Prospective study of immune response to hydralazine and development of antideoxyribonucleoprotein in patients receiving hydralazine

Denatured DNA and nucleohistone are major targets of autoreactivity in drug-related lupus. An examination of the antigenic properties of these materials may be helpful in distinguishing among possible mechanisms by which drugs or their metabolites may be thought to induce autoreactivity. Some such mechanisms are that the drug may: 1) bind to a macromolecule, and serve as a specificity-determining hapten for antibodies that then cross-react with nuclear antigens, 2) bind to a usually nonantigenic molecule of nuclear origin and render it immunogenic, with the major specificity determinants being those of the nuclear macromolecule itself, 3) cause cell damage and release of contents in a form that is immunogenic, 4) combine with selected cell surface receptors and stimulate B cells that are normally silent, or 5 ) eliminate populations of suppressor cells, leaving unregulated B cells free to produce autoreactive products. For both idiopathic and drug-related lupus, there is the basic question of whether the primary process results from an unusual presentation of antigen or from an abnormality or alteration of the immune system itself. In addition, there remains a question of whether the mechanisms are different in idiopathic and drug-related lupus.The autoreactivity of drug-related lupus is restricted in comparison either with the total potential for autoreactivity or with that of idiopathic lupus (1). The frequency of antinuclear autoreactivity and the lupus syndrome among patients given some types of drugs is From the Department of Biochemistry and Pharmacology, Tufts University School of Medicine, Boston, MA 021 11.Supported by grants from the National Science Foundation (currently PCM 79-04057) and grant AM 27232 from the National Institutes of Health.Address reprint requests to B. David Stollar, MD. much higher than the frequency of idiopathic systemic lupus would predict, and Occurrence of the drug-related syndrome does not show the same relationship to age and sex as the idiopathic disease. For these reasons, much attention has been paid to the possibility that the drugs act by selectively modifying nuclear macromolecules, making them more immunogenic for a normal immune system. An examination of the specificities of drug-induced antibodies and the antigenic properties of DNA and nucleoprotein in normal animals can help to test the plausibility of at least the first two mechanisms described above. The scope of nuclear antigenicityThe overall picture of antigenic potential for nuclear antigens in patients and experimental animals can be summarized briefly. Patients with idiopathic systemic lupus form antibodies to both native and denatured DNA and double-stranded RNA as well as to histones, histone-DNA complexes, several ribonucleoproteins, and surface structures of several cell types (Table 1) (2). In patients with drug-related lupus, antiribonucleoprotein antibodies are formed early (3) and antidenatured DNA and antihistone-DNA antibodies predominate later (1,4); anti-native DNA is infrequent if it does occu...

The antigenic potential and specificity of nucleic acids, nucleoproteins, and their modified derivatives

Stollar

1981

Relationship between immune response to hydralazine and to deoxyribonucleoprotein in patients receiving hydralazine

McDuffie

1981

In a prospective study of 21 hypertensive patients receiving hydralazine for 1 year, we found a close reiationship between development of antibodies to deoxyribonucleoprotein (DNP) and to hydralazine but no evidence for cross-reactivity between antibodies to these two antigens. Of 8 patients who developed increased levels of antiDNP, 7 also developed antibodies to hydralazine. Inhibition of the reaction between DNP and antiDNP as measured by radioimmunoassay in 3 patients with hydralazine lupus could not be achieved with large amounts of hydralazine. However, antibodies to DNP produced in guinea pigs immunized with hydralazine conjugates could be inhibited with hydralazine in accordance with previous studies by others on rabbits. In the human, antibodies to DNP which develop during hydralazine administration are not due to cross-reactive antibodies nor do they appear as a result of immune response to an in vivo hydralazine DNP conjugate.In 1972 Hahn et a1 (I) reported that 4 patients with active hydralazine lupus had elevated levels of antibodies to hydralazine in their sera. In 1975 Yamauchi et a1 (2) immunized rabbits with hydralazine-protein conjugates and found that the antibodies produced reacted with both DNA and hydralazine. These two observations suggested that the development of antinuclear antibodies in patients receiving this drug resulted from immunologic cross-reactivity between hydralazine and DNA or deoxyribonucleoprotein (DNP). To test this hypothesis, for one year we (3) followed 21 patients after institution of hydralazine therapy for hypertension to determine whether the associa- tion between immunity to hydralazine and to DNP could be confirmed and to examine the question of whether cross-reactivity between hydralazine and deoxyribonucleoprotein in humans could be established.Antibodies to hydralazine were measured by agglutination of chromic chloride treated erythrocytes coated with conjugates of hydralazine to ovalbumin or to bovine serum albumin. Specificity of the reactions was established by inhibition of agglutination with free hydralazine. Antibodies to DNP were determined by the radioimmunoassay method of Robitaiile and Tan (4) in which immunoreactive DNP isolated by density gradient ultracentrifugation was labeled with '"I. Table 1 indicates that 16 of the 21 patients developed antibodies to hydralazine and that 8 developed antibodies to DNP during the course of the study. Of the 8 individuals who developed antibodies to DNP, 7 also developed antibodies to hydralazine. The eighth patient had an anti-hydralazine titer of 1 :4 which was below our arbitrary level of significance since such titers were occasionally found in hypertensive individuals not known to have taken the drug. Further evidence of an association between immunity to the drug and to DNP was obtained from observations on the 1 patient who developed a mild hydralazine syndrome consisting of arthralgias, malaise, and an elevated sedimentation rate. Figure 1 shows that after 8 months on a dose of 300 mg a day this individ...

Hla–Dr4 and Gm 1;21 haplotypes are associated with pseudolupus induced by venopyronum dragéeaes

Grosse‐Wilde

Genth

ühl

et al. 1987

The phenotypic frequencies of human major histocompatibility complex class I, 11, and I11 antigens and immunoglobulin allotypes (Gm factors) were determined in 56 patients (55 women, 1 man) who had lupus-like disease induced by Venopyronum dragees. The findings in these patients were compared with those of a control group. We found a significant increase of HLA-DR4 (57.1% versus 26.5%, relative risk [RR] 3.7) and a decrease of HLA-DR3 (3.6% versus 19.1%, RR 0.16) in the patient group. In addition, the haplotype Gm 1;21 (60.7% versus 32.9%, RR 3.2), and the phenotype Gm 1,3;5,21 (46.4% versus 25.8%, RR 2.5) were significantly increased. Both the haplotype Gm 1;21 and the phenotype Gm 1,3;5,21 are associated with HLA--DR4 in pseudolupus patients but not in controls. The coincidence of HLA-DR4 and Gm 1;21 markedly