Neuropathologic variations in experimental allergic encephalomyelitis; hemorrhagic encephalomyelitis, perivenous encephalomyelitis, diffuse encephalomyelitis, patchy gliosis.
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Analysis of the hemagglutination activity domains of the Venezuelan equine encephalomyelitis and eastern equine encephalomyelitis viruses.
The hemagglutination (HA) domains of the Venezuelan equine encephalomyelitis (VEE) and the eastern equine encephalomyelitis (EEE) viruses providing the interaction of virions and red blood cells were studied with the use of a panel of 17 hemagglutination inhibition (HI) monoclonal antibodies (MAbs). A highly conserved domain (C domain) forming alphavirus-group-reactive MAbs was identified in the E2 protein of the VEE and EEE viruses. These MAbs inhibited HA of the western equine encephalomyelitis, Semliki Forest, Sindbis, Getah, Aura, Chikungunya and Pixuna viruses. The involvement of amino acid residues 59 and 232 in the formation of the C region was demonstrated by sequencing the gene encoding the E2 protein of three escape variants of the VEE virus.
Alphavirus↗
Hyperacute experimental allergic encephalomyelitis in rhesus monkeys as a model of acute necrotizing hemorrhagic encephalomyelitis.
A comparative study of clinical and morphological findings in three fatal cases of acute necrotizing hemorrhagic encephalomyelitis (ANHE) and hyperacute experimental allergic encephalomyelitis (HEAE) in rhesus monkeys is reported. In all cases ANHE was characterized clinically by definite prodromal respiratory infection. The course was rapidly progressive with fatal termination. The salient histopathological changes were necrosis of blood vessels with plasma exudation and fibrin impregnation, hemorrhages and inflammatory reaction in the damaged cerebral tissue. Perivascular lymphoid histiocytic infiltration with glial proliferation was also noted in all cases. Numerous compound granular cells were found in one case. HEAE was detected in five rhesus monkeys immunized with homological spinal cord emulsion with complete Freund adjuvant. The illness was acute or subacute and the course was rapidly progressive with a fatal end. There was multiple necrosis of small blood vessels with plasma exudation, fibrin impregnation and massive neutrophila infiltration of the damaged brain tissue in all rhesus monkeys with HEAE. There was also widespread glial proliferation and numerous compound granular cells alongside with necrosis of blood vessels in the brain. These findings suggest that HEAE in rhesus monkeys can be viewed as an adequate model of ANHE.
Adolescent↗
Host genetic regulation of acute MHV-4 viral encephalomyelitis and acute experimental autoimmune encephalomyelitis in (BALB/cKe x SJL/J) recombinant-inbred mice.
In the present report we provide the strain distribution patterns of susceptibility to acute mouse hepatitis virus type-4 (MHV-4) encephalomyelitis, acute experimental allergic encephalomyelitis (EAE) and vasoactive amine sensitivity (VAAS) for 9 (CXJ) recombinant-inbred strains between BALB/cKe (C) and SJL/J(J) mice. We confirm that susceptibility to MHV-4 is not linked to the H-2 complex, and that all strains susceptible to acute EAE have both a responder H-2 haplotype (H-2s or H-2d) and induced (B. pertussis) VAAS. In addition, we provide evidence that susceptibility to acute EAE induction is controlled by an additional presently unmapped locus and that an EAE-like histopathological disease does not usually follow MHV-4 infection intracerebrally in animals susceptible to MHV-4, acute EAE and induced VAAS.
Animals↗
Two models of multiple sclerosis: experimental allergic encephalomyelitis (EAE) and Theiler's murine encephalomyelitis virus (TMEV) infection. A pathological and immunological comparison.
