In vitro production of antibodies to histones in patients receiving chronic procainamide therapy

Procainamide related autoimmunity is characterized by the production of antibodies to histones and, in particular, to the H2A-2B dimer. We evaluated in vitro production of antibodies to total histones and the H2A-2B dimer by peripheral blood mononuclear cells (PBMC) from patients chronically exposed to procainamide and related this to in vivo production, and assessed possible immunostimulatory response by the postulated reactive metabolite procainamide hydroxylamine (PAHA) using PAHA conjugated autologous erythrocytes.

We evaluated in vitro spontaneous and mitogen induced production of histone antibodies by PBMC from 26 asymptomatic patients, who were chronically receiving procainamide, in the presence and absence of PAHA conjugated autologous erythrocytes. Correlations with in vivo production were sought.

PBMC from 9 patients revealed significant spontaneous production of histone antibodies, of whom 2 developed procainamide related lupus within 2 mo of the evaluation. There was a significant increase in in vitro production of antibodies to total histones by PBMC that had been cultured in the presence of PAHA-autologous erythrocyte conjugates, but in the absence of mitogens, from 15 (65%) of 23 patients, and of antibodies to H2A-2B by cells from 10 (42%) of 24 patients. Patients' cells that were co-cultured with PAHA-erythrocyte conjugates produced significantly greater amounts of antibodies to both total histones (p = 0.03) and the H2A-2B dimer (p = 0.009) compared with those cultured alone. Co-culture with similarly pretreated erythrocytes also resulted in a significant increase in the production of antibodies to total histones (p < 0.001), but not to the H2A-H2B dimer, by cells from controls.

Some patients receiving chronic procainamide therapy have spontaneous production of histone antibodies. Co-culture with PAHA-erythrocyte conjugates resulted in significantly greater production, suggesting an immunomodulating effect by this metabolite.