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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

Stimulation of increased CNS immune infiltration  and activation of LCMV-memory  CTL by infection with a second  virus not encoding LCMV gene  products. An MBP–NP transgenic  positive mouse was infected with  LCMV followed by VV infection  6 wk later. After another 6 wk, the  mouse was sacrificed and increased  numbers of CD8+ (A) and CD4+  (B) cells compared with those observed after a single LCMV infection were detected in the brain by  immunohistochemical staining as  described in Materials and Methods. Bar, 200 μm; original magnification ×100.
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Figure 6: Stimulation of increased CNS immune infiltration and activation of LCMV-memory CTL by infection with a second virus not encoding LCMV gene products. An MBP–NP transgenic positive mouse was infected with LCMV followed by VV infection 6 wk later. After another 6 wk, the mouse was sacrificed and increased numbers of CD8+ (A) and CD4+ (B) cells compared with those observed after a single LCMV infection were detected in the brain by immunohistochemical staining as described in Materials and Methods. Bar, 200 μm; original magnification ×100.

Mentions: To determine whether enhanced disease following stimulation of the LCMV memory response required that the second restimulating virus encoded the transgene, transgenic mice previously infected with LCMV were given a second infection with either VV, using a recombinant VV not encoding any LCMV genes, or PV, an arenavirus distantly related to LCMV but not sharing any of the defined LCMV CTL epitopes. MBP–NP transgenic positive and negative mice that had been infected with LCMV 6 wk previously were infected with either VV or PV. 4–8 wk later, the mice were killed and CNS tissues were examined. Stimulation of the memory response by these unrelated viruses resulted in enhanced pathology similar to that seen after a second infection with LCMV. This included greater numbers of infiltrating lymphocytes, an increase in the ratio of CD4+ to CD8+ lymphocytes, and a high preponderance of these infiltrates in white matter-rich areas (Fig. 6, A and B). Additionally, activation of microglia and astrocytes, as measured by increased F4/80 and GFAP expression, were observed, as well as increased upregulation of the antigen presentation MHC class I and II molecules throughout the white matter regions. Infiltrating lymphocytes formed lesions within the white matter tracts of the CNS. These lesions showed a loss of MBP staining accompanied by uptake of MBP by activated microglia/macrophages similar to that observed after a second infection with LCMV.


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)

Stimulation of increased CNS immune infiltration  and activation of LCMV-memory  CTL by infection with a second  virus not encoding LCMV gene  products. An MBP–NP transgenic  positive mouse was infected with  LCMV followed by VV infection  6 wk later. After another 6 wk, the  mouse was sacrificed and increased  numbers of CD8+ (A) and CD4+  (B) cells compared with those observed after a single LCMV infection were detected in the brain by  immunohistochemical staining as  described in Materials and Methods. Bar, 200 μm; original magnification ×100.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 6: Stimulation of increased CNS immune infiltration and activation of LCMV-memory CTL by infection with a second virus not encoding LCMV gene products. An MBP–NP transgenic positive mouse was infected with LCMV followed by VV infection 6 wk later. After another 6 wk, the mouse was sacrificed and increased numbers of CD8+ (A) and CD4+ (B) cells compared with those observed after a single LCMV infection were detected in the brain by immunohistochemical staining as described in Materials and Methods. Bar, 200 μm; original magnification ×100.
Mentions: To determine whether enhanced disease following stimulation of the LCMV memory response required that the second restimulating virus encoded the transgene, transgenic mice previously infected with LCMV were given a second infection with either VV, using a recombinant VV not encoding any LCMV genes, or PV, an arenavirus distantly related to LCMV but not sharing any of the defined LCMV CTL epitopes. MBP–NP transgenic positive and negative mice that had been infected with LCMV 6 wk previously were infected with either VV or PV. 4–8 wk later, the mice were killed and CNS tissues were examined. Stimulation of the memory response by these unrelated viruses resulted in enhanced pathology similar to that seen after a second infection with LCMV. This included greater numbers of infiltrating lymphocytes, an increase in the ratio of CD4+ to CD8+ lymphocytes, and a high preponderance of these infiltrates in white matter-rich areas (Fig. 6, A and B). Additionally, activation of microglia and astrocytes, as measured by increased F4/80 and GFAP expression, were observed, as well as increased upregulation of the antigen presentation MHC class I and II molecules throughout the white matter regions. Infiltrating lymphocytes formed lesions within the white matter tracts of the CNS. These lesions showed a loss of MBP staining accompanied by uptake of MBP by activated microglia/macrophages similar to that observed after a second infection with LCMV.

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