title: Male rats develop more severe experimental autoimmune encephalomyelitis than female rats: sexual dimorphism and diergism at the spinal cord level.
abstract: Compared with females, male Dark Agouti (DA) rats immunized for experimental autoimmune encephalomyelitis (EAE) with rat spinal cord homogenate in complete Freund's adjuvant (CFA) exhibited lower incidence of the disease, but the maximal neurological deficit was greater in the animals that developed the disease. Consistently, at the peak of the disease greater number of reactivated CD4+CD134+CD45RC- T lymphocytes was retrieved from male rat spinal cord. Their microglia/macrophages were more activated and produced greater amount of prototypic proinflammatory cytokines in vitro. Additionally, oppositely to the expression of mRNAs for IL-12/p35, IL-10 and IL-27/p28, the expression of mRNA for IL-23/p19 was upregulated in male rat spinal cord mononuclear cells. Consequently, the IL-17+:IFN-γ+ cell ratio within T lymphocytes from their spinal cord was skewed towards IL-17+ cells. Within this subpopulation, the IL-17+IFN-γ+:IL-17+IL-10+ cell ratio was shifted towards IL-17+IFN-γ+ cells, which have prominent tissue damaging capacity. This was associated with an upregulated expression of mRNAs for IL-1β and IL-6, but downregulated TGF-β mRNA expression in male rat spinal cord mononuclear cells. The enhanced GM-CSF mRNA expression in these cells supported the greater pathogenicity of IL-17+ T lymphocytes infiltrating male spinal cord. In the inductive phase of the disease, contrary to the draining lymph node, in the spinal cord the frequency of CD134+ cells among CD4+ T lymphocytes and the frequency of IL-17+ cells among T lymphocytes were greater in male than in female rats. This most likely reflected an enhanced transmigration of mononuclear cells into the spinal cord (judging by the lesser spinal cord CXCL12 mRNA expression), the greater frequency of activated microglia/macrophages and the increased expression of mRNAs for Th17 polarizing cytokines in male rat spinal cord mononuclear cells. Collectively, the results showed cellular and molecular mechanisms underlying the target organ specific sexual dimorphism in the T lymphocyte-dependent immune/inflammatory response, and suggested a substantial role for the target organ in shaping the sexually dimorphic clinical outcome of EAE.
authors.affiliation: Department of Physiology, Faculty of Pharmacy, University of Belgrade, 450 Vojvode Stepe, 11221 Belgrade, Serbia.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Nacka-Aleksić
authors.affiliation: Department of Physiology, Faculty of Pharmacy, University of Belgrade, 450 Vojvode Stepe, 11221 Belgrade, Serbia.
authors.forename: Jasmina
authors.initials: J
authors.lastname: Djikić
authors.affiliation: Immunology Research Centre "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", 458 Vojvode Stepe, 11221 Belgrade, Serbia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Pilipović
authors.affiliation: Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, 450 Vojvode Stepe, 11221 Belgrade, Serbia.
authors.forename: Zorica
authors.initials: Z
authors.lastname: Stojić-Vukanić
authors.affiliation: Immunology Research Centre "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", 458 Vojvode Stepe, 11221 Belgrade, Serbia.
authors.forename: Duško
authors.initials: D
authors.lastname: Kosec
authors.affiliation: Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, 450 Vojvode Stepe, 11221 Belgrade, Serbia.
authors.forename: Biljana
authors.initials: B
authors.lastname: Bufan
authors.affiliation: Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, 450 Vojvode Stepe, 11221 Belgrade, Serbia.
authors.forename: Nevena
authors.initials: N
authors.lastname: Arsenović-Ranin
authors.affiliation: Immunology Research Centre "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", 458 Vojvode Stepe, 11221 Belgrade, Serbia.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Dimitrijević
authors.affiliation: Department of Physiology, Faculty of Pharmacy, University of Belgrade, 450 Vojvode Stepe, 11221 Belgrade, Serbia. Electronic address: Gordana.Leposavic@pharmacy.bg.ac.rs.
authors.forename: Gordana
authors.initials: G
authors.lastname: Leposavić
mesh_terms: D000818:Animals; D065469:Cuniculidae; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D007114:Immunization; D007249:Inflammation / Q000276:immunology*; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D008297:Male; D017628:Microglia / Q000276:immunology; D051381:Rats; D012720:Severity of Illness Index; D012727:Sex Characteristics; D013116:Spinal Cord / Q000276:immunology* / Q000473:pathology
chemical_list: D018836:Inflammation Mediators
keywords: EAE; IL-17+ T cells; Microglia; Proinflammatory cytokines; Sexual dimorphism