This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Redwine, J. M. Articles by Evans, C. F. Search for Related Content PubMed PubMed Citation Articles by Redwine, J. M. Articles by Evans, C. F.

(American Journal of Pathology. 2001;159:1219-1224.)
© 2001 American Society for Investigative Pathology

Short Communications

In Vivo Expression of Major Histocompatibility Complex Molecules on Oligodendrocytes and Neurons during Viral Infection

From the Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Demyelination in multiple sclerosis and in animal models is associated with infiltrating CD8+ and CD4+ T cells. Although oligodendrocytes and axons are damaged in these diseases, the roles T cells play in the demyelination process are not completely understood. Antigen-specific CD8+ T cell lysis of target cells is dependent on interactions between the T cell receptor and major histocompatibility complex (MHC) class I-peptide complexes on the target cell. In the normal central nervous system, expression of MHC molecules is very low but often increases during inflammation. We set out to precisely define which central nervous system cells express MHC molecules in vivo during infection with a strain of murine hepatitis virus that causes a chronic, inflammatory demyelinating disease. Using double immunofluorescence labeling, we show that during acute infection with murine hepatitis virus, MHC class I is expressed in vivo by oligodendrocytes, neurons, microglia, and endothelia, and MHC class II is expressed only by microglia. These data indicate that oligodendrocytes and neurons have the potential to present antigen to T cells and thus be damaged by direct antigen-specific interactions with CD8+ T lymphocytes.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

Antigen-specific T cell lysis of target cells is MHC restricted, and dependent on expression of MHC on the target cell. In most of the normal CNS, MHC expression at the protein level does not occur or is below detection levels. During an inflammatory response or following viral infection, MHC expression in the CNS can be detected. However reports of specific cell types within the CNS that express MHC have often been conflicting, and the number of studies using double labeling techniques to clearly identify cell types expressing MHC in vivo has been limited.⁴

In the present study, we used an established murine model of CNS inflammation and demyelination to determine definitively which cells of the CNS express MHC molecules during an acute viral infection. We used an attenuated variant of murine hepatitis virus (MHV)-JHM (MHV V5A13.1)⁵ that infects neurons and glial cells and induces chronic demyelination. Following an intracranial (i.c.) injection into mice, MHV V5A13.1 spreads throughout the brain and spinal cord causing demyelination and an inflammatory response.^3,5,6 Infectious MHV V5A13.1 is cleared from the CNS of mice by 12 days post infection (dpi),^5,6 although viral RNA persists.¹³ During acute demyelination and inflammation we identified the spinal cord cell types expressing MHC class I and class II molecules in vivo by using double label immunofluorescence imaged by confocal microscopy to colocalize MHC expression with specific cell type markers.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
MHV Injections

Six- to eight-week-old BALB/c female and male mice were anesthetized with methoxyfluorane and intracranially injected with 30 µl of phosphate-buffered saline (PBS) (n = 8) or 10–100 plaque forming units (PFU) of MHV V5A13.1. Following MHV infection, mice were perfused at 10 dpi (n = 6), 14 dpi (n = 3) 24 dpi (n = 3) and 49 dpi (n = 5).

Tissue Preparation

For all double immunolabeling studies, mice were anesthetized with chloral hydrate and transcardially perfused with saline, and spinal cords were removed and stored at -20°C. For immunostaining to identify demyelinated lesions with cyclic nucleotide phosphodiesterase (CNP), mice were anesthetized and transcardially perfused with saline followed by 4% paraformaldehyde.

Immunohistochemistry

Sagittal spinal cord sections were fixed in 95% ethanol at 4°C (15 minutes), blocked with avidin and biotin, and incubated with antibodies to CD4 (clone RM4–5 1:150, Pharmingen, San Diego, CA), CD8 (clone 53–6.7, 1:200 Pharmingen), MHC class I (clone ER-HR-52 1:5000; Bachem, Torrance, CA), or MHC class II (Clone ER-TR-3 1:200; Bachem) at 4°C overnight. Slides were then incubated with a biotinylated anti-rat secondary (Vector Labs, Burlingame, CA), followed by biotin/avidin/horseradish peroxidase (HRP) reagents (Vector Labs), and color was developed with diaminobenzidine (Zymed Labs, San Francisco, CA) for approximately 8 minutes. The reaction was stopped with water, the slides were counterstained with hematoxylin, and slides were mounted with Aquamount (Polysciences, Inc., Warrington, PA).

