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Deficient Natural Killer Dendritic Cell Responses Underlay the Induction of Theiler's Virus-Induced Autoimmunity.

Chastain EM, Getts DR, Miller SD - MBio (2015)

Bottom Line: Viral infection is an important cofactor, along with genetic susceptibility, in the initiation of a variety of organ-specific autoimmune diseases.Thus, in-depth understanding of how virus infections trigger autoimmunity may lead to novel ways to prevent or treat these diseases.Theiler's murine encephalitis virus-induced demyelinating disease (TMEV-IDD) serves as an important model for the human T cell-mediated autoimmune demyelinating disease multiple sclerosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

No MeSH data available.


Related in: MedlinePlus

CNS viral infection results in accumulation of NK1.1-expressing dendritic cells in the CNS of TMEV-IDD-resistant B6 mice. Wild-type B6 and SJL/J mice were i.c. infected with 5 × 106 PFU of TMEV or sham infected. Brains were harvested during acute infection, and mononuclear cells were isolated and stained for flow cytometry. (A) Live CD45+ CD11c+ cells were analyzed for expression of Ly6c and CD11b. Representative flow plots from day 5 post-TMEV infection are shown. (B) Numbers of cells in the CNS expressing Ly6C and CD11b on days 3, 5, and 7 p.i. in TMEV- or sham-infected B6 and SJL/J mice are shown. (C) Live CD3− CD11c+ cells were analyzed for their expression of NK1.1 and DX5. Representative flow plots from day 3 post-TMEV infection of B6 and SJL/J mice are shown. (D) Quantification of CD3− CD11c+ DX5+ cell numbers on days 1, 2, and 3 p.i. in TMEV- or sham-infected B6 and SJL/J mice. (E) Quantification of CD3− CD45+ CD11c+ NK1.1+ DX5+ brain cells on days 1, 3, 5, and 7 p.i. in TMEV- or sham-infected B6 mice are shown. (F) Quantification of total CNS lymphocytes and NKDCs in sham-infected (black bars), UV-inactivated TMEV-infected (hatched bars), or WT TMEV-infected (black bars) B6 mice 3 days p.i. Data are representative of 2 to 3 independent experiments with 3 to 5 mice per group. Error bars show standard deviations. ***, P < 0.001; **, P < 0.01; *, P < 0.05.
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fig1: CNS viral infection results in accumulation of NK1.1-expressing dendritic cells in the CNS of TMEV-IDD-resistant B6 mice. Wild-type B6 and SJL/J mice were i.c. infected with 5 × 106 PFU of TMEV or sham infected. Brains were harvested during acute infection, and mononuclear cells were isolated and stained for flow cytometry. (A) Live CD45+ CD11c+ cells were analyzed for expression of Ly6c and CD11b. Representative flow plots from day 5 post-TMEV infection are shown. (B) Numbers of cells in the CNS expressing Ly6C and CD11b on days 3, 5, and 7 p.i. in TMEV- or sham-infected B6 and SJL/J mice are shown. (C) Live CD3− CD11c+ cells were analyzed for their expression of NK1.1 and DX5. Representative flow plots from day 3 post-TMEV infection of B6 and SJL/J mice are shown. (D) Quantification of CD3− CD11c+ DX5+ cell numbers on days 1, 2, and 3 p.i. in TMEV- or sham-infected B6 and SJL/J mice. (E) Quantification of CD3− CD45+ CD11c+ NK1.1+ DX5+ brain cells on days 1, 3, 5, and 7 p.i. in TMEV- or sham-infected B6 mice are shown. (F) Quantification of total CNS lymphocytes and NKDCs in sham-infected (black bars), UV-inactivated TMEV-infected (hatched bars), or WT TMEV-infected (black bars) B6 mice 3 days p.i. Data are representative of 2 to 3 independent experiments with 3 to 5 mice per group. Error bars show standard deviations. ***, P < 0.001; **, P < 0.01; *, P < 0.05.

Mentions: Viral titers within the brains of both susceptible SJL/J and resistant B6 mice peak at day 5 following intracerebral (i.c.) infection and result in a potent adaptive systemic immune response in both strains peaking 7 to 10 days postinfection (p.i.) (21). Given these kinetics, we examined the phenotype and numbers of various potential CD11c+ DC subsets that appeared within the CNS during the acute infection period. We found that both CD45+ CD11c+ Ly6c+ CD11b− plasmacytoid DCs and CD45+ CD11c+ Ly6c+ CD11bint/lo inflammatory monocytes infiltrated the CNS of both TMEV-infected SJL/J and B6 mice (Fig. 1A). Both of these DC subsets have been shown to be participants during CNS virus infection (22, 23). We were somewhat surprised, however, that there was no significant difference in the number of pDCs or inflammatory monocytes between infected B6 and SJL/J animals.


