Nucleosomes are major T and B cell autoantigens in systemic lupus erythematosus

Objective. Double-stranded DNA (dsDNA) is a well-known target of autoantibo dies in systemic lupus erythematosus (SLE), The majority of these autoantib odies are of the IgG isotype and show affinity maturation, both of which ar e known hallmarks of T cell help. T cell responses to autoantigens, includi ng DNA, have been reported only incidentally in SLE patients. Nevertheless, in murine SLE, naked DNA and complexed DNA (nucleosomes) are known to be r ecognized by T cells. This study aimed to characterize the antinucleosome r esponse and its clinical impact on human SLE, Methods. Nucleosomes were prepared from chicken erythrocytes, Sera from SLE and control patients were investigated by enzyme-linked immunosorbent assa y (ELISA) for nucleosome-specific antibody responses. Peripheral blood mono nuclear cells (PBMC) from SLE and control patients were analyzed by a kinet ic T cell proliferation assay, PBMC were subsequently analyzed for nucleoso me-specific T cell proliferation, Results. Of 136 SLE patients, 56% were seropositive for antinucleosome anti bodies. In contrast, only 3% of 309 control patients (with rheumatoid arthr itis, mixed connective tissue disease, undifferentiated connective tissue d isease, Lyme borreliosis, scleroderma, Sjogren's syndrome, ulcerative colit is, hepatitis B virus infection, or human immunodeficiency virus infection) were seropositive. Thus, the antinucleosome ELISA had a sensitivity of 56% , a specificity of 97%, and a diagnostic confidence of 90% when applied to SLE, It was therefore superior to an anti-DNA ELISA that demonstrated a 69% diagnostic confidence in the same population. Antinucleosome reactivity in SLE patients correlated significantly with disease activity (P < 0.0001), nephritis (P < 0.002), and psychosis (P < 0.02). When proliferation assays were applied, 14 of 26 SLE patients (54%) were positive for nucleosome-spec ific T cells that proliferated in response to their cognate antigen. A supp ressed response was elicited in 3 SLE patients (12%); in these patients, th e PBMC response to nucleosomes was lower than the proliferation of PBMC in the presence of culture medium only. PBMC from the remaining 9 SLE patients (35%) were nonresponsive to nucleosomes in either way. Responding, nonresp onding, and suppressed populations differed from each other significantly ( P < 0.0001). None of the PBMC from 7 healthy donors and 10 control patients could be stimulated with nucleosomal antigens, Conclusion. We present evidence that nucleosomes are major autoantigens in human SLE and that antinucleosomal antibodies are highly specific for the d isease. The antinucleosome ELISA has been shown to be superior to the anti- dsDNA ELISA and may thus be a significantly better tool for diagnosing SLE, Nucleosome-specific T cells in SLE patients may help B cells class switch to IgG and undergo affinity maturation.