Immunofluorescence

To identify demyelinated lesions, coronal sections from paraformaldehyde perfused mice were pretreated with 100% methanol (15 minutes at -20°C), blocked with 25% donor calf serum, and incubated with anti-CNP 1:100 (clone 11–5B, Sigma, St. Louis, MO). Slides were then incubated with an anti-mouse IgG F(ab)₂ conjugated to fluorescein isothiocyanate (FITC) (1 hour at room temperature) and mounted with Vectashield (Vector Labs, used in all immunofluorescence experiments). To identify viral antigen, sagittal spinal cord sections were blocked with donor calf serum, incubated with purified monoclonal antibody 4B62 ⁵ (that recognizes MHV nucleocapsid), rinsed, incubated with anti-mouse secondary antibody conjugated to FITC, rinsed, and mounted. For all double label experiments involving immunofluorescence labeling of MHC class I or class II and a second antigen, sections were serially stained with anti-MHC antibodies followed by antibodies to the second antigen. As a control, the primary antibodies were omitted to ensure fluorescence was specific for antibody binding. To verify specificity of the MHC class I antibody clone ER-HR-52, the antibody was incubated on spinal cords from ß₂-microglobulin knockout mice that lack cell surface MHC class I expression. No MHC class I expression was detected on the blood vessels of ß₂m ^-/- mice, compared to clear detection of MHC class I staining on blood vessels from normal mouse spinal cord. For labeling of MHC antigens, slides were fixed in cold 95% ethanol for 15 minutes, blocked with serum/PBS/3% bovine serum albumin (BSA), and incubated with anti-MHC class I (clone ER-HR-52 1:2000) or MHC class II (clone M5/114, Boehringer Mannheim Biochemicals, Indianapolis, IN, or clone ER-TR-3, Bachem) overnight at 4°C. Slides were then incubated with an anti-rat secondary IgG F(ab)₂ antibody conjugated to a fluorochrome (FITC or Texas Red) absorbed for minimal cross-reactivity with other species (Jackson Immunoresearch, West Grove, PA). For anti-MHC class I antibody clone M1/42 (data not shown, Boehringer Mannheim Biochemicals), slides were incubated with a biotinylated anti-mouse antibody, followed by avidin/biotin/HRP reagents (Vector Labs), followed by incubation with an anti-HRP antibody conjugated to either FITC or Texas Red (Jackson Immunoresearch).

For double immunofluorescence of MHC antigens with CNP, slides were then fixed in 4% paraformaldehyde for 30 minutes followed by cold methanol for 15 minutes at -20°C. They were then blocked and incubated with anti-CNP as described above. Finally, they were incubated with a secondary anti-mouse antibody conjugated to FITC or Texas Red and mounted. For double immunofluorescence of MHC antigens with glial fibrillary acidic protein (GFAP), slides were then fixed in 4% paraformaldehyde and incubated with polyclonal rabbit anti-cow GFAP (1:100, DAKO, Carpinteria, CA) in PBS/3% BSA/0.1% Triton X-100 for 2 hours at room temperature. They were then incubated with an anti-rabbit secondary conjugated to FITC and mounted. For double immunofluorescence of MHC antigens with mac-1 (CD11b) after MHC staining, the slides were incubated with anti-mac-1 directly conjugated to FITC (Pharmingen) for 2 hours at room temperature, rinsed, and mounted. For double immunofluorescence of MHC antigens with CD31, slides were then fixed in 4% paraformaldehyde for 30 minutes at room temperature, and incubated with hamster anti-CD31 (1:100; Chemicon International, Temecula, CA) for 2 hours at room temperature. They were then incubated with an anti-hamster secondary conjugated to FITC (1:200; Jackson Immunoresearch) and mounted. For double immunofluorescence of MHC antigens with neuron specific enolase (NSE), slides were then fixed in 4% paraformaldehyde for 30 minutes at room temperature, incubated with polyclonal anti-mouse NSE (1:50; Polysciences, Warrington, PA) overnight at 4°C, and incubated with a biotinylated anti-mouse antibody (1:400). They were then incubated with an avidin/biotin/HRP complex (Vector Labs) followed by an anti-HRP conjugated to FITC (1:400, Jackson Immunoresearch) and mounted.

Confocal Microscopy

Single plane confocal microscope images were collected sequentially using a Bio-Rad MRC-1024 unit attached to a Zeiss Axiovert S100TV microscope with 40x or 63x objective lenses. A krypton/argon mixed gas laser produced excitation wavelengths at 488 nm and 568 nm for FITC or Texas Red, respectively. In some cases, z-series images from 3 to 5 planes 0.2 µm apart were collected for reconstrution. Individual fluorophore images were merged and pseudocolored using Adobe Photoshop (version 5.5).

