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Viral infection of transgenic mice expressing a viral protein in oligodendrocytes leads to chronic central nervous system autoimmune disease.

Evans CF, Horwitz MS, Hobbs MV, Oldstone MB - J. Exp. Med. (1996)

Bottom Line: One hypothesis for the etiology of central nervous system (CNS) autoimmune disease is that infection by a virus sharing antigenic epitopes with CNS antigens (molecular mimicry) elicits a virus-specific immune response that also recognizes self-epitopes.After clearance, a chronic inflammation of the CNS resulted, accompanied by upregulation of CNS expression of MHC class I and II molecules.These results may explain the association of several different viruses with some human autoimmune diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037, USA.

ABSTRACT
One hypothesis for the etiology of central nervous system (CNS) autoimmune disease is that infection by a virus sharing antigenic epitopes with CNS antigens (molecular mimicry) elicits a virus-specific immune response that also recognizes self-epitopes. To address this hypothesis, transgenic mice were generated that express the nucleoprotein or glycoprotein of lymphocytic choriomeningitis virus (LCMV) as self in oligodendrocytes. Intraperitoneal infection with LCMV strain Armstrong led to infection of tissues in the periphery but not the CNS, and the virus was cleared within 7-14 d. After clearance, a chronic inflammation of the CNS resulted, accompanied by upregulation of CNS expression of MHC class I and II molecules. A second LCMV infection led to enhanced CNS pathology, characterized by loss of myelin and clinical motor dysfunction. Disease enhancement also occurred after a second infection with unrelated viruses that cross-activated LCMV-specific memory T cells. These findings indicate that chronic CNS autoimmune disease may be induced by infection with a virus sharing epitopes with a protein expressed in oligodendrocytes and this disease may be enhanced by a second infection with the same or an unrelated virus. These results may explain the association of several different viruses with some human autoimmune diseases.

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Related in: MedlinePlus

Characterization of T cell lesions by confocal microscopic analysis. An MBP–NP transgenic positive mouse was infected with LCMV, reinfected with LCMV at 6 wk after infection, and killed 12 wk after second infection. Cryocut brain sections were doubled immunofluorescently stained  and analyzed by laser scanning confocal microscopy as described in Materials and Methods. (A) shows double staining of T cell lesions in the cortex with  antibodies to CD8+ T cells ( green) and MBP (red ). (B, C,and D) show a region of the cortex stained with antibodies to F4/80 (B, green), MBP (C, red ),  and the merged view with both labels (D, areas of colocalization of MBP and F4/80 are presented in yellow [arrow]). Bar, 25 μm.
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Figure 4: Characterization of T cell lesions by confocal microscopic analysis. An MBP–NP transgenic positive mouse was infected with LCMV, reinfected with LCMV at 6 wk after infection, and killed 12 wk after second infection. Cryocut brain sections were doubled immunofluorescently stained and analyzed by laser scanning confocal microscopy as described in Materials and Methods. (A) shows double staining of T cell lesions in the cortex with antibodies to CD8+ T cells ( green) and MBP (red ). (B, C,and D) show a region of the cortex stained with antibodies to F4/80 (B, green), MBP (C, red ), and the merged view with both labels (D, areas of colocalization of MBP and F4/80 are presented in yellow [arrow]). Bar, 25 μm.

Mentions: Focal areas with high numbers of infiltrating T cells were found in the parenchyma of the brain associated with myelin tracts. These lesions of infiltrating lymphocytes spanned several consecutive sections, ranged in size from 25–150 μm, and as many as five lesions per sagittal section were found. Immunohistochemical staining showed that they consisted of both CD8+ and CD4+ T cells. Double immunofluorescent labeling of brain sections with antibody to CD8 and MBP and subsequent confocal microscopic analysis revealed a loss of MBP staining at the center of these lesions (Fig. 4 A). Double labeling with antibodies to F4/80 and MBP revealed the presence of activated macrophages/microglia around the lesions and colocalization of MBP within these activated macrophages/microglia (Fig. 4, B–D).


