title: Absence of IFN-γ increases brain pathology in experimental autoimmune encephalomyelitis-susceptible DRB1*0301.DQ8 HLA transgenic mice through secretion of proinflammatory cytokine IL-17 and induction of pathogenic monocytes/microglia into the central nervous system.
abstract: Multiple sclerosis is an inflammatory, demyelinating disease of the CNS of presumed autoimmune origin. Of all the genetic factors linked with multiple sclerosis, MHC class II molecules have the strongest association. Generation of HLA class II transgenic (Tg) mice has helped to elucidate the role of HLA class II genes in chronic inflammatory and demyelinating diseases. We have shown that the human HLA-DRB1*0301 gene predisposes to proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE), whereas HLA-DQβ1*0601 (DQ6) was resistant. We also showed that the DQ6 molecule protects from EAE in DRB1*0301.DQ6 double-Tg mice by producing anti-inflammatory IFN-γ. HLA-DQβ1*0302 (DQ8) Tg mice were also resistant to PLP(91-110)-induced EAE, but production of proinflammatory IL-17 exacerbated disease in DRB1*0301.DQ8 mice. To further confirm the role of IFN-γ in protection, we generated DRB1*0301.DQ8 mice lacking IFN-γ (DRB1*0301.DQ8.IFN-γ(-/-)). Immunization with PLP(91-110) peptide caused atypical EAE in DRB1*0301.DQ8.IFN-γ(-/-) mice characterized by ataxia, spasticity, and dystonia, hallmarks of brain-specific disease. Severe brain-specific inflammation and demyelination in DRB1*0301.DQ8.IFN-γ(-/-) mice with minimal spinal cord pathology further confirmed brain-specific pathology. Atypical EAE in DRB1*0301.DQ8.IFN-γ(-/-) mice was associated with increased encephalitogenicity of CD4 T cells and their ability to produce greater levels of IL-17 and GM-CSF compared with DRB1*0301.DQ8 mice. Further, areas with demyelination showed increased presence of CD68(+) inflammatory cells, suggesting an important role for monocytes/microglia in causing brain pathology. Thus, our study supports a protective role for IFN-γ in the demyelination of brain through downregulation of IL-17/GM-CSF and induction of neuroprotective factors in the brain by monocytes/microglial cells.
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905; Department of Neurology, Mayo Clinic, Rochester, MN 55905; and mangalam.ashutosh@mayo.edu.
authors.forename: Ashutosh K
authors.initials: AK
authors.lastname: Mangalam
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905;
authors.forename: Ningling
authors.initials: N
authors.lastname: Luo
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905;
authors.forename: David
authors.initials: D
authors.lastname: Luckey
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN 55905; and.
authors.forename: Louisa
authors.initials: L
authors.lastname: Papke
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905;
authors.forename: Alyssa
authors.initials: A
authors.lastname: Hubbard
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905;
authors.forename: Arika
authors.initials: A
authors.lastname: Wussow
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905;
authors.forename: Michele
authors.initials: M
authors.lastname: Smart
authors.affiliation: Department of Neurology, Henry Ford Health System, Detroit, MI 48202.
authors.forename: Shailendra
authors.initials: S
authors.lastname: Giri
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905; Department of Neurology, Mayo Clinic, Rochester, MN 55905; and.
authors.forename: Moses
authors.initials: M
authors.lastname: Rodriguez
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905;
authors.forename: Chella
authors.initials: C
authors.lastname: David
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology; D059866:HLA-DQ beta-Chains / Q000235:genetics / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology* / Q000473:pathology; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D018991:Myelin Proteolipid Protein; D015398:Signal Transduction
chemical_list: D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C109756:HLA-DQ8 antigen; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; D020381:Interleukin-17; D018991:Myelin Proteolipid Protein; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor