IFN-γ deficiency exacerbates experimental autoimmune neuritis in mice despite a mitigated systemic Th1 immune response

Previous studies have shown that interferon-gamma (IFN-gamma) is a proinflammatory cytokine that contributes to the pathogenesis of Guillain-Barre syndrome and its animal model, experimental autoimmune neuritis (EAN). Treatments with anti-IFN-gamma antibodies improve clinical outcome in GBS patients and EAN animals and administration of IFN-gamma markedly worsens EAN. Paradoxically, the mice deficient in IFN-gamma remain susceptible to experimental autoimmune encephalomyelitis, an analogous disease in the central nervous system. These observations raise a question whether IFN-gamma might be protective in autoimmune demyelinating diseases. To clarify the role of IFN-gamma in the pathogenesis of autoimmune demyelinating diseases, we used PO protein peptide 180-199 to induce EAN in IFN-gamma knockout (KO) mice. After the acute phase of EAN, the clinical signs of IFN-gamma 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-gamma 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-gamma KO mice when compared with their WT counterparts. The proportions of major histocompatibility complex (MHC) II, macrosialin, and IL-12/1L-23p40 expressing cells, relative to total CE infiltrating cells were correspondingly higher in IFN-gamma KO than in WT mice with EAN. However, IFN-gamma 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-gamma deficiency exacerbates EAN via upregulating Th17 cells despite a mitigated systemic Th1 immune response. (C) 2012 Elsevier B.V. All rights reserved.