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
In agreement with previous reports,^3,13 in spinal cords we identified increased expression of MHC class I and class II molecules in association with infiltrating T lymphocytes and demyelinated lesions as early as 10–14 days dpi (Figure 1 , panels A1-A4). CD8+ T cells (Figure 1 , panel A3) as well as CD4⁺ T cells (not shown) were present. Virally-infected cells were identified in areas of inflammation by immunohistochemical staining with an antibody to the MHV nucleoprotein (Figure 1 , panels C1 and C2). In sham-infected mice, infiltrating lymphocytes and demyelination were not detected, and MHC class I was never detected in the parenchyma, but could be detected on some vessels (Figure 1 , panel B1). At 10 dpi, MHC class I was clearly expressed on many cells identified as oligodendrocytes by staining with an antibody to the oligodendrocyte/myelin-specific protein 2'3'-CNP (Figure 2 , rows A and B). MHC class I was detected around the cell body of oligodendrocytes as well as along myelinated processes. Colocalization of MHC class I with CNP was confirmed with a second anti-MHC class I antibody (clone M1–42, not shown). At 3–7 weeks postinfection, MHC class I expression by oligodendrocytes was much less common than during the acute viral infection (not shown). This corresponds to a well-documented period in which remyelination is observed during MHV infection.⁵ Although MHC class II was also expressed in white matter, its expression was distinct from cell bodies and processes labeled with CNP (Figure 3 , panels A1-A3).

View larger version (72K): [in this window] [in a new window]   Figure 1. MHV V5A13.1 infection induces an inflammatory response and demyelination in mouse spinal cord. Mouse spinal cords taken 10 to 14 days after intracranial infection with MHV have inflammation characterized by expression of MHC class I (A1), MHC class II (A2), and infiltration of CD8+ T cells (A3) compared to PBS-injected mouse spinal cords (B1–B3). In addition, MHV V5A13.1 induces demyelination in ventral-lateral white matter as early as 10 dpi indicated by reduced CNP stain and vacuolization seen in A4, compared to normal white matter seen in PBS injected mice (B4). Viral antigen can be detected at 10 dpi in spinal cord white matter (C1) and gray matter (C2). Original magnifications: A1–A3, B1–B3, 125x; A4, B4, 500x; scale bar in C1,C2, 50 µm.

View larger version (60K): [in this window] [in a new window]   Figure 2. MHC class I expression in mouse spinal cords following MHV V5A13.1 infection. Double immunofluorescence imaged with confocal microscopy was used to identify cells expressing MHC class I (shown in red) and cell type specific markers (green). Colocalization of MHC class I and cell type markers is shown as yellow in the merged panels in the third column. Within or near the edge of a demyelinated lesion at 10–14 dpi, oligodendrocytes (A1) and myelinated processes (B1) labeled with CNP express MHC class I (A2, B2), indicated by yellow structures in A3 and B3. In B3, the arrow indicates a yellow process colocalizing CNP and MHC class I. The arrowhead indicates a green process labeled with CNP only. Spinal cord neurons labeled with NSE (C1, D1) also expressed MHC class I (C2, D2), indicated by the yellow cell in C3 and two yellow cells in D3. Astrocytes labeled with GFAP (E1) did not express MHC class I (E2; merge in E3). Microglia expressed MHC class I as indicated by yellow colocalization (arrow in F3) of Mac-1 (F1) and MHC class I (F2). The arrowhead in F3 indicates a blood vessel labeled with MHC class I. MHC class I expression by endothelial cells was confirmed by colocalization of CD31 (G1) and MHC class I (G2) shown with arrow in G3. Perivascular cells were often seen expressing MHC class I (arrowhead in G3). Rows A and F are three-dimensional reconstructions from 3 to 4 planes 0.2 µm apart. Scale bars, 10 µm.

View larger version (49K): [in this window] [in a new window]   Figure 3. MHC class II expression in mouse spinal cords following MHV V5A13.1 infection. Double immunofluorescence imaged with confocal microscopy was used to identify cells expressing MHC class II (red) and cell type specific markers (green) at 10 to 14 days after i.c. infection with MHV. Colocalization of MHC class II and cell type markers is shown as yellow in the merged panels in the third column. CNP staining (A1) was distinct from MHC class II staining (A2). The arrow in A3 indicates a myelinated process near a non-oligodendrocyte lineage cell expressing MHC class II but not CNP (arrowhead). Astrocyte processes (B1) did not express MHC class II (B2) indicated by lack of colocalization of GFAP (arrow in B3) with MHC class II (arrowhead in B3). Microglia/macrophage lineage cells labeled with Mac-1 (C1) clearly expressed MHC class II (C2) as indicated by yellow colocalization seen in C3. Endothelial cells expressing CD31 (D1) did not express MHC class II (D2), however perivascular cells were often seen that did express MHC class II (arrowhead in D3) adjacent to CD31 expressing endothelial cells (arrow in D3). All panels are single plane images. Scale bars, 10 µm.

