Ken Tsumiyama1, Yumi Miyazaki1, Shunichi Shiozawa1,2,3,4*
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
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.
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).
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.