D-penicillamine-induced autoantibodies in a mouse model

We have previously shown that the administration of D-penicillamine (D-PEN) to patients with rheumatoid arthritis induces circulating insulin autoantibodies (INSAAB). In order to gain further insight into such immune responses, we measured a battery of circulating autoantibodies in 4 strains of mice receiving D-PEN: C57BL/KsJ, BALB/c, C3H/HeJ, and C57BL/6. These rodents groups differ in their degree of susceptibility to streptozotocin (STZ)-induced immune diabetes (SIMD), which is high in the first 2 strains, and mild and nil in the third and fourth, respectively.

Randomly assigned animals from each group were given a weekly subcutaneous (SC) injection of either D-PEN 1 mg, D-PEN 3 mg, or solvent (PBS) for a period of 4 weeks. Serum levels of antibodies to insulin, single stranded DNA (ssDNA), thyroglobulin, and cardiolipin were measured weekly.

Only the C57BL/KsJ and C3H/HeJ mice reacted to D-PEN administration. When compared to the pre-treated and solvent-treated mice, D-PEN 1 mg, and to a lesser degree D-PEN 3 mg, induced elevation of antibodies to insulin and to ssDNA in C57/KsJ mice (p < 0.001), while only ssDNA antibodies were detected in the C3H/HeJ mice (p < 0.0001 for D-PEN 1 mg; p < 0.05 for D-PEN 3 mg). D-PEN had no effect on the level of antibodies to cardiolipin or to thyroglobulin in any of the mice.

This study showed that D-PEN induces an antigen(s)-specific humoral response only in mice already inherently prone to autoimmunity. This model suggests that the activation of autoimmunity by environmental factors is probably facilitated by genetic background, and might partly explain the diversity of autoimmune manifestations in D-PEN-treated patients.