To identify astrocytes, sections were stained with a polyclonal antibody to the astrocyte-specific protein, GFAP. Unlike oligodendrocytes and neurons, astrocytes did not express MHC molecules during MHV V5A13.1-induced demyelination (Figure 2 , panels E1-E3; Figure 3 , panels B1-B3). Figures 2 and 3 show staining of astrocytic processes with GFAP that do not colocalize with MHC. Astrocyte cell bodies also did not costain with MHC class I or II (not shown).

Microglia/macrophage lineage cells were identified with an antibody to CD11b, and most expressed MHC class I following MHV infection (Figure 2 , panels F1-F3). CD11b-positive cells expressing MHC class I had a ramified (or resting) morphology (Figure 2 , panels F1, F3) and a reactive morphology with shorter, broader processes. Microglia/macrophage lineage cells expressing CD11b also expressed MHC class II following MHV infection (Figure 3 , panels C1-C3), and in fact were the only resident cell type in the spinal cord to express MHC class II. Reactive microglia/macrophages with short broad processes expressed MHC class II, while ramified or resting microglia/macrophages typically did not express MHC class II. MHC class II- positive/CD11b-positive cells could be detected throughout white matter and gray matter, but were most abundant in scattered focal regions in white matter.

Vascular endothelial cells expressed MHC class I at low levels in sham-infected mice, and at much higher levels following MHV infection (Figure 2 , panels G1-G3). Endothelial cells did not express MHC class II (Figure 3 , panels D1-D3), although MHC class II expressing cells were often adjacent to endothelial cells in the perivascular region (as in Figure 3 , panel D3). These cells were probably perivascular microglia, infiltrating macrophages, and/or pericytes.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
In these studies we have demonstrated that acute infection with MHV-induced MHC class I expression on oligodendrocytes, neurons, microglia, and endothelia. Since MHV is known to infect all of these cell types,¹⁴ and CD8+ T cells have been implicated in viral clearance, one mechanism of cell damage may be by virus-specific CD8+ T cell lysis. MHC class I was observed on oligodendrocyte cell bodies and processes around demyelinated lesions 10–14 days post infection. There are several reports of MHC class I and class II expression by oligodendrocytes in vitro in response to viral infection or inflammatory cytokines.^15-17 However, there are very few reports of MHC expression by oligodendrocytes in vivo. MHC class II was detected by immunoelectron microscopy during Theiler’s virus infection,¹⁸ and MHC class I and class II were induced on oligodendrocytes by the transgenic expression of IFN as identified by double immunofluorescence labeling.¹⁹ Detection of MHC class I expression by oligodendrocytes in MHV infection provides direct evidence that oligodendrocytes are capable of presenting antigen to CD8+ T cells in vivo.

Neurons and the complex pattern of connections each neuron maintains are extremely difficult or impossible to replace. To prevent cytotoxic T lymphocyte (CTL)-mediated killing, neurons tightly regulate the peptide presentation process. For example, neurons have been shown to express only very low levels of the class I heavy chain and the peptide transporters TAP1 and TAP2.²⁰ MHC class I expression following MHV infection was previously observed in neuron-rich gray matter regions,²¹ although a neuronal phenotype was not confirmed. There are currently very few reports of neurons that express MHC class I in an adult rodent CNS identified by in situ double labeling as shown here. Interestingly, recent reports have identified MHC class I expression in a subset of neurons in the developing and mature cat and rodent CNS.^22,23 This expression appears to be required for activity dependent remodeling and synaptic plasticity, thus indicating that MHC molecules have functions that extend beyond their roles in immune responses.

In vitro studies have demonstrated that electrically silent neurons treated with IFN express MHC class I proteins on the cell surface.^24-26 MHV infection of neurons in vivo may disrupt normal neuronal electrical functions. IFN secreted by infiltrating T cells could then induce MHC class I expression, leading to recognition and lysis by virus-specific CTL. Neurons that were double labeled with MHC class I and NSE in MHV-infected mice were rare. However a low number was anticipated since it was likely that only damaged neurons would express MHC class I. Triple immunofluorescence labeling studies to identify MHV-infected neurons expressing MHC class I were done, but these technically difficult experiments were not successful since the viral antigen staining pattern was often observed as small blebs that resembled dead or dying cells. Although in vitro and in vivo evidence for cell surface expression of MHC class I has been reported,^22-25,27 our experiments do not specifically localize MHC class I to the neuronal cell surface since it is very difficult to distinguish surface staining from cytoplasmic staining in tissue sections. MHC class I staining did not appear to be restricted to the endoplasmic reticulum, but was found throughout the neuronal cytoplasm although it did not extend into axons or dendrites.

