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

Abstract

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...

Segregation of lymphocyte low-molecular-weight DNA and antinuclear-antibodies in a family with systemic lupus erythematosus in first cousins

“…The G-C-rich regions are capable of forming "z" left-handed DNA, which is immunogenic (Lafer et al 1981). Anti-DNA antibodies of systemic lupus may not arise from a coneentional immune response to native nucleic acid (Stollar 1981), which is not immunogenic in mice (Hannema et al 1984), but from contact with unusual fragments of DNA (Madaio et al 1984). Recent information in mice suggests that the ANAs arise from direct antigenic stimulation of the immune system by a highly selected set of nucleoproteins and not from a spontaneous antibody secretion by lymphoid cells (Hardin 1986).…”

Quantitative and Qualitative Analysis of the Balance Between Type 1 and Type 2 Cytokine-producing CD8−and CD8+T Cells in Systemic Lupus Erythematosus

“…Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by polyclonal B cell activation and overproduction of anti-cytoplasmic and anti-nuclear autoantibodies [7]. Cytokines have been suggested to play an important role in the immune dysregulation observed in SLE patients and murine models of lupus.…”

Induction of antiphospholipid autoantibodies by immunization with beta 2 glycoprotein I (apolipoprotein H).

“…Lipids are poor immunogens and usually require a protein or carbohydrate carrier to stimulate antibody production (10,11 ). As in the case of anti-DNA antibodies ( 12,13), aPL directed against acidic PL cannot be induced simply by immunization with phospholipids in Freund's adjuvant. Some aPL have been induced experimentally by complex methods including immunization with cardiolipin and heterologous serum ( 14), frequent intravenous injection of lipid coupled to methylated bovine albumin ( 15 ), intraperitoneal injection of lipid coupled to monoclonal aPL-coated Staphylococcus aureus ( 16), and intrasplenic immunization with Salmonella minnesota coated with lipid ( 17).…”