Antibodies to the five histones and poly(adenosine diphosphate-ribose) in drug induced lupus: implications for pathogenesis.

Abstract

SUMMARY Certain drugs are a frequent source of antinuclear antibody (ANA) induction, and ANA is invariably present in the few patients who progress to the drug induced lupus syndrome. This report concerns the fine specificity of the ANA response to hydralazine, penicillamine, and sulphasalazine therapy. Using highly purified individual histones in fluorimetric assays, antihistone antibodies are always detectable, often in large amounts, but the pattern of response to individual histones is variable and not drug specific. In addition to the response to the three histones Hi, H2B, and H3 reminiscent of idiopathic systemic lupus erythematosus, antibody to histone H2A predominates in some drug induced cases. Contrary to previous thought, histones are not the sole target of the antinuclear response: we also demonstrate a significant correlation between ANA titre and antibody to poly(adenosine diphosphate-ribose). Like the histones, this is a macromolecule that can bind to deoxyribonucleic acid (DNA). It is proposed that drug induced damage to chromatin leads to ANA production, while drug induced impairment of complement activity may then enable these autoantibodies to mediate the lupus syndrome.

Does sulphasalazine cause drug induced systemic lupus erythematosus? No effect evident in a prospective randomised trial of 200 rheumatoid patients treated with sulphasalazine or auranofin over five years

“…ANAs may be detected in as many as 50–90% of patients depending on the drug, dose and duration of treatment 9. The development of ANAs suggests a drug induced autoimmune phenomenon, resulting in other antibodies than the classic antihistones.…”

Drug-induced anti-histone autoantibodies display two patterns of reactivity with substructures of chromatin.

“…Sera from patients with hydralazine-induced lupus were reported to predominantly react with H3 and H4 (9), although other studies failed to detect a distinct pattern of IgG reactivity with individual histones using solid-phase assays (37) or Western blot (12). Chlorpromazine-induced antihistone antibodies were reported to display relatively uniform binding with the substrates tested (5).…”

Juvenile chronic arthritis, chronic iridocyclitis, and reactivity to histones.

“…Development ofsolid phase assays was initially difficult owing to problems of immobilisation of cationic histone antigens.' A fluorimetric assay was used by Hobbs et al to detect antibodies to histones using purified histones,53 54 and found to be more sensitive than the acid elution/ reconstitution method. Non-specific antibody binding is reduced by histone saturation of the tyrosine-glutamic acid copolymer coating the cuvettes.…”