Background Since the discovery of LE cell by Haargraves, reactivity against self has been considered the cause of autoimmune diseases. However, recent immunology tells that autoreactive clones are not forbidden and autoantibodies are seen rather ubiquitously.
Objectives Thus, apart from Mackey’s autoimmune disease theory, we have studied the cause of SLE from a different angle, i.e., a view of systems biology, and shown that systemic autoimmunity necessarily takes place when host’s immune system is over-stimulated by repeated exposure to antigen to levels that surpass system’s self-organized criticality (1,2). Here we characterize the essential component, aiCD4 Tcell, that induces both varieties of autoantibodies and immunopathology, and also clarify the molecular mechanism of antigen cross-presentation responsible for inducing the tissue immunopathology identical to human SLE.
Methods Mice not prone to autoimmune diseases, Balb/c or B57BL/6, were repeatedly immunized without adjuvant more than x8 with OVA, KLH or SEB. Activated CD4 T cells generated were sub-fractionated using cell sorter or were transferred into naïve mice. Antigen cross-presentation was studied in dendritic cell (DC) under confocal laser microscopy and in vivo in transgenic mice.
Results After repeated immunization x12 with antigen, all mice developed varieties of autoantibodies including anti-dsDNA antibody (Ab) and typical immunopathology of SLE. Autoantibody inducing CD4 T cell (aiCD4 T cell) that has passed through de novo TCR revision i.e., V(D)J recombination, was newly generated in mice, where TCRalpha but not TCRbeta was revised. Autoantibodies and immunopathology were completely transferrable into naïve recipients via CD4 and CD8 T cells, respectively. For tissue immunopathology including lupus nephritis, (1) help by aiCD4 T cell and (2) antigen cross-presentation were required. The aiCD4 T cell belonged to CD45RBlo CD122lo subpopulation. In DC, antigen was transfered from endosome to cytoplasm and then cross-presented to CD8 T cells mediated by Sec61.
Conclusions Systemic autoimmunity necessarily takes place when host’s immune system is overstimulated by repeated exposure to antigen to levels that surpass system’s self-organized criticality. Generation of aiCD4 T cell and antigen cross-presentation are essential for causing systemic autoimmunity, i.e., SLE.
Tsumiyama K, Miyazaki Y, Shiozawa S. Self-organized criticality theory of autoimmunity. PLoS ONE 4(12):e8382, 2009.
Hiozawa S. Cause of systemic lupus erythematosus: a novel self-organized criticality theory of autoimmunity. Exp Rev Clin Immunol 7:715-717, 2011.
Disclosure of Interest None Declared
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