A Four-Step Model for the IL-6 Amplifier a Regulator of Chronic Inflammations in Tissue-Specific MHC Class II-Associated Autoimmune Diseases

摘要

It is commonly thought that autoimmune diseases are caused by the breakdown of self-tolerance, which suggests the recognition of specific antigens by autoreactive CD4+ T cells contribute to the specificity of autoimmune diseases (Marrack et al., ; Mathis and Benoist, ). In several cases, however, even for diseases associated with class II major histocompatibility complex (MHC) alleles, the causative tissue-specific antigens recognized by memory/activated CD4+ T cells have not been established (Mocci et al., ; Skapenko et al., ). Rheumatoid arthritis (RA) and arthritis in F759 knock-in mice (F759 mice) are such examples (Atsumi et al., ; Brennan et al., ; Falgarone et al., ). These include associations with class II MHC and CD4 molecules; increased numbers of memory/activated CD4+ T cells; and improved outcomes in response to suppressions and/or deficiencies in class II MHC molecules, CD4+ T cells, and the T cell survival cytokine IL-7. Regarding the development of arthritis in F759 mice, it is not only the immune system, but also non-immune tissue that are involved, indicating that the importance of their interactions (Sawa et al., , ; Ogura et al., ; Hirano, ; Murakami et al., ). Furthermore, we have shown that local events such as microbleeding together with an accumulation of activated CD4+ T cells in a manner independent of tissue antigen-recognitions induces arthritis in the joints of F759 mice (Murakami et al., ). For example, local microbleeding-mediated CCL20 expression induce such an accumulation, causing arthritis development via chronic activation of an IL-17A-dependent IL-6 signaling amplification loop in type 1 collagen+ cells that is triggered by CD4+ T cell-derived cytokine(s) such as IL-17A, which leads to the synergistic activation of STAT3 and NFκB in non-hematopoietic cells in the joint (Murakami et al., ). We named this loop the IL-6-mediated inflammation amplifier, or IL-6 amplifier for short (Ogura et al., ; Hirano, ; Murakami et al., href="#B41" rid="B41" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_259270893">2011). Thus, certain class II MHC-associated, tissue-specific autoimmune diseases, including some RA subtypes, may be induced by local events that cause an antigen-independent accumulation of effector CD4+ T cells followed by the induction of the IL-6 amplifier in the affected tissue. In other words, in certain cases, the target tissue itself may determine the specificity of the autoimmune disease via activation of the IL-6 amplifier. To explain this hypothesis, we have proposed a four-step model for MHC class II-associated autoimmune diseases (Murakami et al., href="#B41" rid="B41" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_259270923">2011): (1) T cell activation regardless of antigen specificity; (2) local events inducing a tissue-specific accumulation of activated T cells; (3) transient activation of the IL-6 amplifier; and (4) enhanced sensitivity to cytokines in the target tissue. The interaction of these events results in chronic activation of the IL-6 amplifier and subsequent manifestation of autoimmune diseases. Thus, the IL-6 amplifier, which is chronically activated by these four events, is a critical regulator of chronic inflammations in tissue-specific MHC class II-associated autoimmune diseases.