Deficient Natural Killer Dendritic Cell Responses Underlay the Induction of Theiler's Virus-Induced Autoimmunity.

Chastain EM, Getts DR, Miller SD - MBio (2015)

CNS viral infection results in accumulation of NK1.1-expressing dendritic cells in the CNS of TMEV-IDD-resistant B6 mice. Wild-type B6 and SJL/J mice were i.c. infected with 5 × 106 PFU of TMEV or sham infected. Brains were harvested during acute infection, and mononuclear cells were isolated and stained for flow cytometry. (A) Live CD45+ CD11c+ cells were analyzed for expression of Ly6c and CD11b. Representative flow plots from day 5 post-TMEV infection are shown. (B) Numbers of cells in the CNS expressing Ly6C and CD11b on days 3, 5, and 7 p.i. in TMEV- or sham-infected B6 and SJL/J mice are shown. (C) Live CD3− CD11c+ cells were analyzed for their expression of NK1.1 and DX5. Representative flow plots from day 3 post-TMEV infection of B6 and SJL/J mice are shown. (D) Quantification of CD3− CD11c+ DX5+ cell numbers on days 1, 2, and 3 p.i. in TMEV- or sham-infected B6 and SJL/J mice. (E) Quantification of CD3− CD45+ CD11c+ NK1.1+ DX5+ brain cells on days 1, 3, 5, and 7 p.i. in TMEV- or sham-infected B6 mice are shown. (F) Quantification of total CNS lymphocytes and NKDCs in sham-infected (black bars), UV-inactivated TMEV-infected (hatched bars), or WT TMEV-infected (black bars) B6 mice 3 days p.i. Data are representative of 2 to 3 independent experiments with 3 to 5 mice per group. Error bars show standard deviations. ***, P < 0.001; **, P < 0.01; *, P < 0.05.
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fig1: CNS viral infection results in accumulation of NK1.1-expressing dendritic cells in the CNS of TMEV-IDD-resistant B6 mice. Wild-type B6 and SJL/J mice were i.c. infected with 5 × 106 PFU of TMEV or sham infected. Brains were harvested during acute infection, and mononuclear cells were isolated and stained for flow cytometry. (A) Live CD45+ CD11c+ cells were analyzed for expression of Ly6c and CD11b. Representative flow plots from day 5 post-TMEV infection are shown. (B) Numbers of cells in the CNS expressing Ly6C and CD11b on days 3, 5, and 7 p.i. in TMEV- or sham-infected B6 and SJL/J mice are shown. (C) Live CD3− CD11c+ cells were analyzed for their expression of NK1.1 and DX5. Representative flow plots from day 3 post-TMEV infection of B6 and SJL/J mice are shown. (D) Quantification of CD3− CD11c+ DX5+ cell numbers on days 1, 2, and 3 p.i. in TMEV- or sham-infected B6 and SJL/J mice. (E) Quantification of CD3− CD45+ CD11c+ NK1.1+ DX5+ brain cells on days 1, 3, 5, and 7 p.i. in TMEV- or sham-infected B6 mice are shown. (F) Quantification of total CNS lymphocytes and NKDCs in sham-infected (black bars), UV-inactivated TMEV-infected (hatched bars), or WT TMEV-infected (black bars) B6 mice 3 days p.i. Data are representative of 2 to 3 independent experiments with 3 to 5 mice per group. Error bars show standard deviations. ***, P < 0.001; **, P < 0.01; *, P < 0.05.
Mentions: Viral titers within the brains of both susceptible SJL/J and resistant B6 mice peak at day 5 following intracerebral (i.c.) infection and result in a potent adaptive systemic immune response in both strains peaking 7 to 10 days postinfection (p.i.) (21). Given these kinetics, we examined the phenotype and numbers of various potential CD11c+ DC subsets that appeared within the CNS during the acute infection period. We found that both CD45+ CD11c+ Ly6c+ CD11b− plasmacytoid DCs and CD45+ CD11c+ Ly6c+ CD11bint/lo inflammatory monocytes infiltrated the CNS of both TMEV-infected SJL/J and B6 mice (Fig. 1A). Both of these DC subsets have been shown to be participants during CNS virus infection (22, 23). We were somewhat surprised, however, that there was no significant difference in the number of pDCs or inflammatory monocytes between infected B6 and SJL/J animals.

Bottom Line: Viral infection is an important cofactor, along with genetic susceptibility, in the initiation of a variety of organ-specific autoimmune diseases.Thus, in-depth understanding of how virus infections trigger autoimmunity may lead to novel ways to prevent or treat these diseases.Theiler's murine encephalitis virus-induced demyelinating disease (TMEV-IDD) serves as an important model for the human T cell-mediated autoimmune demyelinating disease multiple sclerosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

No MeSH data available.


Related in: MedlinePlus