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• W2083002110 abstract "We examine here the outcome of viral encephalomyelitis [mouse hepatitis virus (MHV) A59, Theiler's encephalomyelitis virus, and Coxsackievirus B3] in mice with autoantibodies to a central nervous system (CNS)-specific antigen, myelin oligodendrocyte glycoprotein, that usually develop no clinical disease. Morbidity and mortality of the acute viral CNS disease was augmented by the presence of the autoantibodies in all three viral infections. Transfer of serum containing the autoantibodies at the time of infection with MHV was sufficient to reproduce the exacerbated disease. The presence of the autoantibodies was found to result in increased infiltration of mononuclear cells into the brain. Early demyelination was severely augmented in brains and spinal cords of MHV-infected mice with CNS-specific autoantibodies. The antibody-mediated exacerbation was shown to be independent of the complement system but to require expression of Fc receptors, because it was observed in C′-3-deficient but not in Fc receptor-deficient mice. Our study illustrates the possibility that infections can lead to much more profound immunopathology in the presence of an otherwise latent autoimmune condition. We examine here the outcome of viral encephalomyelitis [mouse hepatitis virus (MHV) A59, Theiler's encephalomyelitis virus, and Coxsackievirus B3] in mice with autoantibodies to a central nervous system (CNS)-specific antigen, myelin oligodendrocyte glycoprotein, that usually develop no clinical disease. Morbidity and mortality of the acute viral CNS disease was augmented by the presence of the autoantibodies in all three viral infections. Transfer of serum containing the autoantibodies at the time of infection with MHV was sufficient to reproduce the exacerbated disease. The presence of the autoantibodies was found to result in increased infiltration of mononuclear cells into the brain. Early demyelination was severely augmented in brains and spinal cords of MHV-infected mice with CNS-specific autoantibodies. The antibody-mediated exacerbation was shown to be independent of the complement system but to require expression of Fc receptors, because it was observed in C′-3-deficient but not in Fc receptor-deficient mice. Our study illustrates the possibility that infections can lead to much more profound immunopathology in the presence of an otherwise latent autoimmune condition. It is now well established in animal models that infectious organisms can trigger or augment immune responses to self-antigens, by mechanisms such as molecular mimicry or bystander activation (see review1von Herrath MG Fujinami RS Whitton JL Microorganisms and autoimmunity: making the barren field fertile?.Nat Rev Microbiol. 2003; 1: 151-157Crossref PubMed Scopus (207) Google Scholar). However, autoimmunity does not always result in clinically apparent disease, and cumulative infections by the same or unrelated agents may be required to unmask a pre-existing autoimmune process.1von Herrath MG Fujinami RS Whitton JL Microorganisms and autoimmunity: making the barren field fertile?.Nat Rev Microbiol. 2003; 1: 151-157Crossref PubMed Scopus (207) Google Scholar Conversely, a viral infection could take a worsened course in autoimmune-prone individuals. It has been shown that infections can provoke relapses or worsen autoimmune conditions in animal models.2Christen U Edelmann KH McGavern DB Wolfe T Coon B Teague MK Miller SD Oldstone MB von Herrath MG A viral epitope that mimics a self antigen can accelerate but not initiate autoimmune diabetes.J Clin Invest. 2004; 114: 1290-1298Crossref PubMed Scopus (102) Google Scholar, 3Panoutsakopoulou V Sanchirico ME Huster KM Jansson M Granucci F Shim DJ Wucherpfennig KW Cantor H Analysis of the relationship between viral infection and autoimmune disease.Immunity. 2001; 15: 137-147Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 4McCoy L Tsunoda I Fujinami RS Multiple sclerosis and virus induced immune responses: autoimmunity can be primed by molecular mimicry and augmented by bystander activation.Autoimmunity. 2006; 39: 9-19Crossref PubMed Scopus (105) Google Scholar This is consistent with reports showing that common infections augment the risk for or the severity of relapses in multiple sclerosis (MS) patients.5Buljevac D Flach HZ Hop WC Hijdra D Laman JD Savelkoul HF van Der Meche FG van Doorn PA Hintzen RQ Prospective study on the relationship between infections and multiple sclerosis exacerbations.Brain. 