A question in the pathogenesis of autoimmunity is why and how autoreactive lymphocytes survive beyond the firewall of immunity. According to the autoimmune disease theory, autoreactive lymphocytes derive from either a few autoreactive clones that escape from thymic negative selection or those reactivated from tolerance. Such restricted clones apparently do not represent wide varieties of TCR repertoire or autoantibody of more than 100 distinct specificities seen in SLE. We instead show that autoreactive clones newly emerge via de novo TCRα, but not TCRβ, revision at periphery from thymus-passed non-autoreactive clones. We name this novel T cell type an autoantibody-inducing CD4 T cell (aiCD4 T cell), which stimulates B cells to generate varieties of autoantibodies and also helps final differentiation of CD8 T cell into CTL via antigen cross-presentation to induce lupus tissue injuries. Our life is a continuous battle against pathogen: host dies if pathogen is too strong due to pathogen-induced tissue injury and the host also dies if defense is too strong due to defense-induced injury, because battle field is our body. To avoid exhaustive battle, our immunity evolved not to eradicate but just suppress pathogen to undersea levels. Thus, repeated exposure to antigen is not exceptional but routine. SLE necessarily emerges when host’s immune system is overstimulated by repeated exposure to pathogen to levels that surpass system’s stability-limit: self-organized criticality theory.
- Copyright © 2013 by The American Association of Immunologists, Inc.