Host defenses were evaluated in 70 healthy aged volunteers. Individuals who had diseases or who were taking medication known to affect the inflammatory and immune responses were excluded from the study. Volunteers were followed for 24 months to correlate their state of health with the evaluation of host defenses. Polymorphonuclear leukocyte function and the serum opsonic capacity for Escherichia coli and Staphylococcus aureus were normal. Assays of complement components and activity revealed unexplained elevations in native C3 and properdin, normal concentrations of factor B, normal conversion of C3 by inulin, and normal levels of hemolytic complement. The levels of IgG and IgA did not differ from levels noted in younger controls, but the concentration of IgM was decreased and that of IgE increased. The prevalence of autoantibodies was low. None of the volunteers were anergic, but lymphocyte responses to mitogens were depressed in three-day cultures. The number and percentages of E-rosette-forming cells and cells bearing surface IgD or IgM were normal. No lymphopenia was noted.

The immune system has evolved in the human being as an elaborate mechanism to distinguish itself from all else that is not self. This process serves in the defence against invaders. The cells of the immune system learn to tolerate all tissues, cells and proteins of the body. Failure to control the state of tolerance results in autoimmunity. The understanding of the role of T-cell receptors (TCR), the Major Histocompatibility Complex (MHC), adhesion molecules and growth factors in antigen recognition has lead to the exploration of various means to modulate the immune response. Safety measures exist to prevent the immune system from attacking its host. The antigen has to be recognized by the T-cell. This involves the TCR and the MHC. In addition it must receive a second signal to become activated. The second signal involves a protein such as B7 binding with CD28. Certain specialized cells, macrophages, dendritic cells and activated B-cells can deliver this second signal for activation; receipt of only one signal can prevent activation. The elucidation of the role of cell-to-cell interactions, the adhesion molecules involved and the accessory growth factors provides modalities for selectively modifying the immune response. This would be of great relevance in autoimmunity and transplantation.

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This controlled study examined the characteristics of serologic abnormalities in 52 patients receiving procainamide for cardiac arrhythmias, who had no symptoms of a connective tissue disease. Antinuclear antibodies occurred in 43 patients (83%). Significant elevation of antibody binding to single-stranded DNA (mean f SEM 30 f 2.6%), double-stranded DNA (13 f l.l%), Z-DNA (optical density 0.54 f 0.06), and p l y A (7.2 2 0.6%) was seen (P < 0.001). Thirty-four patients (65.4%) had antibodies to total histones, most frequently, the J42A/2B dmer. IgG antibodies to H2A/2B correlated with the cumulative procainamide dose. One patient subsequently developed drug-related lupus. Procainamide (PA) is the agent most commonly implicated in drug-related lupus (DRL), with DRL occurring in 30% of patients positive for fluorescent antinuclear antibody (FANA) who take PA. Many of the features of DRL are nonspecific, thus making diagnosis difficult. Autoantibodies have been proposed to be of value in the diagnosis of DRL and, possibly, in the identification of people at risk for the development of DRL (1). Antinuclear and antihistone antibodies (AHA) have been reported to be highly sensitive for DRL (1,2). However, there is little information regarding the prevalence, and type of serologic abnormalities in patients without symptoms of a connective tissue disease. We report here the results of our serologic evaluation of 52 such patients receiving long-term therapy with procainamide. PATIENTS AND METHODSPatients. Fifty-two patients receiving PA who were attending the outpatient departments of the Veterans Administration (VA) or University of Cincinnati (UC) hospitals were included. There were 50 males (39 Caucasian and 11 black) and 2 females (1 black and 1 Caucasian). Their mean age was 65.8 years (range 47-82). The average daily dose of PA was 3.0 gm (range 0.75-5 gm), and the mean duration of therapy was 40 months (range 1 month to 8 years). Patients with evidence of systemic lupus erythematosus (SLE) at the time of study entry were excluded. Reevaluation of all patients was attempted to determine if evidence of lupus subsequently developed. DRL was diagnosed if patients developed musculoskeletal or pleuropericardial features which resolved upon discontinuation of PA. All 52 of these patients are part of a prospective study (3).Controls. Three groups of control subjects were assessed. One was a group of elderly subjects who were preselected based on age. These were 33 Caucasian individuals who were taking no medications; 28 were men and 5

Although there is evidence to suggest that genetic factors play a major role in the pathogenesis of many of the rheumatic diseases, far less is known of their role in the induction and expression of human autoimmunity resulting from long-term exposure to drugs, chemicals and environmental agents. Pharmacogenetic factors represent an important source of interindividual variation in response to drugs; most research to date has focused on genetic polymorphism of drug metabolism via N-acetylation, S-methylation or cytochrome P-450-catalyzed oxidation. In drug-related autoimmunity, there is limited evidence that the host's genetic background plays a major role beyond the expression of autoantibodies. More recent prospective studies have concentrated on the association of MHC-genes in the expression of autoimmunity and the susceptibility of patients to develop drug-related clinical syndromes.

We studied the effect of hydralazine, an antihypertensive drug with lupus-inducing side effects, on the conformation of poly(dG-m5dC).poly(dG-m5dC) and a plasmid with a 23 bp insert of (dG-dC)n.(dG-dC)n sequences. Using an e.l.i.s.a. with a monoclonal anti-(Z-DNA) antibody Z22, we found that hydralazine provoked the Z-DNA conformation in poly(dG-m5dC).poly(dG-m5dC) at 250-500 microM concentration. The supercoiled form of hydralazine-treated plasmid bound to Z22 in a gel-retardation assay. To examine further whether Z-DNA could act as an inciting agent in anti-nuclear antibody production in patients, we analysed 65 sera from 25 hypertensive patients taking hydralazine and found anti-(Z-DNA) antibodies in 82% of these sera. Sera from age-matched normal controls showed no binding to Z-DNA. Data on sera drawn sequentially from four hypertensive patients showed that antibodies were present after the drug treatment. These data demonstrate the presence of a high incidence of anti-(Z-DNA) antibodies in patients treated with hydralazine and suggest that a possible mechanism for the production of autoantibodies in drug-related lupus might involve the induction and stabilization of Z-DNA by drugs.

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