Viral infection of transgenic mice expressing a viral protein in oligodendrocytes leads to chronic central nervous system autoimmune disease.

Evans CF, Horwitz MS, Hobbs MV, Oldstone MB - J. Exp. Med. (1996)

Characterization of T cell lesions by confocal microscopic analysis. An MBP–NP transgenic positive mouse was infected with LCMV, reinfected with LCMV at 6 wk after infection, and killed 12 wk after second infection. Cryocut brain sections were doubled immunofluorescently stained  and analyzed by laser scanning confocal microscopy as described in Materials and Methods. (A) shows double staining of T cell lesions in the cortex with  antibodies to CD8+ T cells ( green) and MBP (red ). (B, C,and D) show a region of the cortex stained with antibodies to F4/80 (B, green), MBP (C, red ),  and the merged view with both labels (D, areas of colocalization of MBP and F4/80 are presented in yellow [arrow]). Bar, 25 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196376&req=5

Figure 4: Characterization of T cell lesions by confocal microscopic analysis. An MBP–NP transgenic positive mouse was infected with LCMV, reinfected with LCMV at 6 wk after infection, and killed 12 wk after second infection. Cryocut brain sections were doubled immunofluorescently stained and analyzed by laser scanning confocal microscopy as described in Materials and Methods. (A) shows double staining of T cell lesions in the cortex with antibodies to CD8+ T cells ( green) and MBP (red ). (B, C,and D) show a region of the cortex stained with antibodies to F4/80 (B, green), MBP (C, red ), and the merged view with both labels (D, areas of colocalization of MBP and F4/80 are presented in yellow [arrow]). Bar, 25 μm.
Mentions: Focal areas with high numbers of infiltrating T cells were found in the parenchyma of the brain associated with myelin tracts. These lesions of infiltrating lymphocytes spanned several consecutive sections, ranged in size from 25–150 μm, and as many as five lesions per sagittal section were found. Immunohistochemical staining showed that they consisted of both CD8+ and CD4+ T cells. Double immunofluorescent labeling of brain sections with antibody to CD8 and MBP and subsequent confocal microscopic analysis revealed a loss of MBP staining at the center of these lesions (Fig. 4 A). Double labeling with antibodies to F4/80 and MBP revealed the presence of activated macrophages/microglia around the lesions and colocalization of MBP within these activated macrophages/microglia (Fig. 4, B–D).

Bottom Line: One hypothesis for the etiology of central nervous system (CNS) autoimmune disease is that infection by a virus sharing antigenic epitopes with CNS antigens (molecular mimicry) elicits a virus-specific immune response that also recognizes self-epitopes.After clearance, a chronic inflammation of the CNS resulted, accompanied by upregulation of CNS expression of MHC class I and II molecules.These results may explain the association of several different viruses with some human autoimmune diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037, USA.

ABSTRACT
One hypothesis for the etiology of central nervous system (CNS) autoimmune disease is that infection by a virus sharing antigenic epitopes with CNS antigens (molecular mimicry) elicits a virus-specific immune response that also recognizes self-epitopes. To address this hypothesis, transgenic mice were generated that express the nucleoprotein or glycoprotein of lymphocytic choriomeningitis virus (LCMV) as self in oligodendrocytes. Intraperitoneal infection with LCMV strain Armstrong led to infection of tissues in the periphery but not the CNS, and the virus was cleared within 7-14 d. After clearance, a chronic inflammation of the CNS resulted, accompanied by upregulation of CNS expression of MHC class I and II molecules. A second LCMV infection led to enhanced CNS pathology, characterized by loss of myelin and clinical motor dysfunction. Disease enhancement also occurred after a second infection with unrelated viruses that cross-activated LCMV-specific memory T cells. These findings indicate that chronic CNS autoimmune disease may be induced by infection with a virus sharing epitopes with a protein expressed in oligodendrocytes and this disease may be enhanced by a second infection with the same or an unrelated virus. These results may explain the association of several different viruses with some human autoimmune diseases.

Show MeSH
Related in: MedlinePlus