Theiler's murine encephalomyelitis virus (TMEV) infection and experimental allergic encephalomyelitis (EAE) are considered among the best models of human multiple sclerosis (MS). In both models, clinical disease is characterized by paralysis, while pathological changes consist of inflammatory demyelination. In both models there is a genetic influence on susceptibility/resistance to the development of disease. This has been thoroughly studied in TMEV infection, and it has been found to depend on both major histocompatibility complex (MHC) and non-MHC genes. At least four genes have been so far identified. Because of this genetic influence, some strains of mice are more susceptible to both clinical and pathological changes than others, and susceptibility appears to best correlate with the ability of a certain murine strain to develop a delayed-type hypersensitivity (DTH) response to viral antigens. We have also observed that even among mice which are equally susceptible clinically, striking differences may be seen under pathological examination. These consist of different gradients of severity of inflammation, particularly in regards to the macrophage component. There is an inverse relationship between the number of macrophages, and their length of stay in the CNS, and the ability of mice to remyelinate their lesions. The most severe lesions are in SJL/J mice, and remyelination in this strain is extremely poor. The least severe lesions in terms of macrophage invasion are in strains such as NZW and RIIIS/J, and these are able to remyelinate lesions very successfully. Murine chronic relapsing EAE (CR-EAE) shows pathological changes in many ways similar to those in TMEV-infected SJL/J mice, although less severe in terms of degrees of macrophage infiltration and tissue destruction. Mice with CR-EAE have a correspondingly limited ability to remyelinate their lesions. In both models the pathology appears to be mediated through a DTH response. However, while in EAE the DTH response is clearly against neuroantigens, the response in TMEV infection is against the virus itself. The end result in both models would be that of myelin destruction through a lymphotoxin-cytokine-mediated mechanism. The importance of the DTH response in both models is well illustrated by the effects of tolerance induction in EAE and TMEV infection to neuroantigens and virus, respectively. These are important models of human MS, since the current hypothesis is that a viral infection early in life, on the appropriate genetic background, may trigger a secondary misdirected immune response which could be directed either against myelin antigens and/or possible persistent virus(es).
Animals↗
Contrasting effects of anti-adhesion molecule therapy in experimental allergic encephalomyelitis and Theiler's murine encephalomyelitis.
An augmentation of experimental allergic encephalomyelitis (EAE) was observed when monoclonal antibody (mAb) to intercellular adhesion molecule 1 (ICAM-1) was administered after adoptive transfer. Clinical disease was more severe in the ICAM-1 specific mAb-treated EAE mice and included prominent ataxia compared to the PBS-treated controls or Theiler's murine encephalomyelitis virus (TMEV) infected mice treated with ICAM-1 specific mAb. Neuropathologic evaluation demonstrated a distinctly different distribution of lesions in the anti-ICAM-1-treated EAE mice which featured prominent demyelination and inflammation in the cerebellum, brainstem and cerebrum. These structures were minimally involved in the control mice and mAb treatment did not alter the neuropathology in TMEV-infected mice. These results indicate that anti-ICAM-1 can alter trafficking of lymphocytes and mononuclear cells in EAE but not TMEV-induced demyelinating disease.
Animals↗
Monoclonal antibody to Theiler's murine encephalomyelitis virus defines a determinant on myelin and oligodendrocytes, and augments demyelination in experimental allergic encephalomyelitis.
Theiler's murine encephalomyelitis virus (TMEV) causes a chronic demyelinating disease in mice. The mechanisms underlying the demyelination have not been fully elucidated. We have raised a mAb to TMEV (DA strain), H8, that reacts both with TMEV VP-1 and galactocerebroside (GC). In mouse brain cultures, cells positive for the mAb H8 epitope were double labeled with antibody to myelin basic protein, indicating that those cells were oligodendrocytes. Further, mAb H8 could immunostain myelin structures in frozen sections from mouse brains. When injected intravenously into mice with acute allergic encephalomyelitis, mAb H8 increased by 10-fold the size of demyelinated areas within the spinal cords. This is the first report demonstrating that an antibody to virus can enhance demyelination of a central nervous system disease. Ig fractions from the sera of mice with chronic TMEV infection had antibody(s) to GC, as well as to TMEV, as determined by ELISA. Furthermore, a competition ELISA for TMEV or GC antigen revealed that sera from these infected mice contained antibody(s) with the same specificity as mAb H8. Our results indicate that antibodies generated by immune response to TMEV can react with myelin and oligodendrocytes, and contribute to demyelination through an immune process.
Animals↗
Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children.
