The histone H2A-H2B dimer is a component of nucleosomes in chromatin and a frequent target of autoantibodies in spontaneous and drug-induced lupus. We obtained a panel of several lgG mAbs reacting with H2A-H2B or DNA from MRL mice which develop a spontaneous lupus-like syndrome. Several of these antibodies do not react with individual histones, but bind strongly to the H2A-H2B dimer and some bind even more strongly to the H2A-H2B-DNA complex. Moreover, these antibodies not only bind to H2A-H2B dimers in the absence of DNA, but also exhibit significant binding to DNA in the absence of histones, indicating an overlap between the anti-histone and anti-DNA specificities. The analysis of the variable region gene sequences of these antibodies shows a recurrent usage of similar VH genes, suggesting a dominant role for the heavy chain in determining binding specificity. The heavy chain third complementarity determining regions of these antibodies are also remarkable for their frequency of D-D fusions and of D segments read in unusual reading frames and for many arginine residues that may contribute to DNA binding. In addition, several antibodies obtained from an individual mouse are clonally related and some differ through somatic mutations, indicating that autoreactive clones are positively selected by nuclear antigens.