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Clinical, immunological, and immunogenetic aspects of autoantibody production against Ro/SSA, La/SSB and their linear epitopes in primary Sjögren's syndrome (pSS): a European multicentre study

A G Tzioufas¹, R Wassmuth², U G Dafni³, A Guialis⁴, H-J Haga⁵, D A Isenberg⁶, R Jonsson⁵, J R Kalden², H Kiener⁷, C Sakarellos⁸, J S Smolen⁷, N Sutcliffe⁶, C Vitali⁹, E Yiannaki¹, H M Moutsopoulos¹

¹ Department of Pathophysiology, School of Medicine, University of Athens, Greece
² Department of Medicine III, Institute for Clinical Immunology, University of Erlangen-Nürnberg, Germany
³ Faculty of Nursing, School of Health Sciences, University of Athens, Greece
⁴ Institute of Biological Research and Biotechnology, The National Hellenic Research Foundation, Athens, Greece
⁵ University of Bergen, Bergen, Norway
⁶ University College, London, UK
⁷ University of Vienna and Lainz Hospital, Vienna, Austria
⁸ Laboratory of Organic Chemistry, Ioannina, Greece
⁹ University of Pisa, Pisa, Italy

Correspondence to:
Correspondence to:
Dr A G Tzioufas, Department of Pathophysiology, School of Medicine, University of Athens, 75 M Asias St 11527 Athens, Greece;
agtzi{at}med.uoa.gr

Objectives: To investigate the clinical and immunogenetic aspects of antibody formation against Ro/SSA and La/SSB as well as their linear B cell epitopes in patients with primary Sjögren's syndrome (pSS) from different European countries.

Patients and methods: Ninety patients with pSS from six European centres were studied. Serum samples from all patients were tested in a control laboratory for anti-Ro/SSA and anti-La/SSB autoantibodies by RNA precipitation assay and autoantibodies to the previously reported B cell linear epitopes of Ro 60 kDa (p169–190aa and p211–232aa) and La/SSB (p147–154aa, p291–302aa, p301–318aa, and p349–364aa). DNA from 88 patients was used for the determination of HLA-DRB1, -DQA1, and -DQB1 genotypes. Analysis of the results was performed in the 88 patients who were genotyped and tested also for antipeptide antibodies.

Results: Antibodies to B cell epitopes of Ro 60 kDa were detected at a low frequency (range 10–37%). In contrast, B cell epitopes of La/SSB were detected frequently (range 58–86%) among the anti-La/SSB positive sera. Autoantibodies to the La/SSB epitope, p349–364aa, were significantly positively associated with longer disease duration (p<0.05), recurrent or permanent parotid gland enlargement (p<0.005), and a higher proportion of non-exocrine manifestations (p<0.005), compared with patients without autoantibodies. The presence of anti-Ro/SSA and anti-La/SSB autoantibodies was significantly associated with the presence of HLA-DRB1*03 and DQB1*02 (p=0.038 and p=0.034, respectively). This association was even more prominent and extended to HLA-DQA1*0501 when patients were stratified according the presence of autoantibodies to discrete La/SSB B cell epitopes in comparison with autoantibody negative patients (p<0.01). They were found also to be highly associated with the alleles HLA-DQB1*02 and HLA-DQA1*0501 as well as the presence of a shared amino acid motif in the region 59–69aa of DQB1 first domain (p<0.01, respectively).

Conclusions: Autoantibodies against La/SSB, binding to four synthetic peptides, derived from the sequence of the La protein were identified with increased frequency in sera of patients with pSS. The formation of autoantibodies against B cell epitope analogues of La/SSB in European patients with pSS may be dependent on the presence of a permissive HLA-DQ heterodimer, most prominently represented by the HLA-DQA1*0501/DQB1*0201 heterodimer, suggesting that a model of HLA restricted presentation of La/SSB peptide determinants is crucial for the autoimmune response against La/SSB.

Keywords: Sjögren's syndrome; anti-Ro/SSA; anti-La/SSB; B cell epitopes; immunogenetic studies

Abbreviations: BSA, bovine serum albumin; MHC, major histocompatibility complex; OR, odds ratio; PBS, phosphate buffered saline; pSS, primary Sjögren' syndrome; SLE, systemic lupus erythematosus

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