Forty-eight children with disseminated demyelination of the CNS, 28 with acute disseminated encephalomyelitis (ADEM), seven with multiphasic disseminated encephalomyelitis (MDEM) and 13 with multiple sclerosis were studied for a mean follow-up period of 5.64 years. The presentation findings of the ADEM/MDEM group were compared with those of the multiple sclerosis group. The following findings were more commonly seen in ADEM/MDEM presentation compared with the multiple sclerosis presentations: predemyelinating infectious disease (74 versus 38%, P: < 0.05); polysymptomatic presentation (91 versus 38%, P: < 0.002); pyramidal signs (71 versus 23%, P: < 0.01); encephalopathy (69 versus 15%, P: < 0.002); and bilateral optic neuritis (23 versus 8%, not significant). Seizures occurred only in the ADEM/MDEM group (17 versus 0%, not significant). Unilateral optic neuritis occurred only in the multiple sclerosis patients (23 versus 0%, P: < 0.01). There were no differences in the frequencies of transverse myelitis, brainstem involvement, cerebellar signs and sensory disturbance between the two groups. ADEM/MDEM patients were more likely to have blood leucocytosis (64 versus 22%, P: < 0.05), CSF lymphocytosis (64 versus 42%, not significant) and CSF protein elevation (60 versus 33%, not significant). Patients presenting with multiple sclerosis were more likely to have intrathecal synthesis of oligoclonal bands on presentation (64 versus 29%, not significant). MRI showed that subcortical white matter lesions were almost universal in both groups, though periventricular lesions were more common in multiple sclerosis (92 versus 44%, P: < 0.01). By contrast, in ADEM/MDEM there was absolute and relative periventricular sparing in 56 and 78% of patients, respectively. Follow-up MRI revealed complete or partial lesion resolution in 90% and no new lesions in the ADEM/MDEM group. All of the multiple sclerosis patients had new lesions on repeat MRI (five during relapse and six during asymptomatic convalescent phases). The outcome in the ADEM patients was mixed; 57% of patients made a complete recovery. The mean follow-up for the 35 ADEM/MDEM patients was 5.78 years (range 1.0-15.4 years). Eight of the 13 multiple sclerosis patients relapsed within the first year; 11 had a relapsing-remitting course, one a primary progressive course and one a secondary progressive course. These differences in the presentation of ADEM/MDEM compared with multiple sclerosis may help in the prognosis given to families regarding the possibility of later development of multiple sclerosis.
Adolescent↗
Two models for multiple sclerosis: experimental allergic encephalomyelitis and Theiler's murine encephalomyelitis virus.
In this review, we compare and contrast two popular models for multiple sclerosis (MS), Theiler's murine encephalomyelitis virus (TMEV) disease and experimental allergic encephalomyelitis (EAE). These models are used to investigate the viral and autoimmune etiology of MS, respectively. Infection with live TMEV is an essential component of TMEV demyelinating disease. TMEV-specific cellular and humoral immunity and apoptosis of infected cells eliminate virus from the gray matter of the central nervous system (CNS) during the acute phase of TMEV disease. In contrast, during the chronic phase, TMEV persistently infects glial cells and/or macrophages in the white matter. During the chronic phase, recruitment of macrophages, TMEV-specific T cells and antibody, with the induction of apoptosis are harmful to the host, leading to inflammation and demyelination. In EAE, induction of encephalitogenic CD4+ T cells is an important component for disease. After stimulation and activation, these T cells upregulate adhesion molecules and are able to enter the CNS. Th1 cytokines augment the recruitment of mononuclear cells in the CNS. Macrophages and/or glial cells secrete cytotoxic factors leading to demyelination in conjunction with B cells secreting anti-myelin antibody. Although immunopathological pathways during the course of the demyelination in TMEV infection and EAE are not always the same, oligodendroglial apoptosis is observed in both models, suggesting that their demyelinating processes share a common terminal pathway and finally lead to quite a similar clinical and pathological picture.
Animals↗
Porcine encephalomyelitis caused by hemagglutinating encephalomyelitis virus.
Six epizootics of encephalomyeltis in suckling pigs in Minnesota were attributed to infection with hemagglutinating encephalomyelitis virus. The disease occurred in 74 litters of pigs and was characterized by sudden onset of tremors, inappetence, weakness, atazia, and hyperesthesia, with high morbidity and case fatality rate. Pathologic changes consisted of marked nonsuppurative, nondemyelinating encephalomyelitis characterized by perivascular mononuclear cuffing, gliosis, neuronal death, and satellitosis. Clinical disease was limited principally to suckling pigs during a single farrowing period and did not recur in the herds involved during the ensuing 18 months.