2002; 125: 952-960Crossref PubMed Scopus (337) Google Scholar, 6Andersen O Lygner PE Bergstrom T Andersson M Vahlne A Viral infections trigger multiple sclerosis relapses: a prospective seroepidemiological study.J Neurol. 1993; 240: 417-422Crossref PubMed Scopus (235) Google Scholar The aforementioned animal reports all studied T-cell-mediated autoimmune responses, but autoantibodies also have an important pathogenic potential (see review7Martin F Chan AC B cell immunobiology in disease: evolving concepts from the clinic.Annu Rev Immunol. 2006; 24: 467-496Crossref PubMed Scopus (297) Google Scholar). In the central nervous system (CNS), autoantibodies to myelin components and to myelin oligodendrocyte glycoprotein (MOG) in particular can play a damaging role. MOG-specific antibodies have been shown to play a major role in the murine model of MS, experimental autoimmune encephalomyelitis (EAE),8Lyons JA Ramsbottom MJ Cross AH Critical role of antigen-specific antibody in experimental autoimmune encephalomyelitis induced by recombinant myelin oligodendrocyte glycoprotein.Eur J Immunol. 2002; 32: 1905-1913Crossref PubMed Scopus (148) Google Scholar and have been clearly associated with demyelinating lesions in MS patients.9Genain CP Cannella B Hauser SL Raine CS Identification of autoantibodies associated with myelin damage in multiple sclerosis.Nat Med. 1999; 5: 170-175Crossref PubMed Scopus (778) Google Scholar They are thus likely to mediate some of the pathology, at least in the subset of patients with lesions presenting antibody depositions.10Lucchinetti C Bruck W Parisi J Scheithauer B Rodriguez M Lassmann H Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination.Ann Neurol. 2000; 47: 707-717Crossref PubMed Scopus (2723) Google Scholar However, the presence of antibodies specific for MOG or other CNS antigens is detected not only in MS patients but also in healthy subjects, albeit with a lower frequency,11Cross AH Trotter JL Lyons J B cells and antibodies in CNS demyelinating disease.J Neuroimmunol. 2001; 112: 1-14Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar and it is thus likely that additional triggers may be required for disease development. Litzenburger et al12Litzenburger T Fassler R Bauer J Lassmann H Linington C Wekerle H Iglesias A B lymphocytes producing demyelinating autoantibodies: development and function in gene-targeted transgenic mice.J Exp Med. 1998; 188: 169-180Crossref PubMed Scopus (201) Google Scholar previously demonstrated that transgenic mice, in which the rearranged VDJ region of a MOG-specific monoclonal antibody H chain replaced the germline JH locus [anti-MOG immunoglobulin (Ig) “knock-in” mice, also referred to as THMOG mice in the present report], exhibited an exacerbated form of EAE. However, without additional autoantigenic immunization, the THMOG mice do not develop spontaneous clinical disease, despite the presence of autoreactive B cells and the release of MOG-specific IgG and IgM in the serum.12Litzenburger T Fassler R Bauer J Lassmann H Linington C Wekerle H Iglesias A B lymphocytes producing demyelinating autoantibodies: development and function in gene-targeted transgenic mice.J Exp Med. 1998; 188: 169-180Crossref PubMed Scopus (201) Google Scholar Because the transgenic B cells in THMOG can undergo normal differentiation and maturation, autoantibodies of different classes and subclasses, membrane-associated or secreted, are generated. Thus, all of the possible interactions of the autoreactive Igs with the other effectors of the immune system can occur in these mice. Therefore, they constituted a good model to evaluate the hypothesis that a viral infection of the CNS would lead to worsened immunopathology and disease, if it were to be superimposed on an underlying humoral autoimmune condition. The neurotropic strains of murine coronaviruses mouse hepatitis virus (MHV) A59, MHV JHM, and related mutants have provided an informative model for the pathogenesis of virus-induced encephalitis and demyelination (see reviews13Lane TE Buchmeier MJ Murine coronavirus infection: a paradigm for virus-induced demyelinating disease.Trends Microbiol. 1997; 5: 9-14Abstract Full Text PDF PubMed Scopus (100) Google Scholar, 14Matthews AE Weiss SR Paterson Y Murine hepatitis virus: a model for virus-induced CNS demyelination.J Neurovirol. 