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Research Article

Autoantibodies associated with lupus induced by diverse drugs target a similar epitope in the (H2A-H2B)-DNA complex.

R L Rubin, S A Bell and R W Burlingame

W. M. Keck Autoimmune Disease Center, Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, California 92037.

Published July 1992

IgG reactivity with the (H2A-H2B)-DNA complex, a subunit of the nucleosome, has been detected in many patients with lupus induced by procainamide and quinidine, but the similarity among the epitopes targeted by these antibodies in this heterogeneous patient group as well as the prevalence of this specificity in lupus induced by other drugs is unknown. Studies with histone-DNA complexes formed by sequential addition on a solid phase demonstrated that complexes containing single histones had negligible antigenicity, indicating that DNA stabilizes a protein epitope in the H2A-H2B dimer or that the complete epitope is generated by a surface feature involving H2A-H2B and DNA. F(ab')2 isolated from a patient with procainamide-induced lupus blocked greater than 90% of the anti-[(H2A-H2B)-DNA] reactivity in six of six sera from patients with lupus induced by procainamide, four of four quinidine-induced patients and in sera from patients with lupus induced by acebutolol, penicillamine, and isoniazid, but not methyldopa or auto-antibodies to the component macromolecules. Fab fragments purified from the IgG of two quinidine-induced lupus patients and patients with isoniazid- and procainamide-induced lupus retained 39% +/- 8% of their original IgG reactivity compared to 34 +/- 28% of the original anti-tetanus toxoid activity of Fab fragments in two of the same sera and two normal sera. These results indicate that anti-[(H2A-H2B)-DNA] does not require divalent antigen-antibody complexes for stability, and that the complete epitope is created by the monomeric, trimolecular histone-DNA complex. We conclude that despite their pharmacologic and chemical heterogeneity, many lupus-inducing drugs elicit near identical autoantibodies.

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