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.

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-DRB10301 gene predisposes to proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE), whereas HLA-DQβ10601 (DQ6) was resistant. We also showed that the DQ6 molecule protects from EAE in DRB10301.DQ6 double-Tg mice by producing anti-inflammatory IFN-γ. HLA-DQβ10302 (DQ8) Tg mice were also resistant to PLP(91-110)-induced EAE, but production of proinflammatory IL-17 exacerbated disease in DRB10301.DQ8 mice. To further confirm the role of IFN-γ in protection, we generated DRB10301.DQ8 mice lacking IFN-γ (DRB10301.DQ8.IFN-γ(-/-)). Immunization with PLP(91-110) peptide caused atypical EAE in DRB10301.DQ8.IFN-γ(-/-) mice characterized by ataxia, spasticity, and dystonia, hallmarks of brain-specific disease. Severe brain-specific inflammation and demyelination in DRB10301.DQ8.IFN-γ(-/-) mice with minimal spinal cord pathology further confirmed brain-specific pathology. Atypical EAE in DRB10301.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.