Anti-subnucleosome reactivities in systemic lupus erythematosus (SLE) patients and their first-degree relatives

Antibodies specific for dsDNA appear to have different genetic origins and pathogenic consequences, compared with histone/dsDNA-specific antibodies, i n a recently described murine model. The purpose of this study was to exami ne if this is also true in human lupus. Sera from 40 SLE families (comprisi ng 40 probands and 153 first-degree relatives), and 45 normal adult control s were assayed for the levels of anti-dsDNA, anti-H1/dsDNA, anti-H2A/H2B/ds DNA, and anti-H3/H4/dsDNA autoantibodies by ELISA. Both the probands and th e first-degree relatives exhibited significantly increased levels of antinu clear antibodies (ANA) targeting the different subnucleosomal epitopes. Imp ortantly, probands with anti-dsDNA antibodies had a significantly higher in cidence of renal disease compared with those with just anti-H2A/H2B/dsDNA a ntibodies, in resonance with murine studies. The frequency of anti-dsDNA an d anti-H2A/H2B/DNA ANA among the first-degree relatives was 11.8% and 18.3% , respectively. Surprisingly, whereas probands with anti-dsDNA ANA had fami lies with several seropositive members, first-degree relatives of patients with anti-H2A/H2B/DNA ANA (but not anti-dsDNA ANA) were uniformly ANA-free. These findings suggest that anti-dsDNA ANA in lupus may not only have wors e disease associations, they may also have very different genetic origins, compared with anti-H2A/H2B/DNA (or anti-nucleosome) ANA.