RELATIONSHIPS AMONG ANTINUCLEAR ANTIBODIES FROM AUTOIMMUNE MRL MICE REACTING WITH HISTONE H2A-H2B DIMERS AND DNA

The histone H2A - H2B dimer is a component of nucleosomes in chromatin and a frequent target of autoantibodies in spontaneous and drug-induc ed lupus. We obtained a panel of several IgG mAbs reacting with H2A - H2B or DNA from MRL mice which develop a spontaneous lupus-like syndro me. Several of these antibodies do not react with individual histones, but bind strongly to the H2A - H2B dimer and some bind even more stro ngly to the H2A - H2B - DNA complex. Moreover, these antibodies not on ly bind to H2A - H2B dimers in the absence of DNA, but also exhibit si gnificant binding to DNA in the absence of histones, indicating an ove rlap between the anti-histone and anti-DNA specificities. The analysis of the variable region gene sequences of these antibodies shows a rec urrent usage of similar V(H) 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 rema rkable for their frequency of D - D fusions and of D segments read in unusual reading frames and for many arginine residues that may contrib ute to DNA binding. In addition, several antibodies obtained from an i ndividual mouse are clonally related and some differ through somatic m utations, indicating that autoreactive clones are positively selected by nuclear antigens.