2002; 8: 76-85Crossref PubMed Scopus (67) Google Scholar). Mice infected with MHV A59 typically undergo a brief period of acute encephalomyelitis followed by an extended period of chronic demyelination. During the acute phase of the infection, the virus can be found in astrocytes, oligodendrocytes, and neurons.15Sun N Perlman S Spread of a neurotropic coronavirus to spinal cord white matter via neurons and astrocytes.J Virol. 1995; 69: 633-641PubMed Google Scholar T cells are responsible for the initial control of the infection,16Gombold JL Sutherland RM Lavi E Paterson Y Weiss SR Mouse hepatitis virus A59-induced demyelination can occur in the absence of CD8+ T cells.Microb Pathog. 1995; 18: 211-221Crossref PubMed Scopus (42) Google Scholar but antibodies are required for complete clearance of the virus and prevention of re-emergence.17Bergmann CC Ramakrishna C Kornacki M Stohlman SA Impaired T cell immunity in B cell-deficient mice following viral central nervous system infection.J Immunol. 2001; 167: 1575-1583PubMed Google Scholar, 18Dandekar AA Jacobsen G Waldschmidt TJ Perlman S Antibody-mediated protection against cytotoxic T-cell escape in coronavirus-induced demyelination.J Virol. 2003; 77: 11867-11874Crossref PubMed Scopus (14) Google Scholar During the second phase of the disease, macrophages19Wu GF Perlman S Macrophage infiltration, but not apoptosis, is correlated with immune-mediated demyelination following murine infection with a neurotropic coronavirus.J Virol. 1999; 73: 8771-8780PubMed Google Scholar but also CD4+20Lane 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: 1415-1424Crossref PubMed Scopus (205) Google Scholar, 21Wu GF Dandekar AA Pewe L Perlman S CD4 and CD8 T cells have redundant but not identical roles in virus-induced demyelination.J Immunol. 2000; 165: 2278-2286PubMed Google Scholar and CD8+21Wu GF Dandekar AA Pewe L Perlman S CD4 and CD8 T cells have redundant but not identical roles in virus-induced demyelination.J Immunol. 2000; 165: 2278-2286PubMed Google Scholar T cells have been shown to mediate the demyelination. We report here that intracranial infection of THMOG mice with MHV A59 results in accelerated kinetics of onset, severity of clinical disease, and increased death in THMOG compared with wild-type mice. The exacerbation of the CNS disease was shown to be transferable by the autoantibodies and was observed in other models of viral encephalitis as well. Immunohistochemical examination of brain sections and fluorescence-activated cell sorting analysis of infiltrating cells in brains showed an overall increase of the number of mononuclear cells. Demyelination was found to be augmented in brains and spinal cords of mice with anti-MOG antibodies. Fc receptor-deficient mice were shown to be protected from the autoantibody-mediated enhanced pathology, indicating that the mechanism for the exacerbation involved Fc-mediated effects. Thus, autoantibodies specific for antigens in the immunologically privileged CNS in combination with local, virally induced inflammation and tissue destruction can lead to increased sensitivity of disease. THMOG mice encode the rearranged cDNA of the pathogenic MOG-specific monoclonal antibody 8.18C5 in place of the germline JH locus.12Litzenburger T Fassler R Bauer J Lassmann H Linington C Wekerle H Iglesias A B lymphocytes producing demyelinating autoantibodies: development and function in gene-targeted transgenic mice.J Exp Med. 1998; 188: 169-180Crossref PubMed Scopus (201) Google Scholar This results in MOG-binding Ig surface expression on about one-third of the B cells that can undergo normal class-switching and secretion and affinity maturation after encountering the antigen.12Litzenburger T Fassler R Bauer J Lassmann H Linington C Wekerle H Iglesias A B lymphocytes producing demyelinating autoantibodies: development and function in gene-targeted transgenic mice.J Exp Med. 1998; 188: 169-180Crossref PubMed Scopus (201) Google Scholar C57Bl/6 control mice were obtained from The Scripps Research Institute breeding facility. CD4-KO and CD8-KO mice obtained from Dan Littman (Sloan-Kettering Institute, New York, NY) and C′-3-KO and inducible NO synthase (iNOS)-KO mice purchased from the Jackson Laboratory (Bar Harbor, ME) (all on a C57Bl/6 background) were bred at Scripps. Fcer1-KO mice (583-M, C57Bl/6 background) were purchased from Taconics Transgenics (Germantown, NY). All experiments were conducted in accordance with the Scripps Research Institute Institutional Animal Care and Use Committee guidelines. Mouse hepatitis virus-attenuated neurotropic isolate A-59 was grown on delayed brain tumor (DBT) cells. Theiler's murine encephalomyelitis virus (TMEV) Daniel's strain obtained from Dr. D. McGavern (The Scripps Research Institute) was grown on BHK21 cells. Viral titers were determined by plaque assay on DBT cells. Coxsackievirus B3 was grown and titered as previously described.22Feuer R Mena I Pagarigan RR Harkins S Hassett DE Whitton JL Coxsackievirus B3 and the neonatal CNS: the roles of stem cells, developing neurons, and apoptosis in infection, viral dissemination, and disease.Am J Pathol. 