Since no MHC proteins were detected on astrocytes at any time point examined, the role of astrocytes in vivo in the inflammatory response following MHV V5A13.1 does not appear to involve antigen presentation. This lack of MHC expression by astrocytes in an inflamed CNS is consistent with other in vivo observations during MHV infection²⁸ and with our own studies of CNS inflammation in transgenic mice¹⁹ (J Redwine, L Shriver, and C Evans, manuscript in preparation). In vitro, MHC class I and class II expression can be induced on astrocytes in response to interferon- or viral infection.^29,30 However, MHC expression by astrocytes in vitro can be inhibited by neuronal contact or brain-derived gangliosides,^31,32 so these factors may actively suppress MHC expression by astrocytes in vivo.

Microglia expressed MHC class I and were the only cell type found to express MHC class II at all time points examined following MHV infection. Therefore these cells are the only cell type capable of presenting antigen to both CD8+ and CD4+ T cells. Resident microglia and infiltrating macrophages likely play major roles in regulating chronic inflammation by presenting antigen and expressing chemokines that attract T cells and/or macrophages.^3,13 Microglia can also express B7 costimulatory molecules^33,34 which increases the ability of these cells to activate T cells.

CNS endothelial cells were found to express MHC class I but not MHC class II following MHV infection. Although some studies of different models have reported MHC class II expression on endothelial cells,³⁵ others have reported MHC class II expression on perivascular cells but not endothelial cells.³⁶ The disparate findings may be due to the different models studied, or to the resolution of the various detection methods. Vessel endothelial cells and perivascular cells are likely important in antigen presentation to lymphocytes being recruited into the CNS. In addition, endothelial cells express the receptor for MHV,^37,38 so they may play a role in virus dissemination throughout the CNS.

Clearly, the mechanisms of MHV-induced pathology are multifactorial, since some demyelination can occur even in the absence of functional MHC class I or CD8+ T cells.³⁹ We found that at early time points post-MHV infection, oligodendrocytes expressed MHC class I, but expression decreased during the chronic phase of disease. Initial damage to CNS cells by virus-specific CD8+ T cells and by lytic viral infection may initiate a cascade of immune responses resulting in chronic demyelination that would not require continuing MHC class I expression. For example, macrophages may subsequently present viral antigen to CD4+ T cells in the context of MHC class II, thus continuing a local cycle of cytokine and chemokine production, T cell activation, and tissue damage.³ In light of these findings with MHV, it is possible that in humans, a CNS viral infection could result in the up-regulation of MHC class I molecules on oligodendrocytes or neurons during acute disease, thus rendering them susceptible to attack by CD8+ T cells. Chronic disease could then result due to a cascade of immune responses involving mechanisms such as epitope spreading.⁴⁰ Our findings of in vivo expression of MHC class I by oligodendrocytes and neurons are novel and have broad implications for the pathogenesis of neurological diseases that involve CD8+ T cell infiltration, such as MS.

	Acknowledgements

 
We thank L.P. Shriver, G.F. Rall, M. Manchester, and D.B. McGavern for helpful comments on the manuscript, Shannon Murray for technical assistance, and M.B.A. Oldstone for helpful suggestions and support. This is manuscript 13653-NP from The Scripps Research Institute.

	Footnotes

 
Address reprint requests to Claire F. Evans whose current address is Digital Gene Technologies Inc., 11149 N. Torrey Pines Rd., La Jolla, CA 92037. E-mail: cevans{at}dgt.com

Supported in part by a grant to C. F. E. from the National Multiple Sclerosis Society, and by National Institutes of Health grants NS37135 (to C. F. E.), AI43103 (to M. J. B.) and NS38719 (to M. B. A. Oldstone). J. M. R. was supported by NIH Training Grant 5 T32 AG00080–21 and a postdoctoral fellowship from the National Multiple Sclerosis Society.

Jeffrey M. Redwine’s current address is Neurome Inc., 11149 N. Torrey Pines Rd., La Jolla, CA 92037.

