self-organized criticality theory of autoimmunity自组织临界性理论的自身免疫.pdfVIP

Self-Organized Criticality Theory of Autoimmunity 1 1 1,2,3,4 Ken Tsumiyama , Yumi Miyazaki , Shunichi Shiozawa * 1 Department of Biophysics, Kobe University Graduate School of Health Science, Kobe, Japan, 2 Department of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan, 3 The Center for Rheumatic Diseases, Kobe University Hospital, Kobe, Japan, 4 Global Center of Excellence (GCOE), Tokyo, Japan Abstract Background: The cause of autoimmunity, which is unknown, is investigated from a different angle, i.e., the defect in immune ‘system’, to explain the cause of autoimmunity. Methodology/Principal Findings: Repeated immunization with antigen causes systemic autoimmunity in mice otherwise not prone to spontaneous autoimmune diseases. Overstimulation of CD4+ T cells led to the development of autoantibody-inducing CD4+ T (aiCD4+ T) cell which had undergone T cell receptor (TCR) revision and was capable of inducing autoantibodies. The aiCD4+ T cell was induced by de novo TCR revision but not by cross-reaction, and subsequently overstimulated CD8+ T cells, driving them to become antigen-specific cytotoxic T lymphocytes (CTL). These CTLs could be further matured by antigen cross- presentation, after which they caused autoimmune tissue injury akin to systemic lupus erythematosus (SLE). Conclusions/Significance: Systemic autoimmunity appears to be the inevitable consequence of over-stimulating the host’s immune ‘system’ by repeated immunization with antigen, to the levels that surpass system’s self-organized criticality. Citation: Tsumiyama K, Miyazaki Y, Shiozawa S (2009) Self-Organized Criticality Theory of Autoimmunity. PLoS ONE 4(12): e8382. doi:10.1371/jour