2003; 163: 1379-1393Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar Pichinde virus stocks were grown and titrated on Vero cells. Isoflurane-anesthetized mice were inoculated with 30 μl containing the virus diluted in sterile phosphate-buffered saline (PBS), using a 27-gauge needle with no more than 2-mm penetration of the cranium just lateral of the midline. Signs of clinical CNS disease were monitored daily and scored using standards as described in Figure 1. Serum from THMOG mice was obtained by retroorbital bleeding or cardiac puncture and pooled to be used for transfer experiments. Recipient animals received 500 μl of the serum pool intraperitoneally at the time of the viral infection, whereas controls received the same volume of normal mouse serum or in later repeat experiments, PBS, because normal serum was found to have no measurable effect on the course of the infection. Mice were euthanized with an overdose of chloral hydrate diluted in saline and perfused with 10 ml of 10% formalin. After fixation overnight, brains and spinal cord paraffin-embedded sections were stained by hematoxylin and eosin (H&E) (to evaluate infiltration) and luxol fast blue (for demyelination). Brains from PBS-perfused mice were mechanically disrupted between frosted slides. The lipid components and debris were removed after collagenase (Sigma C-6885) treatment and centrifugation through Percoll (Sigma). Brains of groups of five or six mice were pooled to obtain enough mononuclear cells to assay. Fc receptors were blocked (14-0161; eBiosciences, San Diego, CA), and cells were stained with antibodies directly coupled to fluorochromes. Data were acquired on a BD FACSCalibur. CD11b+ (for macrophages/microglia) or CD45+ (for the other cell types) cells were gated to analyze the expression of specific markers. All antibodies were obtained from eBiosciences. Significance was evaluated using Mann-Whitney (for day-by-day differences between clinical scores, viral titers or ratio of areas affected by demyelination), Fisher's exact test (for incidence of disease in the autoimmune mice when there was none in the control group), or log-rank survival (for differences in mortality over entire experiments) tests using the GraphPad/Instat software. THMOG and C57Bl/6 mice were infected with three increasing doses of MHV, strain A59. Typical symptoms of encephalitis were observed in both groups and for each of the viral doses. However, clinical signs of CNS disease occurred earlier and were stronger in the THMOG mice compared with Bl6 controls (Figure 1, top). The three viral doses also resulted in an increased death rate in THMOG mice in comparison with controls (Figure 1, bottom). To rule out that the enhanced disease observed in the transgenic mice could have been caused by the absence of a functional antibody repertoire or any other possible genetic defect, we first examined the outcome of the CNS infection by MHV A59 in heterozygous THMOG mice obtained by backcrossing the transgenic mice with the parental C57Bl/6 strain. The acute encephalitis was also exacerbated in these mice compared with controls (Figure 2A), indicating that the aggravation of disease was probably due to the presence of CNS-specific B cells or autoantibodies. We then examined whether the transgenic B cells, the autoantibodies, or both were responsible for the increased CNS disease. We first transferred purified THMOG B cells to WT mice and observed some exacerbation of the CNS disease compared with controls receiving wild-type B cells, although to a much lesser extent than in the original THMOG animals (data not shown). However, when serum from uninfected THMOG mice was transferred to wild-type recipients at the time of infection with MHV, an exacerbation of CNS disease similar to the levels found in MHV-infected THMOG mice was observed (Figure 2B). In addition, transfer of Protein-A purified antibodies from the serum of THMOG resulted in a comparable exacerbation