Accepted for publication July 2, 2001.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Lucchinetti CF, Bruck W, Rodriguez M, Lassman H: Distinct patterns of multiple sclerosis pathology indicates heterogeneity in pathogenesis. Brain Pathol 1996, 6:259-274[Medline]
2. Rodriguez M, Oleszak E, Leibowitz J: Theiler’s murine encephalomyelitis: a model of demyelination and persistence of virus. Crit Rev Immunol 1987, 7:325-365[Medline]
3. Lane TE, Liu MT, Chen BP, Asensio VC, Samawi RM, Paoletti AD, Campbell IL, Kunkel SL, Fox HS, Buchmeier MJ: A central role for CD4(+) T cells and RANTES in virus-induced central nervous system inflammation and demyelination. J Virol 2000, 74:1415-1424[Abstract/Free Full Text]
4. Lampson LA: Interpreting MHC class I expression and class I/class II reciprocity in the CNS: reconciling divergent findings. Microsc Res Tech 1995, 32:267-285[Medline]
5. Dalziel RG, Lampert PW, Talbot PJ, Buchmeier MJ: Site-specific alteration of murine hepatitis virus type-4 peplomer glycoprotein E2 results in reduced neurovirulence. J Virol 1986, 59:463-471[Abstract/Free Full Text]
6. Fazakerley JK, Parker SE, Bloom F, Buchmeier MJ: The V5A13.1 envelope glycoprotein deletion mutant of mouse hepatitis virus type-4 is neuroattenuated by its reduced rate of spread in the central nervous system. Virology 1992, 187:178-188[Medline]
7. Brooks BR, Walker DL: Progressive multifocal leukoencephalopathy. Neurol Clin 1984, 2:299-313[Medline]
8. Houtman JJ, Fleming JO: Pathogenesis of mouse hepatitis virus-induced demyelination. J Neurovirol 1996, 2:361-376[Medline]
9. Lin X, Pease LR, Murray PD, Rodriguez M: Theiler’s virus infection of genetically susceptible mice induces central nervous system-infiltrating CTLs with no apparent viral or major myelin antigenic specificity. J Immunol 1998, 160:5661-5668[Abstract/Free Full Text]
10. Rodriguez M, Sriram S: Successful therapy of Theiler’s virus-induced demyelination (DA strain) with monoclonal anti-Lyt-2 antibody. J Immunol 1988, 140:2950-2955[Abstract]
11. Murray PD, McGavern DB, Lin X, Njenga MK, Leibowitz J, Pease LR, Rodriguez M: Perforin-dependent neurologic injury in a viral model of multiple sclerosis. J Neurosci 1998, 18:7306-7314[Abstract/Free Full Text]
12. Dethlefs S, Brahic M, Larsson-Sciard EL: An early, abundant cytotoxic T-lymphocyte response against Theiler’s virus is critical for preventing viral persistence. J Virol 1997, 71:8875-8878[Abstract]
13. Lane TE, Asensio VC, Yu N, Paoletti AD, Campbell IL, Buchmeier MJ: Dynamic regulation of alpha- and beta-chemokine expression in the central nervous system during mouse hepatitis virus-induced demyelinating disease. J Immunol 1998, 160:970-978[Abstract/Free Full Text]
14. Stohlman SA, Bergmann CC, Van Der Veen RC, Hinton DR: Mouse hepatitis virus-specific cytotoxic T lymphocytes protect from lethal infection without eliminating virus from the central nervous system. J Virol 1995, 69:684-694[Abstract]
15. Suzumura A, Lavi E, Weiss SR, Silberberg DH: Coronavirus infection induces H-2 antigen expression on oligodendrocytes and astrocytes. Science 1986, 232:991-993[Abstract/Free Full Text]
16. Turnley AM, Miller JF, Bartlett PF: Regulation of MHC molecules on MBP positive oligodendrocytes in mice by IFN-gamma and TNF-alpha. Neurosci Lett 1991, 123:45-48[Medline]
17. Jurewicz A, Biddison WE, Antel JP: MHC class I-restricted lysis of human oligodendrocytes by myelin basic protein peptide-specific CD8 T lymphocytes. J Immunol 1998, 160:3056-3059[Abstract/Free Full Text]
18. Rodriguez M, Pierce ML, Howie EA: Immune response gene products (Ia antigens) on glial and endothelial cells in virus-induced demyelination. J Immunol 1987, 138:3438-3442[Abstract]
19. Horwitz MS, Evans CF, Klier G, Oldstone MBA: Detailed in vivo analysis of interferon-gamma induced MHC expression in the CNS: astrocytes fail to express MHC class I and II molecules. Lab Invest 1999, 79:235-242[Medline]
20. Joly E, Oldstone MBA: Neuronal cells are deficient in loading peptides onto MHC class I molecules. Neuron 1992, 8:1185-1190[Medline]
