Role of cyclin kinase inhibitor p21 in systemic autoimmunity

The cyclin kinase inhibitor protein p21 affects multiple processes relevant to the immune system, including cell cycle progression, replicative senesc ence, hemopoietic stem cell quiescence, and apoptosis. Therefore, malfuncti on of this protein may be a contributor to the pathogenesis of systemic aut oimmunity. Here, we report that mixed background p21-deficient 129/Sv x C57 BL/6 mice showed increased in vitro and in vivo T cell cycling and activati on, moderate hypergammaglobulinemia and, at low penetrance, anti-chromatin autoantibodies. Homeostatic anti-self MHC/peptide ligand-induced proliferat ion of p21-deficient T cells was also enhanced. However, lymphoid organ enl argement was very mild, presumably due to increased apoptosis of the rapidl y dividing cells. Moreover, the older p21-deficient mice had kidney patholo gy representing a similar, but slightly more advanced, state than that seen in the control mice. The timing and severity of the above serologic, cellu lar, and histologic manifestations in p21-deficient mice were unaffected by gender. Thus, p21 deficiency significantly enhances T cell activation and homeostatic proliferation, and can induce mild autoimmune manifestations at a low incidence without gender bias, but does not in itself generate the f ull spectrum of lupus-like disease.