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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

Summary of MBP–NP and –GP transgenic mouse lines. (A)  pMBP001 contains 1.9 kb of the MBP gene promoter/enhancer sequences, and polyadenylation and splice signals from the PLP gene. The  LCMV NP and GP genes were cloned into the BamHI site of pMBP001  to give pMBP–NP and pMBP–GP. Expression of spliced mRNA in  transgenic mice was determined by RT-PCR using primers that hybridized within the transgene and the PLP exon 7 as indicated by arrows,  with the resulting RT-PCR products of 510 bp (MBP–NP) or 780 bp  (MBP–GP). (B) RNA from the brains (Brn) and spleens (Spl ) of MBP– NP and –GP transgenic mice was subjected to RT-PCR as described in  Materials and Methods to detect transgene-specific spliced RNA (see A). M,  molecular weight markers. (C) The transgenic mouse lines studied are  listed with the relative copy number of the transgene and the results of  RT-PCR transgene mRNA studies.
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Figure 1: Summary of MBP–NP and –GP transgenic mouse lines. (A) pMBP001 contains 1.9 kb of the MBP gene promoter/enhancer sequences, and polyadenylation and splice signals from the PLP gene. The LCMV NP and GP genes were cloned into the BamHI site of pMBP001 to give pMBP–NP and pMBP–GP. Expression of spliced mRNA in transgenic mice was determined by RT-PCR using primers that hybridized within the transgene and the PLP exon 7 as indicated by arrows, with the resulting RT-PCR products of 510 bp (MBP–NP) or 780 bp (MBP–GP). (B) RNA from the brains (Brn) and spleens (Spl ) of MBP– NP and –GP transgenic mice was subjected to RT-PCR as described in Materials and Methods to detect transgene-specific spliced RNA (see A). M, molecular weight markers. (C) The transgenic mouse lines studied are listed with the relative copy number of the transgene and the results of RT-PCR transgene mRNA studies.

Mentions: The cDNAs of the LCMV NP and GP genes were cloned behind the MBP promoter to direct expression to CNS oligodendrocytes as indicated in Fig. 1 A. This MBP promoter vector had previously been shown to drive expression of a transgene specifically in CNS oligodendrocytes in transgenic mice (18). Eight founders were identified carrying the LCMV–NP construct, and seven MBP–GP carriers were identified. Because greater than 97% of the LCMV-specific CTL response on the H-2d background is to an epitope in NP (16), the MBP–NP mice were bred to BALB/cByJ (H-2d) mice to maximize the proportion of NP-reactive CTL after LCMV infection. Likewise, because the majority of LCMVspecific CTL react with two epitopes in GP on the H-2b background (25), the MBP–GP mice were bred to C57BL/6 (H-2b) mice.


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)

Summary of MBP–NP and –GP transgenic mouse lines. (A)  pMBP001 contains 1.9 kb of the MBP gene promoter/enhancer sequences, and polyadenylation and splice signals from the PLP gene. The  LCMV NP and GP genes were cloned into the BamHI site of pMBP001  to give pMBP–NP and pMBP–GP. Expression of spliced mRNA in  transgenic mice was determined by RT-PCR using primers that hybridized within the transgene and the PLP exon 7 as indicated by arrows,  with the resulting RT-PCR products of 510 bp (MBP–NP) or 780 bp  (MBP–GP). (B) RNA from the brains (Brn) and spleens (Spl ) of MBP– NP and –GP transgenic mice was subjected to RT-PCR as described in  Materials and Methods to detect transgene-specific spliced RNA (see A). M,  molecular weight markers. (C) The transgenic mouse lines studied are  listed with the relative copy number of the transgene and the results of  RT-PCR transgene mRNA studies.
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Related In: Results  -  Collection

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

Figure 1: Summary of MBP–NP and –GP transgenic mouse lines. (A) pMBP001 contains 1.9 kb of the MBP gene promoter/enhancer sequences, and polyadenylation and splice signals from the PLP gene. The LCMV NP and GP genes were cloned into the BamHI site of pMBP001 to give pMBP–NP and pMBP–GP. Expression of spliced mRNA in transgenic mice was determined by RT-PCR using primers that hybridized within the transgene and the PLP exon 7 as indicated by arrows, with the resulting RT-PCR products of 510 bp (MBP–NP) or 780 bp (MBP–GP). (B) RNA from the brains (Brn) and spleens (Spl ) of MBP– NP and –GP transgenic mice was subjected to RT-PCR as described in Materials and Methods to detect transgene-specific spliced RNA (see A). M, molecular weight markers. (C) The transgenic mouse lines studied are listed with the relative copy number of the transgene and the results of RT-PCR transgene mRNA studies.
Mentions: The cDNAs of the LCMV NP and GP genes were cloned behind the MBP promoter to direct expression to CNS oligodendrocytes as indicated in Fig. 1 A. This MBP promoter vector had previously been shown to drive expression of a transgene specifically in CNS oligodendrocytes in transgenic mice (18). Eight founders were identified carrying the LCMV–NP construct, and seven MBP–GP carriers were identified. Because greater than 97% of the LCMV-specific CTL response on the H-2d background is to an epitope in NP (16), the MBP–NP mice were bred to BALB/cByJ (H-2d) mice to maximize the proportion of NP-reactive CTL after LCMV infection. Likewise, because the majority of LCMVspecific CTL react with two epitopes in GP on the H-2b background (25), the MBP–GP mice were bred to C57BL/6 (H-2b) mice.

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