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

Abstract

Increasing evidence suggests that autoantibodies in the rheumatic diseases are a consequence of immune selection by selfmaterial, but the nature of the in vivo immunogen is unknown. Insight into this problem may be obtained by measuring autoantibody binding to various forms of a target antigen. Antihistone antibodies arising as a side effect of therapy with various drugs offer an opportunity to explore this premise because many forms of histone have been characterized and adapted to ELISA formats. Two patterns of antibody reactivity were observed. All 21 patients with symptomatic procainamide-induced lupus and 7 of 12 patients with quinidine-induced lupus had IgG antibodies reacting predominantly with the (H2A-H2B)-DNA complex and with chromatin. In contrast, antibodies in 19 of 24 patients taking procainamide without accompanying lupus-like symptoms did not show any pattern. The second pattern was observed in 18/19 chlorpromazinetreated patients and 14/17 patients with hydralazine-induced lupus in which IgM antibodies displayed more reactivity with DNA-free histones than with the corresponding histone-DNA complexes and almost no binding to Hl-stripped chromatin. Absorption studies were entirely consistent with these results. Thus, the two patterns of reactivity with nucleosomal components reflect the molecular substructure of chromatin, suggesting that two processes underlie antihistone antibody induction by drugs. In one, IgG autoantibodies appear to be elicited by chromatin, whereas in the other, autoimmune tolerance to native chromatin appears largely intact, and IgM antibodies may be driven by DNA-free histone. (J. Clin. Invest. 1991. 88:680-690.)

Autoimmunity caused by disruption of central T cell tolerance. A murine model of drug-induced lupus.

“…Most human subjects undergoing long-term treatment with procainamide remain asymptomatic with predominately IgM antibodies to dDNA and denatured histones, whereas the 20% of patients who develop lupus-like symptoms typically have less antidDNA but highly elevated IgG antichromatin (3,25). The restriction in the immune response to the (H2A-H2B)-DNA *Mice subjected to intrathymic PAHA or PBS were killed either 3 or 5 wk after the second injection.…”

“…In our recent studies, exposure of T cell clones to micromolar concentrations of PAHA prevented induction of anergy in an in vitro system that may reflect the events accompanying positive selection of T cells on self-antigen in the thymus (62). The general importance of this mechanism is suggested by the high precursor frequency of chromatin-reactive T cells in murine (63) and human lupus (64) and by the ubiquitous presence of antichromatin antibodies in lupus induced by several drugs (3,65), in idiopathic SLE (26,54,66), and in murine models of SLE (30,51).…”

“…Sera from typical patients with procainamide-induced lupus showing the characteristic IgG reactivity with (H2A-H2B)-DNA complex and serum from a normal control have been described in detail (3,25). Serum from a patient with SLE was typical of patients showing reactivity to multiple components of chromatin including (H2A-H2B)-DNA and native DNA as previously described (26).…”

“…Procainamide poses the greatest risk for development of this syndrome with an annual incidence of ‫ف‬ 20% among treated patients (1). Most patients treated with procainamide develop histone-reactive antibodies and antidenatured DNA (anti-dDNA) 1 antibodies after prolonged therapy (2), whereas IgG antibodies to the (H2A-H2B)-DNA subunit of chromatin are a serologic marker in patients who develop procainamide-induced lupus (3). Numerous studies have been undertaken to explore how procainamide induces autoimmunity.…”

Clinical Course of Drug-Induced Lupus and Immunological Profile of Patients

“…An association with antibodies against histone protein components involved in the nuclear chromatin structure is established in DIL (2,3). Nearly 50 % of DIL cases are positive for anti-single-stranded DnA (anti-ssDnA) antibodies.…”