Role of Cyclin Kinase Inhibitor p21 in Systemic Autoimmunity

• Published in: The Journal of immunology (1950) 2001-10, Vol.167 (7), p.4067-4074
• Main Authors: Santiago-Raber, Marie-Laure, Lawson, Brian R, Dummer, Wolfgang, Barnhouse, Marlene, Koundouris, Stefanos, Wilson, Curtis B, Kono, Dwight H, Theofilopoulos, Argyrios N
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Autoimmune Diseases - etiology; Autoimmune Diseases - immunology; Autoimmune Diseases - pathology; Autoimmunity; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p21; cyclin-dependent kinase inhibitors; Cyclin-Dependent Kinases - antagonists & inhibitors; Cyclins - genetics; Cyclins - physiology; Female; Hypergammaglobulinemia - blood; Immunophenotyping; Kidney - pathology; Lymphocyte Activation; Lymphocyte Subsets - classification; Lymphoid Tissue - immunology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; p21 protein; Superantigens - immunology; Survival Rate; T-Lymphocytes - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.167.7.4067

The cyclin kinase inhibitor protein p21 affects multiple processes relevant to the immune system, including cell cycle progression, replicative senescence, hemopoietic stem cell quiescence, and apoptosis. Therefore, malfunction of this protein may be a contributor to the pathogenesis of systemic autoimmunity. Here, we report that mixed background p21-deficient 129/Sv x C57BL/6 mice showed increased in vitro and in vivo T cell cycling and activation, moderate hypergammaglobulinemia and, at low penetrance, anti-chromatin autoantibodies. Homeostatic anti-self MHC/peptide ligand-induced proliferation of p21-deficient T cells was also enhanced. However, lymphoid organ enlargement was very mild, presumably due to increased apoptosis of the rapidly dividing cells. Moreover, the older p21-deficient mice had kidney pathology representing a similar, but slightly more advanced, state than that seen in the control mice. The timing and severity of the above serologic, cellular, 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 full spectrum of lupus-like disease.