title: Estrogen regulates T helper 17 phenotype and localization in experimental autoimmune arthritis.
abstract: BACKGROUND
  The incidence and progression of many autoimmune diseases are sex-biased, which might be explained by the immunomodulating properties of endocrine hormones. Treatment with estradiol potently inhibits experimental autoimmune arthritis. Interleukin-17-producing T helper cells (Th17) are key players in several autoimmune diseases, particularly in rheumatoid arthritis. The aim of this study was to investigate the effects of estrogen on Th17 cells in experimental arthritis.
  
  
  METHODS
  Ovariectomized DBA/1 mice treated with 17β-estradiol (E2) or placebo were subjected to collagen-induced arthritis (CIA), and arthritis development was assessed. Th17 cells in joints and lymph nodes were studied by flow cytometry. Lymph node Th17 cells were also examined in ovariectomized estrogen receptor α-knockout mice (ERα-/-) and wild-type littermates, treated with E2 or placebo and subjected to antigen-induced arthritis.
  
  
  RESULTS
  E2-treated mice with established CIA showed reduced severity of arthritis and fewer Th17 cells in joints compared with controls. Interestingly, E2-treated mice displayed increased Th17 cells in lymph nodes during the early phase of the disease, dependent on ERα. E2 increased the expression of C-C chemokine receptor 6 (CCR6) on lymph node Th17 cells as well as the expression of the corresponding C-C chemokine ligand 20 (CCL20) within lymph nodes.
  
  
  CONCLUSIONS
  This is the first study in which the effects of E2 on Th17 cells have been characterized in experimental autoimmune arthritis. We report that E2 treatment results in an increase of Th17 cells in lymph nodes during the early phase of arthritis development, but leads to a decrease of Th17 in joints during established arthritis. Our data suggest that this may be caused by interference with the CCR6-CCL20 pathway, which is important for Th17 cell migration. This study contributes to the understanding of the role of estrogen in the development of autoimmune arthritis and opens up new fields for research concerning the sex bias in autoimmune disease.
authors.affiliation: Department of Rheumatology and Inflammation Research, Centre for Bone and Arthritis Research, The Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30, Gothenburg, Sweden. annica.andersson@rheuma.gu.se.
authors.forename: Annica
authors.initials: A
authors.lastname: Andersson
authors.affiliation: Department of Rheumatology and Inflammation Research, Centre for Bone and Arthritis Research, The Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30, Gothenburg, Sweden. alexandra.stubelius@rheuma.gu.se.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Stubelius
authors.affiliation: Department of Rheumatology and Inflammation Research, Centre for Bone and Arthritis Research, The Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30, Gothenburg, Sweden. merja.nurkkala@rheuma.gu.se.
authors.forename: Merja Nurkkala
authors.initials: MN
authors.lastname: Karlsson
authors.affiliation: Department of Rheumatology and Inflammation Research, Centre for Bone and Arthritis Research, The Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30, Gothenburg, Sweden. cecilia.engdahl@rheuma.gu.se.|Department of Internal Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, The Sahlgrenska Academy, University of Gothenburg, Vita Stråket 11, 413 45, Gothenburg, Sweden. cecilia.engdahl@rheuma.gu.se.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Engdahl
authors.affiliation: Department of Rheumatology and Inflammation Research, Centre for Bone and Arthritis Research, The Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30, Gothenburg, Sweden. malin.erlandsson@gu.se.
authors.forename: Malin
authors.initials: M
authors.lastname: Erlandsson
authors.affiliation: Department of Rheumatology and Inflammation Research, Centre for Bone and Arthritis Research, The Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30, Gothenburg, Sweden. louise.grahnemo@gu.se.
authors.forename: Louise
authors.initials: L
authors.lastname: Grahnemo
authors.affiliation: Department of Internal Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, The Sahlgrenska Academy, University of Gothenburg, Vita Stråket 11, 413 45, Gothenburg, Sweden. marie.lagerquist@medic.gu.se.
authors.forename: Marie K
authors.initials: MK
authors.lastname: Lagerquist
authors.affiliation: Department of Rheumatology and Inflammation Research, Centre for Bone and Arthritis Research, The Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30, Gothenburg, Sweden. ulrika.islander@gu.se.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Islander
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology; D054418:Chemokine CCL20 / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D016130:Immunophenotyping; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010052:Ovariectomy; D054399:Receptors, CCR6 / Q000378:metabolism; D012737:Sex Factors; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: C493447:CCL20 protein, mouse; C498126:CCR6 protein, mouse; D054418:Chemokine CCL20; D047628:Estrogen Receptor alpha; D004967:Estrogens; D054399:Receptors, CCR6; D004958:Estradiol