Induction of autoimmunity in normal mice by thymectomy and administration of polyclonal B cell activators: association with contrasuppressor function.

In order to gain insight into the role of polyclonal B cell activation in the development of autoimmunity, non-autoimmune mice were given chronic injections of polyclonal B cell activators (PBA). In addition, to assess the contribution of T cell regulation of such PBA-induced B cell hyperactivity, the additional effect of postnatal thymectomy was studied. Mice that were postnatally thymectomized and given PBA (LPS +/- poly rI X rC) thrice weekly were found to have elevated levels of IgG and significantly increased serum concentrations of anti-ssDNA. This anti-DNA production was greater than that observed with PBA alone or with thymectomy alone. The entire experiment was repeated with different non-autoimmune mice with the same result. Numbers of proliferating cells in the spleens of the mice in the various groups were analysed by flow cytometry. The number of cells in S+G2+M phases of the cell cycle was significantly increased by PBA or thymectomy alone as well as by the combination. As a result, B cell proliferation was not sufficient to result in maximal anti-ssDNA; an additional T cell defect was required. This was further studied in an in vitro assay for suppressor and contrasuppressor activity. In three separate experiments, mice which were clinically autoimmune were found to have defective suppressor function and the presence of abnormal contrasuppressor activity, whereas non-autoimmune controls had normal suppressor function and no contrasuppressor function. These results indicate that the combination of PBA and thymectomy can most easily induce autoimmunity. The autoimmune state so induced in non-autoimmune strains was associated with a failure of normal suppressor function and the abnormal presence of contrasuppressor function. These results have important implications for spontaneously occurring autoimmune diseases.