AUTOANTIBODY TO THE NUCLEOSOME SUBUNIT (H2A-H2B)-DNA IS AN EARLY AND UBIQUITOUS FEATURE OF LUPUS-LIKE CONDITIONS

Chromatin, a huge polymer of nucleosomes, has been implicated as an im portant target of autoantibodies in idiopathic and drug-induced lupus for decades, but the antigenicity of chromatin has only recently been dissected. IgG reactivity with the (H2A-H2B)-DNA complex, a subunit of the nucleosome, is present in the majority of patients with systemic lupus erythematosus, in >90% of patients with lupus induced by procain amide and in individual patients with lupus induced by a variety of ot her drugs, but is not seen in people taking these medications who are clinically asymptomatic. Anti-[(H2A-H2B)-DNA] accounted for the bulk o f the anti-chromatin activity in drug-induced lupus. The earliest dete ctable autoantibody in lupus-prone mice recognized similar epitopes in the (H2A-H2B)-DNA subnucleosome complex; as the immune response progr essed, native DNA and other constituents of chromatin became antigenic . The importance of chromatin-reactive T cells in the anti-[(H2A-H2B)- DNA] response is suggested by the presence of somatic mutations in ant ibody V-H and V-L regions, their predominant IgG isotype and the simil arity in kinetics of their production to that of conventional T cell d ependent antigens. Together with the serologic data from human lupus-l ike disease, these results are consistent with chromatin being a commo n stimulant for both B and T cells. While chromatin-reactive antibodie s are closely associated with systemic disease and have recently been implicated in glomerulonephritis in SLE, the absence of renal disease in drug-induced lupus indicates that additional abnormalities are requ ired to manifest the serious pathogenic potential of anti-[(H2A-H2B)-D NA] antibodies.