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

Abstract

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.

Subgroups of Sjögren syndrome patients according to serological profiles

“…Some studies also correlated anti-Ro/La antibody positivity to recurrent or permanent parotid gland enlargement [5,22,34] decreased salivary flow [22], more intense symptoms from the eyes, worse Schirmer test and Rose Bengal staining scores [36] and positive salivary gland biopsy [5]. In pSS the degree of labial salivary gland infiltration [37], as well as the development of germinal centre like structures [38] has been associated with the presence of anti-Ro/SSA and anti-La/SSB antibodies.…”

“…Several studies reported a higher prevalence of extraglandular manifestations in SS patients positive for anti-Ro/La [5,22,34]. In a French cohort of 445 pSS patients anti-Ro/SSA and anti-La/SSB antibodies correlated with a younger age at diagnosis and a higher prevalence of recurrent parotidomegaly, cutaneous vasculitis, Raynaud phenomenon and renal involvement.…”

“…In patients with pSS the presence of anti-Ro/SSA and anti-La/SSB antibodies has been associated with earlier disease onset [22e24], longer disease duration [34] and female sex [35]. Some studies also correlated anti-Ro/La antibody positivity to recurrent or permanent parotid gland enlargement [5,22,34] decreased salivary flow [22], more intense symptoms from the eyes, worse Schirmer test and Rose Bengal staining scores [36] and positive salivary gland biopsy [5].…”

Demonstration of high prevalence of SS-A antibodies in a general population: Association with HLA-DR and enterovirus antibodies

“…The whole ANA group comprises autoantibodies against diverse nuclear components with different clinical impacts [3]. Some of them are rare while others have been found frequently, including SS-A(Ro) and SS-B(La) antibodies that are associated with systemic autoimmune diseases as Sjögren's syndrome, systemic lupus erythematosus and rheumatoid arthritis [4]. Detection of ANA and antibodies to SS-A and SS-B is a possible way to identify persons with a predisposition to rheumatic autoimmune diseases [2].…”

Genetics of Inflammatory Bowel Diseases – Past, Present, and Future

“…The biological significance of the determination of HLA studies to understand the variability of the inflammatory process can be seen in other diseases; HLA-DRB1 and HLA-DRB3 specificities in sarcoidosis patients identified that the presence of HLA-DRB1*03 favors a course of disease which is associated with Lofgren's syndrome [12]. Also the presence of anti-Ro/SSA and anti-La/SSB autoantibodies was significantly associated with the presence of HLA-DRB1*03 and HLA-DQB1*02 in patients with primary Sjögren's syndrome [13].…”