21. Pearce BD, Hobbs MV, McGraw TS, Buchmeier MJ: Cytokine induction during T-cell-mediated clearance of mouse hepatitis virus from neurons in vivo. J Virol 1994, 68:5483-5495[Abstract/Free Full Text]
22. Corriveau RA, Huh GS, Shatz CJ: Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. Neuron 1998, 21:505-520[Medline]
23. Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM, Shatz CJ: Functional requirement for class I MHC in CNS development and plasticity. Science 2000, 290:2155-2159[Abstract/Free Full Text]
24. Neumann H, Cavalie A, Jenne DE, Wekerle H: Induction of MHC class I genes in neurons. Science 1995, 269:549-552[Abstract/Free Full Text]
25. Neumann H, Schmidt H, Cavalie A, Jenne D, Wekerle H: Major histocompatibility complex (MHC) class I gene expression in single neurons of the central nervous system: differential regulation by interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha. J Exp Med 1997, 185:305-316[Abstract/Free Full Text]
26. Medana IM, Gallilmore A, Oxenius A, Martinic MMA, Wekerle H, Neumann H: MHC class I-restricted killing of neurons by virus-specific CD8 T lymphocytes is effected through the fas/fasL, but not the perforin pathway. Eur J Immunol 2000, 30:3623-3633[Medline]
27. Pereira RA, Simmons A: Cell surface expression of H2 antigens on primary sensory neurons in response to acute but not latent herpes simplex virus infection in vivo. J Virol 1999, 73:6484-6489[Abstract/Free Full Text]
28. Sun N, Grzybicki D, Castro RF, Murphy S, Perlman S: Activation of astrocytes in the spinal cord of mice chronically infected with a neurotropic coronavirus. Virology 1995, 213:482-493[Medline]
29. Vidovic M, Sparacio SM, Elovitz M, Benveniste EN: Induction and regulation of class II major histocompatibility complex mRNA expression in astrocytes by interferon-gamma and tumor necrosis factor-alpha. J Neuroimmunol 1990, 30:189-200[Medline]
30. Gilmore W, Correale J, Weiner LP: Coronavirus induction of class I major histocompatibility complex expression in murine astrocytes is virus strain specific. J Exp Med 1994, 180:1013-1023[Abstract/Free Full Text]
31. Massa PT: Specific suppression of major histocompatibility complex class I and class II genes in astrocytes by brain-enriched gangliosides. J Exp Med 1993, 178:1357-1363[Abstract/Free Full Text]
32. Tontsch U, Rott O: Intercellular regulation of major histocompatibility complex class I expression in neural cells. Immunology 1993, 80:507-509[Medline]
33. Williams K, Ulvestad E, Antel JP: B7/BB-1 antigen expression on adult human microglia studied in vitro and in situ. Eur J Immunol 1994, 24:3031-3037[Medline]
34. De Simone R, Giampaolo A, Giometto B, Gallo P, Levi G, Peschle C, Aloisi F: The costimulatory molecule B7 is expressed on human microglia in culture and in multiple sclerosis acute lesions. J Neuropathol Exp Neurol 1995, 54:175-187[Medline]
35. Santambrogio L, Pakaski M, Wong ML, Cipriani B, Brosnan CF, Lees MB, Dorf ME: Antigen presenting capacity of brain microvasculature in altered peptide ligand modulation of experimental allergic encephalomyelitis. J Neuroimmunol 1999, 93:81-91[Medline]
36. Gehrmann J, Matsumoto Y, Kreutzberg GW: Microglia: intrinsic immunoeffector cell of the brain. Brain Res Rev 1995, 20:269-287[Medline]
37. Godfraind C, Langreth SG, Cardellichio CB, Knobler R, Coutelier JP, Dubois-Dalcq M, Holmes KV: Tissue and cellular distribution of an adhesion molecule in the carcinoembryonic antigen family that serves as a receptor for mouse hepatitis virus. Lab Invest 1995, 73:615-627[Medline]
38. Godfraind C, Havaux N, Holmes KV, Coutelier JP: Role of virus receptor-bearing endothelial cells of the blood-brain barrier in preventing the spread of mouse hepatitis virus-A59 into the central nervous system. J Neurovirol 1997, 3:428-434[Medline]
39. Houtman JJ, Fleming JO: Dissociation of demyelination and viral clearance in congenitally immunodeficient mice infected with murine coronavirus JHM. J Neurovirol 1996, 2:101-110[Medline]
40. Vanderlugt CL, Begolka WS, Neville KL, Katz-Levy Y, Howard LM, Eagar TN, Bluestone JA, Miller SD: The functional significance of epitope spreading and its regulation by co-stimulatory molecules. Immunol Rev 1998, 164:63-72[Medline]

