Recent studies indicate that IFN-α is involved in pathogenesis of systemic lupus erythematosus. However, direct proof that IFN-α is not only necessary, but also sufficient to induce lupus pathogenicity is lacking. In this study, we show that in vivo adenovector-mediated delivery of murine IFN-α results in preautoimmune (New Zealand Black (NZB) × New Zealand White (NZW))F1, but not in normal, mice, in a rapid and severe disease with all characteristics of systemic lupus erythematosus. Anti-dsDNA Abs appeared as soon as day 10 after initiation of IFN-α treatment. Proteinuria and death caused by glomerulonephritis occurred in all treated mice within, respectively, ∼9 and ∼18 wk, at a time when all untreated (NZB × NZW)F1 did not show any sign of disease. IFN-α in vivo induced an overexpression of B lymphocyte stimulator in circulation at similar levels in both the preautoimmune and the normal mouse strains. All effects elicited by IFN-α were dose dependent. (NZB × NZW)F1 infused with purified murine IFN-α also showed acceleration of lupus. Thus, prolonged expression of IFN-α in vivo induces early lethal lupus in susceptible animals.

Objective. To compare the humoral response to nucleosomes with the response to their individual components (double-stranded DNA [dsDNA] and histones) and to assess the involvement of antinucleosome antibadies in immune deposits in the kidney of MRL mice.Methods. We used enzyme-liked immunosorbent assays of sera and kidney eluates for antibody activity against purified nucleosomes, dsDNA, and histones.Results. Antinucleosome antibodies emerged before anti-dsDNA and antihistone antibodies. A fraction of antinucleosome antibodies reacted exclusively with nucleosomes and not with their components, dsDNA and histones. These nucleosome-restricted antibodies were detected in the proteinuric MRL mouse kidney eluate.Conclusion. Our findings support the notion that nucleosomes play a major role in the emergence of antinuclear autoantibodies and that antinucleosome antibodies might be involved in the nephritogenic process in murine lupus. IAnti-double-stranded DNA (anti-dsDNA) and antihistone antibodies have been found in murine models of systemic lupus erythematosus (SLE) (1). A number of experimental findings suggest that the production of these autoantibodies is antigen-driven (2,3), but the origin and nature of the antigen(s) are elusive.

Objective. To study the frequency and disease specificity of antinucleosome antibody reactivity in diverse connective tissue diseases (CTD), and to determine factors, such as antibody subclass, that may influence the pathogenicity of these antibodies in relation to disease activity. Methods. IgG and IgM antinucleosome activities on nucleosome core particles from 496 patients with 13 different CTD and 100 patients with hepatitis C were measured by enzyme-linked immunosorbent assay (ELISA). Of the patients with CTD, 120 had systemic lupus erythematosus (SLE), 37 had scleroderma (sys-temic sclerosis; SSc), 20 had mixed connective tissue disease (MCTD), and 319 had other CTD, including Sjögren's syndrome, inflammatory myopathy, rheuma-toid arthritis, primary antiphospholipid syndrome, We-gener's granulomatosis, Takayasu arteritis, giant cell arteritis, relapsing polychondritis, Behçet's syndrome, and sarcoidosis. Antinucleosome-positive sera were further analyzed, by isotype-specific ELISA, for antinucleo-some and anti-double-stranded DNA (anti-dsDNA) IgG subclasses. Results. SLE, SSc, and MCTD were the only 3 CTD in which antinucleosome IgG were detected (71.7%, 45.9%, and 45.0% of patients, respectively). Antinucleosomes of the IgG3 subclass were present at high levels in patients with active SLE and were virtually absent in those with SSc, MCTD, or inactive SLE, and their levels showed a positive correlation with SLE disease activity. Of note, an increase in levels of anti-nucleosome of the IgG3 isotype was observed during SLE flares, and this increase was found to be closely associated with active nephritis. Levels of antinucleo-some of the IgG1 subclass showed a trend toward an inverse correlation with SLE disease activity. No significant fluctuation in the anti-dsDNA isotype profile was observed in relation to SLE severity or clinical signs. Conclusion. Our data suggest that IgG anti-nucleosome is a new marker that may help in the differential diagnosis of CTD; antinucleosome of the IgG3 isotype might constitute a selective biologic marker of active SLE, in particular, of lupus nephritis.

Objective. To assess nucleosome plasma levels in patients with systemic lupus erythematosus (SLE) and to study the correlations with serum antinucleosome, anti-double-stranded DNA (anti-dsDNA), and antihistone antibody activities, as well as with disease activity (by the SLE Disease Activity Index [SLEDAI]).Methods. In a cross-sectional study, we assessed 58 SLE patients for their plasma nucleosome levels. Plasma nucleosome levels as well as serum antinucleosome, anti-double-stranded DNA, and antihistone antibody activities were assessed by enzyme-linked immunosorbent assay. SLE activity was evaluated using the SLEDAI.Results. The mean (.t SD) plasma nucleosome concentration in SLE patients was 52 2 159 ng/ml (range 5-1,180), and was significantly higher than that of the controls (16 2 8.8 ng/ml, range 8-52; P = 0.03).