of MHV-induced encephalitis as the serum (data not shown). These studies clearly mapped the cause for enhancement of the virally induced CNS disease in THMOG mice to the anti-MOG autoantibodies. We then tested the effects of the presence of the anti-MOG antibodies in other nonlethal viral models of CNS infection to determine whether viruses from different families and with different degrees of pathogenicity could be exacerbated by the presence of anti-MOG autoantibodies. Although no difference was observed in the clinically silent encephalitis induced by 105 plaque-forming units (PFU) of Pichinde virus, an exacerbation of the CNS disease by the autoantibodies was observed in mice infected with both TMEV and CV B3 (Table 1). C57Bl/6 are genetically resistant to TMEV infection, ie, the virus replicates but does not cause detectable inflammation or demyelination,23Rodriguez M Leibowitz J David CS Susceptibility to Theiler's virus-induced demyelination: mapping of the gene within the H-2D region.J Exp Med. 1986; 163: 620-631Crossref PubMed Scopus (171) Google Scholar and as expected, no behavioral signs of acute CNS disease were seen in the control mice. However, 44% of the THMOG heterozygous animals developed a clinically evident disease, and one-half of the sick animals died within the 1st week (Table 1). Likewise, no signs of disease could be observed in any of the 2-week-old control pups infected with 103 or 104 PFU CV B3, whereas 20 or 100% of the heterozygous autoimmune mice became sick, respectively (Table 1). This was reflected by a profound difference in the weights of the two groups when injected with 104 PFU CV B3: all of the pups initially gained weight at an equal rate (111 ± 3% in THMOG± versus 108 ± 4% in controls at 5 days after infection). The transgenic animals then started to grow at a slower rate and eventually lost weight, resulting in an average of 109 ± 2% of their starting weight at day 10 after infection, versus 137 ± 1% in the controls (P < 0.01, Mann-Whitney test). These experiments show that the adverse effects of pre-existing autoantibodies can have an impact on the outcome of a variety of viral encephalitis. They also show that exacerbation can occur over a large spectrum of clinical manifestations of encephalitis: Autoantibodies can transform a clinically silent infection into a symptomatic disease (TMEV and CV B3), transform a mild CNS pathology into a lethal one (MHV A59, 10 PFU), or accelerate the clinical course (MHV A59, 1000 PFU).Table 1Outcome of Other Viral CNS Infections in Control and THMOG Heterozygous MiceVirusDose (PFU)C57Bl/6 controlsTHMOG +/−Clinical signsMortalityClinical signsMortality (days)‡Number of deaths over total number of animals studied and timing of death.IncidenceScoreIncidence*Number of mice with detectable clinical disease over total number in each group.Score (days)†Highest average clinical score for each group, and the day after infection when it was observed.Pichinde10E50/4N.A.0/40/4N.A.0/4TMEV10E50/5N.A.0/54/90.83 ± 0.59 (5)2/9 (5, 7)CV B310E30/5N.A.0/52/50.70 ± 0.19 (15)1/5 (16)10E40/5N.A.0/57/7§P < 0.01, Fisher's exact test.1.5 ± 0.14 (9)0/7The viruses were injected i.c. at the indicated doses in 2-week-old (CV B3) or 6-week-old (Pichinde and TMEV) mice. The table summarizes the follow-up of the clinical status and mortality in control (C57Bl/6) and autoimmune (heterozygous THMOG) animals. N.A., not applicable.* Number of mice with detectable clinical disease over total number in each group.† Highest average clinical score for each group, and the day after infection when it was observed.‡ Number of deaths over total number of animals studied and timing of death.§ P < 0.01, Fisher's exact test. Open table in a new tab The viruses were injected i.c. at the indicated doses in 2-week-old (CV B3) or 6-week-old (Pichinde and TMEV) mice. The table summarizes the follow-up of the clinical status and mortality in control (C57Bl/6) and autoimmune (heterozygous THMOG) animals. N.A., not applicable. To test whether viral replication was required to trigger disease in mice with CNS autoantibodies, we injected 5 × 105 PFU equivalent of UV-inactivated MHV A59, which did not cause any detectable clinical disease in homozygous THMOG mice over a 21-day period (n = 2; data not shown). Likewise, no sign of clinical disease was detected in such mice on infection by 100 PFU of MHV A59 via the intraperitoneal route (n = 2; data not shown), a dose that results in a clinically silent hepatitis