# MECHANISMS UNDERLYING PROCAINAMIDE-INDUCED AUTOIMMUNITY

> **NIH NIH R01** · SCRIPPS CLINIC AND RESEARCH FOUNDATION · 1987 · $138,483

## Abstract

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.

## Key facts

- **NIH application ID:** 3156802
- **Project number:** 2R01AR034358-04
- **Recipient organization:** SCRIPPS CLINIC AND RESEARCH FOUNDATION
- **Principal Investigator:** ROBERT L RUBIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $138,483
- **Award type:** 2
- **Project period:** 1984-09-01 → 1992-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3156802

## Citation

> US National Institutes of Health, RePORTER application 3156802, MECHANISMS UNDERLYING PROCAINAMIDE-INDUCED AUTOIMMUNITY (2R01AR034358-04). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/3156802. Licensed CC0.

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