A four-step model for the IL-6 amplifier, a regulator of chronic inflammations in tissue-specific MHC class II-associated autoimmune diseases - PubMed (original) (raw)
A four-step model for the IL-6 amplifier, a regulator of chronic inflammations in tissue-specific MHC class II-associated autoimmune diseases
Masaaki Murakami et al. Front Immunol. 2011.
Abstract
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., 2001; Mathis and Benoist, 2004). 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., 2000; Skapenko et al., 2005). Rheumatoid arthritis (RA) and arthritis in F759 knock-in mice (F759 mice) are such examples (Atsumi et al., 2002; Brennan et al., 2002; Falgarone et al., 2009). 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., 2006, 2009; Ogura et al., 2008; Hirano, 2010; Murakami et al., 2011). 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., 2011). 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., 2011). We named this loop the IL-6-mediated inflammation amplifier, or IL-6 amplifier for short (Ogura et al., 2008; Hirano, 2010; Murakami et al., 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., 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.
Keywords: IL-6-mediated inflammation amplifier; MHC class II association; Th17 cells; autoimmune diseases; chemokines; cytokines; inflammation.
Figures
Figure 1
IL-6 amplifier activation plays a role in the development of autoimmune diseases such as arthritis in F759 mice and EAE. IL-17A-triggerred positive feedback of IL-6 signaling, which results in synergistic hyper-expressions of chemokines and IL-6 itself in type 1 collagen+ cells, is enhanced in a manner dependent on NF-κB and STAT3, which our themselves stimulated by IL-17A in the presence of an IL-6 signal (bar graph). We named this IL-17A-dependent IL-6 signaling amplification loop in type 1 collagen+ cells the IL-6-mediated inflammation amplifier, or IL-6 amplifier for short. Importantly, activation of the IL-6 amplifier is critical not only for the development of arthritis in F759 mice but also for MOG antigen-specific, T cell-mediated experimental autoimmune encephalomyelitis (EAE; Ogura et al., 2008).
Figure 2
A four-step model for MHC class II-associated autoimmune diseases. Certain class II MHC-associated autoimmune diseases arise through a series of four steps: (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, which is triggered by CD4+ T cell-derived cytokines such as IL-17A; and (4) enhanced sensitivity to T cell-derived cytokines and/or IL-6 in type 1 collagen+ cells in the target tissue. Following these four steps, chronic activation of the IL-6 amplifier followed by the development of an autoimmune disease occurs. It is likely that each step interacts with the others, and the degree of the contribution of each to the pathogenesis varies with the disease.
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