Autoantigenic histone epitopes: a comparison between procainamide‐ and hydralazine‐induced lupus

Abstract

Using the technique of immunoblotting, we assessed the ability of sera from 19 patients with druginduced lupus to bind individual histones and specific histone fragments. The pattern of histone epitopes bound by sera from 9 patients with procainamideinduced lupus was very similar to that described previously in spontaneous systemic lupus erythematosus. In contrast, sera from 10 patients with hydralazineinduced lupus bound a broader array of individual histones and recognized a different set of histone epitopes. We conclude that these 2 drugs induce antihistone antibodies through somewhat different mechanisms, which possibly involve differences in their ability to structurally alter chromatin.Antibodies to histones occur in virtually all patients with drug-induced lupus (1,2). Previous studies using solid-phase immunoassays have demonstrated that such antibodies bind individual histones as well as complexes of histones H2A-H2B and of Previously published in abstract form: Craft JE, Bernstein RM, Hardin JA. Clin Res 33: 505A, 1985.From the

Reactivity of Autoantibodies in Systemic <i>Lupus etythematosu</i><i>s</i> with Synthetic Core Histone Peptides

“…Furthermore, the sera of NZB/NZW mice, which are considered to be a mu rine experimental model for human SLE, have been found to contain antibodies to individual histones [15,16] as well as to conformational epitopes present in histone complexes but absent in free histones [16]. The fine specificity of antihistone autoantibodies oc curring in SLE and in drug-induced lupus has been studied in several laboratories [17][18][19][20][21][22], The N-and Cterminal regions of the histone molecules were found to represent major antigenic domains recognized by autoantibodies. Because these domains are generally exposed on nucleosomes, several authors [18,20,23] have suggested that intact chromatin could represent the immunogen involved in SLE.…”

Methyldopa‐induced systemic lupus erythematosus

“…In some patients with procainamide-and hydralazineinduced lupus, sera will also show weak reactivity with HI. Sera from SLE patients react with HI and several other histones in a nonspecific manner (12). Antihistone antibodies in our patient were directed primarily against H 1, without reactivity against other histones.…”

Lupus‐inducing drugs alter the structure of supercoiled circular dna domains

“…Since the formation of nucleosomes is affected by DNA supercoiling (3639), the possible unwinding of chromosomal domains by the drugs could influence the binding of histones or the positioning of histone octamers in the core particles. The rearranged histone-DNA complexes, or histones that are no longer bound to the nucleosome, could induce an immunoresponse that results in the production of antihistone autoantibodies, which is a characteristic feature of drug-induced lupus (20)(21)(22).…”

“…More importantly, spontaneously occurring autoantibodies against lefthanded DNA have been identified in the sera of spontaneously autoimmune MRL/Mp-/pr/lpr mice, as well as in humans with systemic lupus erythematosus or rheumatoid arthritis (15)(16)(17). The presence and specificities of these autoantibodies suggest a possible involvement of left-handed Z-DNA structures, or of a dynamic B-Z equilibrium, in the induction of these autoantibodies (18).There is substantial evidence that procainamide (PROC) and hydralazine (HYD) induce the production of antinuclear antibodies in humans (19)(20)(21)(22). These antibodies are directed mainly against individual histones or histone complexes and, occasionally, are directed against nucleic acids.…”

“…There is substantial evidence that procainamide (PROC) and hydralazine (HYD) induce the production of antinuclear antibodies in humans (19)(20)(21)(22). These antibodies are directed mainly against individual histones or histone complexes and, occasionally, are directed against nucleic acids.…”