研究実績

IL-6-gp130-STAT3-IL-7 カスケードにより自己免疫疾患が発症することを明らかにしました。

免疫反応と非免疫組織の相互作用により自己免疫疾患が発症するという概念を提唱します。

Sawa, S., D. Kamimura, G.-H. Jin, H. Morikawa, H. Kamon, M. Nishihara, K. Ishihara, M. Murakami, and T. Hirano. Autoimmune arthritis associated with mutated IL-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4+ T. J. Exp. Med. published on line 22 May 2006 (In This Issue) (J Exp Med) (PubMed) (Nature Reviews Immunology Research Highlights)

Hyperresponsiveness to the interleukin (IL)-6 family of cytokines triggers a spontaneous rheumatoid arthritis (RA)-like disease in mice (Atsumi et al, JEM 2002)(PubMed). Now, Sawa and colleagues show that excessive IL-6 signaling drives hyperproliferation of CD4+ T cells, which then attack the joints.

IL-6 has been implicated in RA and other T cell-driven autoimmune diseases. Indeed, a previous study by this group showed that an activating mutation in the gp130 subunit of the IL-6 receptor caused a lymphocyte-driven arthritis in mice. But the mechanism was unclear. The authors now show that disease development in these mice depends on CD4+ T cells, but not on cytolytic CD8+ T cells or antibody-producing B cells.

The CD4+ cells did not appear to cause disease because of an affinity for joint-specific antigens. Rather, the cells simply proliferated excessively in the mutant mice. This hyperproliferation was not the fault of the T cell, as wild-type CD4+ T cells also multiplied excessively and caused disease when transferred into irradiated mutant mice.

Rather, the gp130 mutation caused nonhematopoietic cells to produce excess IL-7--a growth factor that triggers T cell proliferation. This is the first evidence that IL-6 family cytokines can trigger IL-7 production.

These data suggest that IL-6, which is elevated in the serum and joints of patients with RA, might exacerbate disease by inducing IL-7 and thus driving T cell activation. What causes the overstimulated T cells to attack the joints in the first place remains a mystery. J Exp. Med. In This Issue

Autoimmunity: Cytokine partnership to destruction: Researchers reporting in The Journal of Experimental Medicine have identified the mechanism behind a form of spontaneous autoimmune arthritis that occurs in mice with a mutation in the interleukin-6 (IL-6) receptor subunit gp130. Intriguingly, it turns out that signalling by this mutant IL-6 receptor in non-haematopoietic cells ----, taken from Nature Reviews Immunology 6:493, 2006, July Issue, Research Highlights.

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研究実績

IL-6-gp130-STAT3-IL-7 カスケードにより自己免疫疾患が発症することを明らかにしました。