title: Estrogen treatment induces a novel population of regulatory cells, which suppresses experimental autoimmune encephalomyelitis.
abstract: Multiple sclerosis (MS) is a debilitating neurological disease characterized by a progressive loss of motor and sensory function, eventually leading to paralysis and death. The primary cause of neurological impairment is demyelination of the central nervous system (CNS) caused by an inflammatory autoimmune response. Previous studies have shown that the severity of MS is reduced during pregnancy, suggesting that the increased level of sex hormones may reduce the autoimmune response. Recently, we have shown that estrogen treatment confers protection from experimental autoimmune encephalomyelitis (EAE), which is an animal model for MS. However, the cellular basis of estrogen's action remains unknown. In the current study, we demonstrate that estrogen treatment led to the induction of a novel subpopulation of regulatory cells in spleen and CNS, which also occurs naturally in pregnant mice. These previously uncharacterized cells display a low level expression of CD45 (CD45(dim)) and no detectable expression of many cell surface markers related to TCR signaling, including CD3 and TCR. However, these cells retained expression of VLA-4, an extracellular protein involved in cellular migration. Several lines of evidence suggest that these novel cells, defined as CD45(dim)VLA-4(+) cells, may play a role in the protective effects of estrogen in EAE. Injection of purified CD45(dim)VLA-4(+) cells conferred protection from spontaneous EAE (Sp-EAE). In contrast, injection of CD45(high)VLA-4(+) cells exacerbated the disease course. CD45(dim)VLA-4(+) cells also suppressed antigen-specific proliferation of primed lymphocytes in coculture. A better understanding of how CD45(dim)VLA-4(+) cells suppress the harmful immune response of EAE may help in explaining the induction of immune tolerance during pregnancy and lead to novel therapeutic approaches to combat MS and other autoimmune diseases.
authors.affiliation: Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA. matejuka@ohsu.edu
authors.forename: Agata
authors.initials: A
authors.lastname: Matejuk
authors.forename: Antony C
authors.initials: AC
authors.lastname: Bakke
authors.forename: Corwyn
authors.initials: C
authors.lastname: Hopke
authors.forename: Jami
authors.initials: J
authors.lastname: Dwyer
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Vandenbark
authors.forename: Halina
authors.initials: H
authors.lastname: Offner
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002490:Central Nervous System / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D016130:Immunophenotyping; D039041:Integrin alpha4beta1 / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000276:immunology*; D011247:Pregnancy / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D004967:Estrogens; D039041:Integrin alpha4beta1; D017493:Leukocyte Common Antigens