title: Synthetic Retinoid AM80 Ameliorates Lung and Arthritic Autoimmune Responses by Inhibiting T Follicular Helper and Th17 Cell Responses.
abstract: Rheumatoid arthritis is an autoimmune disorder that affects the joints and other organs. Pulmonary complications contribute significantly to rheumatoid arthritis 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 Th17 cells are known to promote inflammation and autoantibody production. Using the K/BxN autoimmune arthritis model, we elucidate a novel mechanism whereby oral AM80 administration suppressed lung mucosa-associated Tfh and autoantibody 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 tissues, Peyer's patches, and thus reduced the systemic autoantibodies. 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 autoantibody 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 the 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.
authors.affiliation: Department of Immunobiology, University of Arizona, Tucson, AZ 85719; and.
authors.forename: Debdut
authors.initials: D
authors.lastname: Naskar
authors.affiliation: Department of Immunobiology, University of Arizona, Tucson, AZ 85719; and.
authors.forename: Fei
authors.initials: F
authors.lastname: Teng
authors.affiliation: Department of Immunobiology, University of Arizona, Tucson, AZ 85719; and.
authors.forename: Krysta M
authors.initials: KM
authors.lastname: Felix
authors.affiliation: Department of Immunobiology, University of Arizona, Tucson, AZ 85719; and.
authors.forename: C Pierce
authors.initials: CP
authors.lastname: Bradley
authors.affiliation: Department of Immunobiology, University of Arizona, Tucson, AZ 85719; and joycewu@email.arizona.edu.|Arizona Arthritis Center, College of Medicine, University of Arizona, Tucson, AZ 85719.
authors.forename: Hsin-Jung Joyce
authors.initials: HJ
authors.lastname: Wu
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000517:prevention & control; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology; D001565:Benzoates / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000276:immunology; D004195:Disease Models, Animal; D016023:Integrins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D007422:Intestines / Q000276:immunology; D008168:Lung / Q000166:cytology / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D051379:Mice; D010581:Peyer's Patches / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D001565:Benzoates; D016023:Integrins; D013764:Tetrahydronaphthalenes; C061133:tamibarotene