diseases, although their precise clinical significance is still unknown; however, they are frequently not detected by classic anti-Ro/SSA methods, which have a bias towards anti-Ro-60 kDa. Anti-SSA/Ro52 serum is precipitin negative, not picked up by SSA/Ro enzyme-linked

Autoimmune liver diseases

Anti-Ro/SSa52 specificity is frequent in autoimmune liver diseases. Granito et al. [17] found that it was the most frequent anti-ENA reactivity in primary biliary cirrhosis (PBC, 28%), and that anti-Ro/SSA52 were in a more advanced histological stage and had higher serum bilirubin and IgM levels at the time of diagnosis. They also found that anti-Ro/SSA52 antibodies were highly specific for PBC in autoimmune liver diseases and may therefore be diagnostically relevant in patients who are

Anti-Ro/SSA52 antibodies in cancer

The Ro/SSA52 gene has been mapped to the end of the short arm of human chromosome 11 by means of in situ hybridisation [41]. It has been found that an SNP in intron 3 is closely associated with the presence of anti-Ro/SSA52 autoantibodies in primary SS, an interesting finding in the light of the fact that alternative mRNA is made by deleting exon 4 (which encodes a putative leucine zipper domain) to generate a shorter version of the Ro52 protein.

There is accumulating evidence that chromosome

Conclusions

The fact that anti-SSA/Ro52 autoantibodies are more frequently found than other autoantibodies reflects the accessible and ubiquitous nature of the antigen, whereas the variety of the involved districts and described symptoms is due to the structural variability of the antigen determinants. The measurement of anti-Ro antibody levels should be performed rather than simply test for their presence and that fetal echocardiography should be reserved for pregnant women with high levels. However,

Take-home messages

•
Anti-Ro/SSAs are the most prevalent ENA specificity identified in laboratories.
•
The role of anti-SSA/Ro52 antibodies in neonatal lupus has been well established, but their relationship with cardiac arrhythmias in adults is still debated.
•
Anti-SSA/Ro52 occur in nearly 30% of myositis patients and in up to 72% of anti-Jo-1 positive sera from myositis patients.
•
Anti-SSA/Ro52 co-occurs in nearly 20% of SSc patients.
•
Anti-SSA/Ro52 specificity has been frequently found in autoimmune liver diseases.
•

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ReviewClinical and laboratory aspects of Ro/SSA-52 autoantibodies

Abstract

Introduction

Section snippets

Isolated anti-Ro/SSA52 antibody positivity

Autoimmune liver diseases

Anti-Ro/SSA52 antibodies in cancer

Conclusions

Take-home messages

Autoimmun Rev

Biochem Biophys Res Commun

J Autoimmun

Autoimmunity Rev.

Autoimmunity Rev.

Autoimmunity Rev.

J Am Coll Cardiol

Autoimmunity Rev

Best Pract Res Clin Haematol

Detection and identification of antinuclear antibodies (ANA) in a large community hospital

Acta Clin Belg

Precipitating auto-antibodies in the connective tissue diseases

Ann Rheum Dis

Characterization of a soluble cytoplasmic antigen reactive with sera from patients with systemic lupus erythematosus

J Immunol

Antibodies to cellular antigens in Sjogren's syndrome

J Clin Invest

Anti-SSA/Ro and anti-SSB/La antibodies. What's new?

Ann.Med. Interne (Paris).

Anti-52 kDa Ro(SSA) autoantibodies in different autoimmune diseases preferentially recognize epitopes on the central region of the antigen

J Rheumatol

Isotope switching and titer variation of anti-Ro/SSA antibodies over time in 100 patients with undifferentiated connective tissue disease (UCTD)

Clin Exp Rheumatol

Prevalence of disease-specific antinuclear antibodies in general population: estimates from annual physical examinations of residents of a small town over a 5-year period

Mod Rheumatol

Anti-Ro52 reactivity is an independent and additional serum marker in connective tissue disease

Ann Rheum Dis

Specific testing for “isolated” anti-52kD SSA/Ro antibodies during standard anti-extractable nuclear antigen testing is of limited clinical value

J Clin Pathol

Anti-Ro52 antibodies frequently co-occur with anti-Jo-1 antibodies in sera from patients with idiopathic inflammatory myopathy

Clin Exp Immunol

Immunoserological aspects of idiopathic inflammatory muscle disease

Wien Klin Wochenschr

Review
Clinical and laboratory aspects of Ro/SSA-52 autoantibodies