Animals↗
Quantitative trait loci disposing for both experimental arthritis and encephalomyelitis in the DA rat; impact on severity of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis and antibody isotype pattern.
Quantitative trait loci (QTL) controlling inflammatory diseases with different organ specificity may hypothetically either be unique for one disease or shared among different diseases. We have investigated whether five non-MHC QTL controlling susceptibility to experimental arthritis in the DA rat also influence myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in an F2 intercross between inbred DA and PVG.RT1a rats. Two of the five chromosome regions affecting arthritis in the DA rat also regulate phenotypes of EAE. The DA allele at markers in Cia3 (collagen-induced arthritis QTL) on chromosome 4 is associated with more severe EAE and high levels of anti-MOG antibodies of the IgG2c subclass. Since production of antibodies of the IgG2c subclass may be stimulated by Th1 cells, and there is previous evidence that such cells promote EAE, it is possible that both of the studied phenotypes are controlled by the same gene or genes regulating Th1/Th2 cell differentiation. Furthermore, we show that Oia2 (oil-induced arthritis QTL) on chromosome 4 regulates levels of anti-MOG antibodies of the IgG1 subclass and of anti-MOG IgE, but that this gene region does not affect clinical disease severity in our study. Since production of IgE and IgG1 may be stimulated by Th2 cells, this QTL may also control Th1/Th2 bias. We conclude that Cia3 and Oia2 regulate MOG-induced EAE in rats. Furthermore, since both EAE and arthritis phenotypes co-localize to these gene regions, they may harbor genes which are key regulators of pathogenic immune responses.
Animals↗
Anti-synaptic antibody in allergic encephalomyelitis. II. The synapse-blocking effects in tissue culture of demyelinating sera from experimental allergic encephalomyelitis.
It has been suggested that demyelination cannot account for all of the observed clinical symptoms of multiple sclerosis (MS), in particular the rapidity of onset and remission of the disease, and attention has been focussed on the role of the synapse in 'demyelinating diseases'. In the present paper we have attempted to resolve the fundamental question of the site of action of a demyelinating disease, experimental allergic encephalomyelitis (EAE), by the use of cultures of neonatal rat cerebellum. Electrophysiological and morphological development in these cultures run hand-in-hand, and in the first few days in vitro there is a 4-5 day period when synapses are both seen ultrastructurally and known to be functioning but before the onset of myelination. The serum from guinea pigs with EAE was added to these cultures at different stages during their development and the morphological and electrophysiological effects observed. An abolitionary effect on the bioelectric activity of the culture was only observed when the serum was added to mature, myelinated cultures. Also the same active sera had no effect on synaptic activity before myelination had occurred. We conclude that the synaptic blocking effect occurs only when myelin is destroyed.
Animals↗
Anti-endothelial cell antibody and immune complexes in the sera of animals with acute experimental allergic encephalomyelitis and chronic relapsing experimental allergic encephalomyelitis.
Blood-brain barrier (BBB) injury occurs in both acute and chronic relapsing experimental allergic encephalomyelitis (EAE). Sera from animals in which these forms of EAE had been induced were examined for anti-endothelial cell antibodies and immune complexes by enzyme-linked immunosorbent assay (ELISA) using either cultured endothelial cells or Raji cells. IgG binding to endothelial cells was significantly increased in the sera of animals with acute EAE and chronic relapsing EAE, compared to controls. Increased levels of circulating immune complexes were also detected in the sera of some animals with chronic relapsing EAE, especially those in an exacerbation. It is suggested that the anti-endothelial cell antibody and immune complexes detected may play pathogenetic roles in the destruction of the BBB in EAE.
Animals↗
Regulation of experimental autoimmune encephalomyelitis: inhibition of adoptive experimental autoimmune encephalomyelitis by 'recovery-associated suppressor cells'.