with active viral replication for over a week in C57Bl/6 mice (R.B. and M.J.B., personal observations). Thus, neither the disruption of the blood brain barrier, viral antigens in the CNS, nor infection of a peripheral organ elicited enhanced immunopathology in THMOG mice, showing that active viral replication in the CNS was required. Viral titers in the brains of control C57Bl/6 mice and mice with autoantibodies (THMOG homo- and heterozygous mice and C57Bl/6 recipients of anti-MOG serum) were then compared at different time points. No significant difference was found in the titers in mice with autoantibodies compared with the controls from day 3 (data not shown) up to days 5 and 6 (Figure 3) after the infection, which indicates that the virus replicates initially at similar rates in all of the animals. However, although the titers started to decrease in both groups at day 7, the reduction of the viral load was less pronounced in mice with anti-MOG autoantibodies compared with controls (Figure 3). Thus, the ability to control the viral CNS infection is slightly impaired in the presence of the CNS autoantibodies. To exclude any systemic defect on the cytotoxic immune response to MHV in the MOG-Ig mice, we compared the frequencies of virus-specific CD8+ T cells in the spleen of controls and recipients of anti-MOG serum by enzyme-linked immunospot (ELISPOT) assays, which were performed as described previously.24Botten J Alexander J Pasquetto V Barrowman P Ting J Peters B Southwood S Stewart B Rodriguez-Carreno MP Mothe B Whitton JL Sette A Buchmeier MJ Identification of protective Lassa virus epitopes that are restricted by HLA-A2.J Virol. 2006; 80: 8351-8361Crossref PubMed Scopus (53) Google Scholar We found no significant difference in the frequencies of purified CD8+ cells that responded to the immunodominant MHV A59 epitope S598-605, which is located in the viral envelope protein, at day 5 or 7 after infection (data not shown). Thus, the autoantibodies did not alter the systemic antiviral cytotoxic immune response. To study the mechanisms responsible for the autoantibody-mediated augmentation of viral encephalitis, we chose a model that results in severe outcome in a majority of the autoimmune mice while sparing most of the control animals, and the following experiments have thus all been performed with 10 PFU of MHV A59. H&E-stained brain and spinal cord sections obtained from controls and mice with autoantibodies were examined for the presence of infiltrating cells. The degree of infiltration appeared to be augmented in mice with autoantibodies compared with control animals at days 7 to 9 after infection. Both the frequency of perivascular cuffing and the number of infiltrating cells within inflammation areas were higher in mice with autoantibodies compared with controls (Figure 4, A–E). Morphologically, the infiltrates appeared to be composed of mixed inflammatory cell populations, with numerous neutrophils being seen both in the controls and in the mice with autoantibodies (Figure 4, F–G). To determine more precisely the nature of the infiltrating cells, we performed flow cytometry experiments on mononuclear cells purified from infected brains. Enumeration of the purified cells from individual brains confirmed the increased cellularity in the brains of mice with autoantibodies (Figure 4H). The presence of the autoantibodies resulted in no significant differences in the numbers of T or B lymphocytes (Figure 4I). On the contrary, the frequency of NK cells and blood-borne macrophages was somewhat more elevated in mice with autoantibodies (Figure 4I). Altogether, these results show that brain infiltration of lymphocytes, and in particular cells bearing Fc receptors, is augmented by the presence of anti-MOG antibodies during MHV A59 encephalitis. Both MHV A59 and anti-MOG antibodies (in EAE models) can provoke demyelination on their own. To evaluate the eventual additive effects of their joint presence in the CNS, we examined sections from brains and spinal cords of MHV-infected autoimmune and control mice for the presence of demyelinating lesions at 7 to 9 days after infection. The vast majority of the demyelinating areas were found in the central white matter of the cerebellum, in the brainstem, and in the region surrounding the third ventricle, both in controls and in mice with autoantibodies, but the extent of the lesions was found to be augmented in the latter group. In wild-type mice brains, small lesions were detected in