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

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

Research output: Contribution to journalArticle

15 Citations (Scopus)

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-DQb1∗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-DQb1∗0302 (DQ8) Tg mice were also resistant to PLP91-110-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-gγ -/-). Immunization with PLP91-110 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. The Journal of Immunology, 2014, 193: 4859-4870.

Original languageEnglish (US)
Pages (from-to)4859-4870
Number of pages12
JournalJournal of Immunology
Volume193
Issue number10
DOIs
StatePublished - Nov 15 2014

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Encephalomyelitis
Microglia
Autoimmune Experimental Encephalomyelitis
Transgenic Mice
Monocytes
Central Nervous System
Demyelinating Diseases
Cytokines
Interleukin-17
Brain
Granulocyte-Macrophage Colony-Stimulating Factor
Pathology
Multiple Sclerosis
CNS Demyelinating Autoimmune Diseases
Proteolipids
MHC Class II Genes
Dystonia
Brain Diseases
Encephalitis
Ataxia

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

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

In: Journal of Immunology, Vol. 193, No. 10, 15.11.2014, p. 4859-4870.

Research output: Contribution to journalArticle

Mangalam, Ashutosh K. ; Luo, Ningling ; Luckey, David ; Papke, Louisa ; Hubbard, Alyssa ; Wussow, Arika ; Smart, Michele ; Giri, Shailendra ; Rodriguez, Moses ; David, Chella. / 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. In: Journal of Immunology. 2014 ; Vol. 193, No. 10. pp. 4859-4870.
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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-DQb1∗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-DQb1∗0302 (DQ8) Tg mice were also resistant to PLP91-110-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-gγ -/-). Immunization with PLP91-110 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. The Journal of Immunology, 2014, 193: 4859-4870.",
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AU - Luo, Ningling

AU - Luckey, David

AU - Papke, Louisa

AU - Hubbard, Alyssa

AU - Wussow, Arika

AU - Smart, Michele

AU - Giri, Shailendra

AU - Rodriguez, Moses

AU - David, Chella

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N2 - 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-DQb1∗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-DQb1∗0302 (DQ8) Tg mice were also resistant to PLP91-110-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-gγ -/-). Immunization with PLP91-110 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. The Journal of Immunology, 2014, 193: 4859-4870.

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