Somatic Mutation and Autoimmunity

Upon reading Christopher Goodnow’s recent Review article in Cell, which emphasized the overlapping role of somatic mutation in autoimmunity and cancer (Goodnow, 2007), I was reminded of a graduate lecture course given by Professor Roderick MacLeod in 1995 at the University of Illinois. While introducing F.M. Burnet’s clonal selection theory to our small class, Professor MacLeod mentioned Burnet’s idea that germline and somatic mutations provide the inherited and stochastic mechanisms that disrupt tolerance and result in autoimmunity. In his Review article, Goodnow independently derives and extends this idea using compelling examples from more than 30 years of molecular and cellular immunology research that has accumulated since Burnet’s insight. However, I recall during our class discussion that we did not find the potential impact of somatic mutation entirely satisfying. Three issues arose: sex, aging, and epitope spreading. Autoimmune diseases commonly afflict the young and middle-aged. In contrast, the most significant risk factor for cancer is increasing age. According to the Surveillance Epidemiology and End Results (SEER) database, an analysis of data from 2000 to 2004 revealed that the median age for developing cancer in the United States is 67 years (Ries et al., 2007). If the accumulation of somatic mutations is a major factor for developing autoimmunity, one would expect a similar median age of onset for autoimmune disease. One explanation for this apparent discrepancy is the reduction in lymphocyte production by the bone marrow and thymus as we enter middle age (Linton and Dorshkind, 2004). This reduction in naive and potentially self-reactive lymphocytes could lead to substantially fewer opportunities for selfreactive rogue lymphocyte clones to arise due to somatic mutation in