Role of polyreactive autoantibodies in the physiopathology of Sjögren’s Syndrome

Abstract

[eng] Sjögren's syndrome (SjS) is a chronic autoimmune disease that mainly affects the exocrine glands and is characterized by the presence of antinuclear antibodies such as anti-Ro52 and anti-dsDNA. Our previous analysis of the B lymphocyte repertoire in NOD.H-2h4 mice, which spontaneously develop SjS-like disease, showed that these mice had a higher frequency of autoreactive/polyreactive B lymphocyte clones that increased with age compared to B6 (WT type) mice. No loss of polyreactivity due to antibody class switching to IgG or somatic mutation was observed. Furthermore, surprisingly, all anti-Ro52 IgG autoantibodies were polyreactive. Given the B-cell dysfunction in SjS and the possible involvement of Ro52 in its pathogenesis, we hypothesized that polyreactive antibodies recognizing Ro52 might be a key factor in the development of the disease. Therefore, we predict that polyreactive anti-Ro52 antibodies (H2h4.7.50 and H2h4.7.94), obtained from NOD.H-2h4 mice, would induce pathogenic phenomena when injected into genetically susceptible mice, whereas the polyreactive anti-Ro52 antibody (B6.2.58) obtained from the non-autoimmune B6 strain would not induce disease development. On the other hand, we considered the possibility of identifying new autoantigens by analyzing our library of monoclonal antibodies derived from the NOD.H-2h4 strain. Polyreactive anti-Ro52 antibodies were injected into autoimmune MRL/lpr mice infected with murine cytomegalovirus, and evaluation of their pathogenic effect was performed by measuring serum anti-dsDNA and anti-Ro52 autoantibodies, lymphocytic infiltration in exocrine glands, and analyzing lymphocytic subpopulations in spleen and bone marrow. The H2h4.7.50 antibody induced increased serum autoantibody levels, as well as increased salivary gland infiltration, mainly by CD8 T lymphocytes, which were also increased in the spleen. The B6.2.58 antibody, however, showed no effect on disease progression. On the other hand, the antibodies selected from the library as potential new autoantibodies because of their salivary gland-specific pattern were found to be highly polyreactive. In conclusion, the observed pathogenic effects induced by H2h4.7.50 indicate the role of polyreactive anti-Ro52 IgG2 antibodies in the pathogenesis of SjS.