Absence of IFN-γ increases brain pathology in experimental autoimmune encephalomyelitis-susceptible DRB10301.DQ8 HLA transgenic mice through secretion of proinflammatory cytokine IL-17 and induction of pathogenic monocytes/microglia into the central nervous system

Ashutosh K Mangalam; Ningling Luo; David Luckey; Louisa Papke; Alyssa Hubbard; Arika Wussow; Michele Smart; Shailendra Giri; Moses Rodriguez; Chella David

doi:10.4049/jimmunol.1302008

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Absence of IFN-γ increases brain pathology in experimental autoimmune encephalomyelitis-susceptible DRB10301.DQ8 HLA transgenic mice through secretion of proinflammatory cytokine IL-17 and induction of pathogenic monocytes/microglia into the central nervous system

Journal article

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Absence of IFN-γ increases brain pathology in experimental autoimmune encephalomyelitis-susceptible DRB10301.DQ8 HLA transgenic mice through secretion of proinflammatory cytokine IL-17 and induction of pathogenic monocytes/microglia into the central nervous system

Ashutosh K Mangalam, Ningling Luo, David Luckey, Louisa Papke, Alyssa Hubbard, Arika Wussow, Michele Smart, Shailendra Giri, Moses Rodriguez and Chella David

Journal of immunology (Baltimore, Md. : 1950), Vol.193(10), pp.4859-4870

11/15/2014

DOI: 10.4049/jimmunol.1302008

PMCID: PMC4233133

PMID: 25339670

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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.

Signal Transduction

HLA-DQ beta-Chains - immunology

Humans

Interleukin-17 - immunology

Encephalomyelitis, Autoimmune, Experimental - immunology

Monocytes - immunology

HLA-DQ beta-Chains - genetics

HLA-DQ Antigens - immunology

Microglia - immunology

Encephalomyelitis, Autoimmune, Experimental - chemically induced

Monocytes - pathology

Microglia - pathology

Encephalomyelitis, Autoimmune, Experimental - genetics

Interferon-gamma - genetics

Interferon-gamma - deficiency

Myelin Proteolipid Protein

Encephalomyelitis, Autoimmune, Experimental - pathology

HLA-DRB1 Chains - genetics

HLA-DRB1 Chains - immunology

Gene Expression Regulation

Interleukin-17 - genetics

Granulocyte-Macrophage Colony-Stimulating Factor - genetics

Mice, Knockout

Animals

Granulocyte-Macrophage Colony-Stimulating Factor - immunology

HLA-DQ Antigens - genetics

Interferon-gamma - immunology

Brain - pathology

Mice

Brain - immunology

Details

Title: Subtitle: Absence of IFN-γ increases brain pathology in experimental autoimmune encephalomyelitis-susceptible DRB10301.DQ8 HLA transgenic mice through secretion of proinflammatory cytokine IL-17 and induction of pathogenic monocytes/microglia into the central nervous system
Creators: Ashutosh K Mangalam - Department of Immunology, Mayo Clinic, Rochester, MN 55905; Department of Neurology, Mayo Clinic, Rochester, MN 55905; and mangalam.ashutosh@mayo.edu
Ningling Luo - Department of Immunology, Mayo Clinic, Rochester, MN 55905
David Luckey - Department of Immunology, Mayo Clinic, Rochester, MN 55905
Louisa Papke - Department of Neurology, Mayo Clinic, Rochester, MN 55905; and
Alyssa Hubbard - Department of Immunology, Mayo Clinic, Rochester, MN 55905
Arika Wussow - Department of Immunology, Mayo Clinic, Rochester, MN 55905
Michele Smart - Department of Immunology, Mayo Clinic, Rochester, MN 55905
Shailendra Giri - Department of Neurology, Henry Ford Health System, Detroit, MI 48202
Moses Rodriguez - Department of Immunology, Mayo Clinic, Rochester, MN 55905; Department of Neurology, Mayo Clinic, Rochester, MN 55905; and
Chella David - Department of Immunology, Mayo Clinic, Rochester, MN 55905
Resource Type: Journal article
Publication Details: Journal of immunology (Baltimore, Md. : 1950), Vol.193(10), pp.4859-4870
DOI: 10.4049/jimmunol.1302008
PMID: 25339670
PMCID: PMC4233133
NLM abbreviation: J Immunol
ISSN: 0022-1767
eISSN: 1550-6606
Publisher: United States
Grant note: R01 NS052173 / NINDS NIH HHS UL1 TR000135 / NCATS NIH HHS NS52173 / NINDS NIH HHS
Language: English
Date published: 11/15/2014
Academic Unit: Pathology; Iowa Neuroscience Institute
Record Identifier: 9983905646102771

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