Stochastic control of anti-Sm autoantibodies in MRL/Mp-lpr/lpr mice.

Abstract

MRL/Mp-lpr/lpr autoimmune mice consistently show an -25% incidence of the systemic lupus eyrthematosus marker autoantibody anti-Sm. In the present report, we show that the failure to find anti-Sm antibodies in three-quarters of 5-mo-old MRL/lpr mice was not an artifact of an insensitive assay, but rather that the mice fell into two populations as regards their anti-Sm positivity. Based on an extensive analysis of the inci- dence of anti-Sm positivity in 5-mo-old mice according to their cage of residence, we found no evidence for genetic, environ- mental, or parental influences on the propensity of an individ- ual animal to become anti-Sm positive. Also, the gender of the mouse, its Sm antigen level, or its length of survival were not related to anti-Sm antibody, nor was the anti-Sm antibody status of either parent. Some animals became anti-Sm positive after 5 mo of age, but this was less likely than becoming posi- tive before 5 mo of age. Finally, a survey of 205 autoimmune C57BL/6-lpr/lpr mice confirmed the uniqueness of the MRL background for this autoantibody response. These results to- gether indicate that the possibility of making anti-Sm antibod- ies is under genetic control, but that the expression of this capability in an individual animal is governed by stochastic events. We hypothesize further that such random processes may involve the expression of particular immunoglobulin vari- able-region genes combined with mechanisms of extensive so- matic mutation or positive feedback amplification, which would transmute an initial monoclonal response into an even- tual polyclonal one.