Synthetic Retinoid AM80 Ameliorates Lung and Arthritic Autoimmune Responses by Inhibiting T Follicular Helper and Th17 Cell Responses.
Synthetic Retinoid AM80 Ameliorates Lung and Arthritic Autoimmune Responses by Inhibiting T Follicular Helper and Th17 Cell Responses.
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DOI：
10.4049/jimmunol.1601776
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发表时间：
2017-03-01
期刊：
影响因子：
--
通讯作者：
Wu HJ
中科院分区：
文献类型：
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作者：
Naskar D;Teng F;Felix KM;Bradley CP;Wu HJ
Rheumatoid arthritis (RA) is an autoimmune disorder that affects both joints and other organs. Pulmonary complications contribute significantly to RA mortality. Retinoic acid and its synthetic compound AM80 play roles in immunoregulation but their effect on mucosal autoimmunity remains largely unknown. T follicular helper (Tfh) and T helper 17 (Th17) cells are known to promote inflammation and auto-antibody (auto-Ab) production. Using the K/BxN autoimmune arthritis model, we elucidate a novel mechanism whereby oral AM80 administration suppressed lung mucosa-associated Tfh and auto-Ab responses by increasing the gut-homing α4β7 integrin expression on Tfh cells. This diverted Tfh cells from systemic (non-gut) inflamed sites such as the lung into the gut-associated lymphoid tissue, Peyer’s patches (PPs), and thus reduced the systemic auto-Abs. AM80 also inhibited the lung Th17 response. AM80’s effect in the lungs was readily applied to the joints as AM80 also inhibited Tfh and Th17 responses in the spleen, the major auto-Ab producing site known to correlate with K/BxN arthritis severity. Finally, we used anti-β7 treatment as an alternative approach demonstrating that manipulating T cell migration between gut and systemic sites alters the systemic disease outcome. The β7 blockade prevented both Tfh and Th17 cells from entering the non-immunopathogenic site, the gut, and retained these T effector cells in the systemic sites leading to augmented arthritis. These data suggest a dual beneficial effect of AM80, targeting both Tfh and Th17 cells, and warrant strict safety monitoring of gut-homing perturbing agents used in treating intestinal inflammation.