This article has been cited by other articles:

				T. W. Phares, C. Ramakrishna, G. I. Parra, A. Epstein, L. Chen, R. Atkinson, S. A. Stohlman, and C. C. Bergmann Target-Dependent B7-H1 Regulation Contributes to Clearance of Central Nervous Sysyem Infection and Dampens Morbidity J. Immunol., May 1, 2009; 182(9): 5430 - 5438. [Abstract] [Full Text] [PDF]

				K. Baur, M. Rauer, K. Richter, A. Pagenstecher, J. Gotz, J. Hausmann, and P. Staeheli Antiviral CD8 T Cells Recognize Borna Disease Virus Antigen Transgenically Expressed in either Neurons or Astrocytes J. Virol., March 15, 2008; 82(6): 3099 - 3108. [Abstract] [Full Text] [PDF]

				S. A. Stohlman, D. R. Hinton, B. Parra, R. Atkinson, and C. C. Bergmann CD4 T Cells Contribute to Virus Control and Pathology following Central Nervous System Infection with Neurotropic Mouse Hepatitis Virus J. Virol., March 1, 2008; 82(5): 2130 - 2139. [Abstract] [Full Text] [PDF]

				P. Saikali, J. P. Antel, J. Newcombe, Z. Chen, M. Freedman, M. Blain, R. Cayrol, A. Prat, J. A. Hall, and N. Arbour NKG2D-Mediated Cytotoxicity toward Oligodendrocytes Suggests a Mechanism for Tissue Injury in Multiple Sclerosis J. Neurosci., January 31, 2007; 27(5): 1220 - 1228. [Abstract] [Full Text] [PDF]

				J. M. Gonzalez, C. C. Bergmann, C. Ramakrishna, D. R. Hinton, R. Atkinson, J. Hoskin, W. B. Macklin, and S. A. Stohlman Inhibition of Interferon-{gamma} Signaling in Oligodendroglia Delays Coronavirus Clearance without Altering Demyelination Am. J. Pathol., March 1, 2006; 168(3): 796 - 804. [Abstract] [Full Text] [PDF]

				C. Ramakrishna, R. A. Atkinson, S. A. Stohlman, and C. C. Bergmann Vaccine-Induced Memory CD8+ T Cells Cannot Prevent Central Nervous System Virus Reactivation. J. Immunol., March 1, 2006; 176(5): 3062 - 3069. [Abstract] [Full Text] [PDF]

				E Fainardi, R Rizzo, L Melchiorri, M Castellazzi, E Paolino, M R Tola, E Granieri, and O R Baricordi Intrathecal synthesis of soluble HLA-G and HLA-I molecules are reciprocally associated to clinical and MRI activity in patients with multiple sclerosis Multiple Sclerosis, February 1, 2006; 12(1): 2 - 12. [Abstract] [PDF]

				J. D. Rempel, L. A. Quina, P. K. Blakely-Gonzales, M. J. Buchmeier, and D. L. Gruol Viral Induction of Central Nervous System Innate Immune Responses J. Virol., April 1, 2005; 79(7): 4369 - 4381. [Abstract] [Full Text] [PDF]

				A. Alba, M. C. Puertas, J. Carrillo, R. Planas, R. Ampudia, X. Pastor, F. Bosch, R. Pujol-Borrell, J. Verdaguer, and M. Vives-Pi IFN{beta} Accelerates Autoimmune Type 1 Diabetes in Nonobese Diabetic Mice and Breaks the Tolerance to {beta} Cells in Nondiabetes-Prone Mice J. Immunol., December 1, 2004; 173(11): 6667 - 6675. [Abstract] [Full Text] [PDF]

				S. C. Byram, M. J. Carson, C. A. DeBoy, C. J. Serpe, V. M. Sanders, and K. J. Jones CD4-Positive T Cell-Mediated Neuroprotection Requires Dual Compartment Antigen Presentation J. Neurosci., May 5, 2004; 24(18): 4333 - 4339. [Abstract] [Full Text] [PDF]

				C. C. Bergmann, B. Parra, D. R. Hinton, C. Ramakrishna, K. C. Dowdell, and S. A. Stohlman Perforin and Gamma Interferon-Mediated Control of Coronavirus Central Nervous System Infection by CD8 T Cells in the Absence of CD4 T Cells J. Virol., February 15, 2004; 78(4): 1739 - 1750. [Abstract] [Full Text] [PDF]

				E. L. Oleszak, J. R. Chang, H. Friedman, C. D. Katsetos, and C. D. Platsoucas Theiler's Virus Infection: a Model for Multiple Sclerosis Clin. Microbiol. Rev., January 1, 2004; 17(1): 174 - 207. [Abstract] [Full Text] [PDF]

				F. Giuliani, C. G. Goodyer, J. P. Antel, and V. W. Yong Vulnerability of Human Neurons to T Cell-Mediated Cytotoxicity J. Immunol., July 1, 2003; 171(1): 368 - 379. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Redwine, J. M. Articles by Evans, C. F. Search for Related Content PubMed PubMed Citation Articles by Redwine, J. M. Articles by Evans, C. F.