a majority of the animals, but the mice with autoantibodies displayed lesions that were both more widespread in the tissue and larger in size (Figure 5A, left panel). This difference was even more pronounced in spinal cords, with only a small subset of the control mice displaying lesions at 7 to 10 days after infection [Figure 5, A (right panel) and B], whereas most animals with autoantibodies showed heavy demyelination in coronal (Figure 5A, right panel) and longitudinal (Figure 5, C and D) sections. These results show that demyelination plays a role in the enhancement of the CNS disease in our model. To investigate the possible involvement of different effectors that have been associated with demyelination and CNS pathology in other models, we compared the outcome of CNS infection by MHV A59 in the presence or absence of anti-MOG antibodies in different KO mouse models. In the absence of either the CD4+ or the CD8+ T cells, control of the MHV A59 infection of the CNS is impaired. The mortality was found to be much higher for the control group in CD8 KO mice than what we had observed in WT C57Bl/6 mice. However, an exacerbation of the disease in the presence of autoantibodies was still observed in the absence of CD4 or CD8, both at the clinical (data not shown) and survival (Table 2) levels. Likewise, the exacerbation of CNS disease was still evident in the absence of a functional complement system in C′-3 KO mice (Table 2). Last, in mice deficient in iNOS, all of the controls survived, whereas all of the mice transferred with anti-MOG serum succumbed to the infection (Table 2). These results show that neither CD4 T cells, CD8 T cells, complement, nor iNOS alone is responsible for the autoantibody-mediated pathology.Table 2Autoantibodies Exacerbate MHV A59 Encephalitis in KO Mice ModelsMock transferAnti-MOG serum transferCD4 KO2/129/13*P < 0.05.CD8 KO6/109/10†P = 0.063.C′-3 KO3/118/11*P < 0.05.iNOS KO0/66/6‡P < 0.001.The mortality of CD4 KO, iNOS KO, and C′-3 KO mice infected with 10 PFU of MHV A59 was significantly augmented in the presence of anti-MOG antibodies. The absence of CD8+ cells results in higher fatalities in the control group than in wild-type mice, but some exacerbation was still observed upon transfer of autoimmune serum.* P < 0.05.† P = 0.063.‡ P < 0.001. Open table in a new tab The mortality of CD4 KO, iNOS KO, and C′-3 KO mice infected with 10 PFU of MHV A59 was significantly augmented in the presence of anti-MOG antibodies. The absence of CD8+ cells results in higher fatalities in the control group than in wild-type mice, but some exacerbation was still observed up" @default.
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• W2083002110 title "Exacerbated Pathology of Viral Encephalitis in Mice with Central Nervous System-Specific Autoantibodies" @default.
• W2083002110 cites W1479712964 @default.
• W2083002110 cites W1483565518 @default.
• W2083002110 cites W1486125213 @default.
• W2083002110 cites W1563564485 @default.
• W2083002110 cites W1966291398 @default.
• W2083002110 cites W1991204721 @default.
• W2083002110 cites W1993719044 @default.
• W2083002110 cites W2008126075 @default.
• W2083002110 cites W2014220557 @default.
• W2083002110 cites W2029232806 @default.
• W2083002110 cites W2030834650 @default.
• W2083002110 cites W2032582850 @default.
• W2083002110 cites W2037320008 @default.
• W2083002110 cites W2049460970 @default.
• W2083002110 cites W2050170323 @default.
• W2083002110 cites W2050348658 @default.
• W2083002110 cites W2074769546 @default.
• W2083002110 cites W2086080135 @default.
• W2083002110 cites W2086518669 @default.
• W2083002110 cites W2093860288 @default.
• W2083002110 cites W2099049360 @default.
• W2083002110 cites W2099895225 @default.
• W2083002110 cites W2102697241 @default.
• W2083002110 cites W2118966296 @default.
• W2083002110 cites W2129163782 @default.
• W2083002110 cites W2136716619 @default.
• W2083002110 cites W2147062889 @default.
• W2083002110 cites W2148010692 @default.
• W2083002110 cites W2148443138 @default.
• W2083002110 cites W2154119643 @default.
• W2083002110 cites W2154319889 @default.
• W2083002110 cites W2156005606 @default.
• W2083002110 cites W2159265131 @default.
• W2083002110 cites W2163745551 @default.
• W2083002110 cites W2166213347 @default.
• W2083002110 cites W2171925564 @default.
• W2083002110 cites W4232105308 @default.
• W2083002110 doi "https://doi.org/10.2353/ajpath.2007.060893" @default.
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