Henri Chabre

Presence of antinucleosome autoantibodies in a restricted set of connective tissue diseases: Antinucleosome antibodies of the IgG3 subclass are markers of renal pathogenicity in systemic lupus erythematosus

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 (systemic sclerosis; SSc), 20 had mixed connective tissue disease (MCTD), and 319 had other CTD, including Sjögrens syndrome, inflammatory myopathy, rheumatoid arthritis, primary antiphospholipid syndrome, Wegeners granulomatosis, Takayasu arteritis, giant cell arteritis, relapsing polychondritis, Behçets syndrome, and sarcoidosis. Antinucleosome-positive sera were further analyzed, by isotype-specific ELISA, for antinucleosome 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 antinucleosome of the IgG3 isotype was observed during SLE flares, and this increase was found to be closely associated with active nephritis. Levels of antinucleosome 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 antinucleosome 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.

Early anti-nucleosome autoantibodies from a single MRL+/+ mouse: fine specificity, V gene structure and pathogenicity.

In systemic lupus erythematosus, the nucleosome assumes a central role in the autoimmune response to self antigens. To gain insight into the etiology and pathogenesis of anti‐nucleosome antibodies (Ab), we analyzed a panel of six IgG‐secreting hybridomas derived from a single young MRL +/+ mouse at the onset of the autoimmune response. All monoclonal antibodies (mAb) bound exclusively the native nucleosome, and represented five different clonotypes that recognized diverse nucleosomal epitopes, typical of a polyclonal response. The VH‐complementarity‐determining region (CDR)3 regions exhibited unique stretches of charged amino acids with different polarity that may be important for the interaction with the nucleosome. These early anti‐nucleosome mAb displayed striking structural differences with not only anti‐DNA, but also with anti‐nucleosome Ab, that appear later in disease. Two of the mAb deposited in kidney glomeruli after in vivo administration to RAG‐1‐deficient mice, suggesting that diverse B cell clones, possibly selected by the nucleosome itself, may play a role in the initiation of kidney damage.

L'apparition des anticorps anti-nucléosome précède celle des anti-DNA double brin et des anti-histones au cours du lupus murin

Collected samples serum of 30 MRL lpr/lpr and 15 MRL MP +/ + were tested by ELISA on purified mononucleosomes and its individual components, dsDNA and histones. Anti-mononucleosome anti-bodies can be detected as early as 10 and 23 week of age for MRL lpr/lpr and MP +/ +, respectively, and arose before anti-dsDNA and anti-histone antibodies.