title: IFN-γ deficiency exacerbates experimental autoimmune neuritis in mice despite a mitigated systemic Th1 immune response.
abstract: Previous studies have shown that interferon-gamma (IFN-γ) is a proinflammatory cytokine that contributes to the pathogenesis of Guillain-Barré syndrome and its animal model, experimental autoimmune neuritis (EAN). Treatments with anti-IFN-γ antibodies improve clinical outcome in GBS patients and EAN animals and administration of IFN-γ markedly worsens EAN. Paradoxically, the mice deficient in IFN-γ remain susceptible to experimental autoimmune encephalomyelitis, an analogous disease in the central nervous system. These observations raise a question whether IFN-γ might be protective in autoimmune demyelinating diseases. To clarify the role of IFN-γ in the pathogenesis of autoimmune demyelinating diseases, we used P0 protein peptide 180-199 to induce EAN in IFN-γ knockout (KO) mice. After the acute phase of EAN, the clinical signs of IFN-γ KO mice were significantly more severe than those of wild type (WT) controls. After antigenic stimulation, the proliferation of splenic mononuclear cells was significantly higher in IFN-γ KO than in WT mice with EAN. At the peak of EAN, the proportion of interleukin (IL)-17A expressing cells in cauda equina (CE) infiltrating cells, and the levels of IL-17A in sera were elevated in IFN-γ KO mice when compared with their WT counterparts. The proportions of major histocompatibility complex (MHC) II, macrosialin, and IL-12/IL-23p40 expressing cells, relative to total CE infiltrating cells were correspondingly higher in IFN-γ KO than in WT mice with EAN. However, IFN-γ deficiency reduced the production of NO by cultured macrophages in response to proinflammatory stimuli and induced a systemic Th2-oriented immune response. In conclusion, IFN-γ deficiency exacerbates EAN via upregulating Th17 cells despite a mitigated systemic Th1 immune response.
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden.
authors.forename: Hong-Liang
authors.initials: HL
authors.lastname: Zhang
authors.forename: Sheikh
authors.initials: S
authors.lastname: Azimullah
authors.forename: Xiang-Yu
authors.initials: XY
authors.lastname: Zheng
authors.forename: Xiao-Ke
authors.initials: XK
authors.lastname: Wang
authors.forename: Naheed
authors.initials: N
authors.lastname: Amir
authors.forename: Eric P
authors.initials: EP
authors.lastname: Mensah-Brown
authors.forename: Mariam
authors.initials: M
authors.lastname: Al Shamsi
authors.forename: Allen
authors.initials: A
authors.lastname: Shahin
authors.forename: Rayomand
authors.initials: R
authors.lastname: Press
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.forename: Abdu
authors.initials: A
authors.lastname: Adem
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D020022:Genetic Predisposition to Disease; D007371:Interferon-gamma / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009444:Neuritis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D007371:Interferon-gamma