A well known side effect of procainamide therapy is the production of antinuclear antibodies and, less frequently, systemic symptoms resembling lupus erythematosus. Autoantibodies elicited by procainamide are restricted to histones and dDNA, but these are heterogeneous within the patient population, and evidence for a generalized immune dysregulation due to procainamide therapy was obtained. Our working model for procainamide-induced autoimmunity is that reactive, transient metabolites of procainamide are generated in localized immunological compartments, triggering autoantigen release and producing cytotoxic or dysfunctional effects on selective subsets of lymphocytes. Preliminary studies demonstrated that phagocytic cells can metabolize procainamide to a cytotoxic product, and we propose to identify the enzymatic pathway responsible for procainamide oxidation. The sensitivity of lymphocyte subsets to procainamide metabolites will be studied by using a bioassay and measurements of lymphocyte functions such as proliferation, specific antibody synthesis and IL-2 production. Leukocytes from patients with a medical history of drug-induced lupus will be compared with asymptomatic procainamide-treated patients and with a normal population for sensitivity to the toxic effect of procainamide and with a normal population for sensitivity to the toxic effect of procainamide metabolites and for capacity to produce these metabolites after initiation of phagocytosis. The hypothesis will be tested that extracellular nucleohistone, generated secondary to release from a DNA repair process or as a result of cell death, becomes immunogenic due to excessive antigen load and is presented to the immune system in a unique form. Finally, a murine model for procainamide-induced autoimmunity will be developed based on administration of procainamide metabolite to normal mice with the genetic capacity to produce anti-histone antibodies. These studies will establish in vitro mechanisms for elicitation of autoantibodies by drugs such as procainamide, and the murine model will provide an in vivo system for testing these mechanisms and defining the sequence of events leading up to this form of autoimmunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR034358-07
Application #
3156807
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1984-09-01
Project End
1992-08-31
Budget Start
1990-09-01
Budget End
1991-08-31
Support Year
7
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Burlingame, R W; Rubin, R L; Rosenberg, A M (1993) Autoantibodies to chromatin components in juvenile rheumatoid arthritis. Arthritis Rheum 36:836-41
Rubin, R L; Bell, S A; Burlingame, R W (1992) Autoantibodies associated with lupus induced by diverse drugs target a similar epitope in the (H2A-H2B)-DNA complex. J Clin Invest 90:165-73
Rubin, R L (1992) Autoantibody specificity in drug-induced lupus and neutrophil-mediated metabolism of lupus-inducing drugs. Clin Biochem 25:223-34
Burlingame, R W; Rubin, R L (1992) Anti-histone autoantibodies recognize centromeric heterochromatin in metaphase chromosomes and hidden epitopes in interphase cells. Hum Antibodies Hybridomas 3:40-7
Bell, S A; Hobbs, M V; Rubin, R L (1992) Isotype-restricted hyperimmunity in a murine model of the toxic oil syndrome. J Immunol 148:3369-76
Burlingame, R W; Rubin, R L (1991) Drug-induced anti-histone autoantibodies display two patterns of reactivity with substructures of chromatin. J Clin Invest 88:680-90
Roberts, D E; Peebles, C; Curd, J G et al. (1991) Autoantibodies to native myeloperoxidase in patients with pulmonary hemorrhage and acute renal failure. J Clin Immunol 11:389-97
Rubin, R L; Burlingame, R W (1991) Drug-induced autoimmunity: a disorder at the interface between metabolism and immunity. Biochem Soc Trans 19:153-9
Rubin, R L; Tang, F L; Tsay, G et al. (1990) Pseudoautoimmunity in normal mice: anti-histone antibodies elicited by immunization versus induction during graft-versus-host reaction. Clin Immunol Immunopathol 54:320-32
Burlingame, R W; Rubin, R L (1990) Subnucleosome structures as substrates in enzyme-linked immunosorbent assays. J Immunol Methods 134:187-99

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