Autoantibodies to hnRNP-A2 in SLE: identification of disease-specific linear epitopes and correlation with disease activity and clinical features

The autoantigen hnRNP-A2 (RA33) is targeted by autoantibodies (autoAbs) of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). To define the humoral autoimmune response in more detail, a series of overlapping peptides covering the N-terminal part hnRNP-A2 known to harbour the major epitopes was studied by ELISA in sera from patients with SLE (n = 40), RA (n = 50), MCTD (n = 11) and other rheumatic diseases (n = 86) and from healthy subjects (n = 29). Anti-peptide reactivities were detected in 25% of SLE sera but only rarely in patients with RA or MCTD. Since most of the SLE patients investigated had inactive disease, we next studied sequential sera of 15 individual patients. Of those, only three patients were completely negative for hnRNP-A2 antibodies, while all the other patients showed at least one positive reaction during the observation period. These were directed to the full-length protein and/or to 4 of the 13 peptides used: p35–55, p50–70, p90–116 and p155–175. Interestingly, autoreactivities to the first three peptides were significantly associated with each other but not with reactivity to p155–175 or to the complete protein. This cluster of reactivity was also not linked to any clinical marker of disease. In contrast, p155–175 was strongly correlated with reactivity to the complete protein (P < 0.001) and both reactivities were associated with autoAb to dsDNA and correlated significantly with clinical disease activity, skin involvement and proteinuria (P < 0.01). Remarkably, immunohistochemical analysis revealed overexpression of hnRNP-A2 in affected skin of SLE patients. These data, together with previously published findings in murine SLE models, are suggestive of an involvement of hnRNP-A2 autoimmunity in the pathogenesis of SLE.