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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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Expression of cytokines and measurement of clinical motor dysfunction in transgenic mice infected twice with LCMV. (A) mRNAs for various cytokines were detected by RNase protection assays using RNA isolated from mouse brains as described in Materials and Methods. Nontransgenic  (NTG) or transgenic (TG) mice were infected with LCMV, 6 wk later given a second LCMV infection, and sacrificed 4 wk later (n = 2–4). PI units,  phosphoroimage units as defined in Materials and Methods. Values are plotted as mean ± SE. (B) MBP–NP mice were infected with LCMV and 6 wk  later reinfected with LCMV. Four transgenic positive (open circles) and negative (closed circles) mice were tested for motor dysfunction on a rotorod apparatus in three consecutive trials as described in Materials and Methods. The time on the rotorod was measured, with a maximum of 180 s. The standard error is shown for all trials except the transgenic negative third trial, in which 3 out of 4 mice remained on the rod for the maximum time allowed.
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Figure 5: Expression of cytokines and measurement of clinical motor dysfunction in transgenic mice infected twice with LCMV. (A) mRNAs for various cytokines were detected by RNase protection assays using RNA isolated from mouse brains as described in Materials and Methods. Nontransgenic (NTG) or transgenic (TG) mice were infected with LCMV, 6 wk later given a second LCMV infection, and sacrificed 4 wk later (n = 2–4). PI units, phosphoroimage units as defined in Materials and Methods. Values are plotted as mean ± SE. (B) MBP–NP mice were infected with LCMV and 6 wk later reinfected with LCMV. Four transgenic positive (open circles) and negative (closed circles) mice were tested for motor dysfunction on a rotorod apparatus in three consecutive trials as described in Materials and Methods. The time on the rotorod was measured, with a maximum of 180 s. The standard error is shown for all trials except the transgenic negative third trial, in which 3 out of 4 mice remained on the rod for the maximum time allowed.

Mentions: To characterize the nature of the CNS-directed immune response, RNA extracts from the brains of MBP–NP transgenic positive and negative mice undergoing the double infection protocol were subjected to an RNase protection assay using probes to a number of cytokines (20). Brains from transgenic mice first infected with LCMV, secondarily infected 6 wk later with either LCMV or VV–NP, and sacrificed after another 4 wk, contained increased message levels of the following cytokines when compared with uninfected mice, or doubly infected nontransgenic mice: IFN-γ, TNF-α, TNF-β, IL-1α, IL-1β, and IL-12p40 (Fig. 5 A). No mRNAs for IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, or IL-13 were detected in transgenic positive or negative brains. Nontransgenic mice showed minor increases in the levels of TNF-α, TNF-β, and IL-1β message at 4 wk after second infection. This was most likely the result of immune surveillance and trafficking after viral induction of the memory immune response.


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)

Expression of cytokines and measurement of clinical motor dysfunction in transgenic mice infected twice with LCMV. (A) mRNAs for various cytokines were detected by RNase protection assays using RNA isolated from mouse brains as described in Materials and Methods. Nontransgenic  (NTG) or transgenic (TG) mice were infected with LCMV, 6 wk later given a second LCMV infection, and sacrificed 4 wk later (n = 2–4). PI units,  phosphoroimage units as defined in Materials and Methods. Values are plotted as mean ± SE. (B) MBP–NP mice were infected with LCMV and 6 wk  later reinfected with LCMV. Four transgenic positive (open circles) and negative (closed circles) mice were tested for motor dysfunction on a rotorod apparatus in three consecutive trials as described in Materials and Methods. The time on the rotorod was measured, with a maximum of 180 s. The standard error is shown for all trials except the transgenic negative third trial, in which 3 out of 4 mice remained on the rod for the maximum time allowed.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196376&req=5

Figure 5: Expression of cytokines and measurement of clinical motor dysfunction in transgenic mice infected twice with LCMV. (A) mRNAs for various cytokines were detected by RNase protection assays using RNA isolated from mouse brains as described in Materials and Methods. Nontransgenic (NTG) or transgenic (TG) mice were infected with LCMV, 6 wk later given a second LCMV infection, and sacrificed 4 wk later (n = 2–4). PI units, phosphoroimage units as defined in Materials and Methods. Values are plotted as mean ± SE. (B) MBP–NP mice were infected with LCMV and 6 wk later reinfected with LCMV. Four transgenic positive (open circles) and negative (closed circles) mice were tested for motor dysfunction on a rotorod apparatus in three consecutive trials as described in Materials and Methods. The time on the rotorod was measured, with a maximum of 180 s. The standard error is shown for all trials except the transgenic negative third trial, in which 3 out of 4 mice remained on the rod for the maximum time allowed.
Mentions: To characterize the nature of the CNS-directed immune response, RNA extracts from the brains of MBP–NP transgenic positive and negative mice undergoing the double infection protocol were subjected to an RNase protection assay using probes to a number of cytokines (20). Brains from transgenic mice first infected with LCMV, secondarily infected 6 wk later with either LCMV or VV–NP, and sacrificed after another 4 wk, contained increased message levels of the following cytokines when compared with uninfected mice, or doubly infected nontransgenic mice: IFN-γ, TNF-α, TNF-β, IL-1α, IL-1β, and IL-12p40 (Fig. 5 A). No mRNAs for IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, or IL-13 were detected in transgenic positive or negative brains. Nontransgenic mice showed minor increases in the levels of TNF-α, TNF-β, and IL-1β message at 4 wk after second infection. This was most likely the result of immune surveillance and trafficking after viral induction of the memory immune response.

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