We have previously shown the presence of suppressor cells in Lewis rats at the time of spontaneous recovery from experimental autoimmune encephalomyelitis (EAE). These cells, called 'recovery-associated suppressor cells' (RASC), are capable of preventing active EAE and inhibiting in vitro the specific proliferative response of encephalitogenic anti-MBP T cell line cells. The present investigations were undertaken in order to lend support to the hypothesis that RASC play an active role in the recovery. We found that RASC can prevent adoptive EAE when admixed with already activated, but not resting, anti-MBP T cells or when injected into the recipients separately from the encephalitogenic cells. They can also arrest the course of an ongoing disease when injected after the beginning of the clinical signs. This study provides the first direct demonstration of the downregulation of an ongoing EAE by suppressor cells.
Animals↗
Heat shock proteins and experimental autoimmune encephalomyelitis. II: environmental infection and extra-neuraxial inflammation alter the course of chronic relapsing encephalomyelitis.
We wished to study how infections might trigger relapses of autoimmune diseases such as multiple sclerosis (MS) and encephalomyelitis (EAE). We hypothesized that immune responses to heat shock proteins (hsp) induced by an infection could modulate responses to autoantigens. We induced extra-neuraxial inflammation in SJL mice housed either in specific-pathogen free (SPF) or conventional facilities. Mice in conventional housing are continuously exposed to large numbers of infectious agents. Spleen cell proliferative responses to human HSP60 and bacterial HSP65 were measured as were numbers of cells secreting IFN-gamma or IL-5. Proliferative responses to HSP60 were increased in conventionally housed mice compared to SPF mice and this was associated with skewing of secreted cytokines toward a Th2 pattern. Skewing toward a Th1 pattern was noted in SPF mice. Acute and relapsing EAE was induced in both groups of mice. Acute EAE was, in general, equivalent in all groups. However, SPF mice had more severe relapses than did conventionally housed animals and these differences were amplified by extra-neuraxial inflammation. Immunocytochemical analyses of brains from mice with relapsing EAE showed that increased numbers of brain gamma/delta cells were associated with disease remission. Our data suggest that frequent exposure to infectious agents leads to a relative Th2 skewing of immune responses to hsp and that this is associated with milder, less frequent relapses of EAE. They also support the concept that immune responses to hsp are of potential importance in exacerbating and perpetuating organ-restricted autoimmune diseases.
Animals↗
Genetic resistance to the induction of experimental allergic encephalomyelitis in Lewis rats. I. Genetic analysis of an apparent mutant strain with phenotypic resistance to experimental allergic encephalomyelitis.
Clinical resistance to the induction of experimental allergic encephalomyelitis was observed in a closed colony of Lewis (designated Le-R) rats. Disease susceptibility in randomly bred animals appeared to increase with increasing age. In the small group of young Le-R rats, which were susceptible, disease onset was delayed, severity of symptoms was reduced, and duration of clinical signs was abbreviated compared to conventional Lewis rats. The severity of histologic neural tissue lesions correlated with clinical observations. Breeding experiments indicated that most Le-R rats were resistant to disease induction regardless of whether their ancestors had been selected for susceptibility or resistance. The F3 generation of resistant lineage was uniformly resistant at all ages tested. Virtually all (Lewis X Le-R)F1 rats of either sex were resistant when challenged at 7-8 wk of age indicating that resistance was a dominant autosomal trait. Approximately half of (F1 X Lewis) backcross rats developed paralytic EAE whereas one-fourth were entirely resistant, suggesting that disease resistance may be mediated by one or two genes. Le-R rats shared at least some of the Lewis rat major histocompatibility antigens. Resistance apparently did not reflect a nonspecific impairment of cellular immune responsiveness. Le-R rats, which had been challenged with myelin basic protein, developed antigen-reactive cells specific for basic protein or its encephalitogenic fragment. Spleen cells obtained from basic protein-sensitized Le-R rats did not adoptively transfer disease into Lewis rats. In contrast, spleen cells obtained from basic protein-sensitized Lewis rats readily transferred disease into both Lewis and Le-R recipients. These data suggest that disease resistance may be a result of an immunologic deficit (or suppressor cell activity) expressed during the differentiation of antigen-reactive cells into disease-inducing effector cells.
Age Factors↗
Subtle encephalomyelitis in children: a variant of acute disseminated encephalomyelitis.
Four children with chronic, mild, nonspecific symptoms are described in whom magnetic resonance imaging (MRI) showed the presence of multifocal white-matter lesions suggestive of acute disseminated encephalomyelitis. The children ranged in age from 14 months to 15 years. The clinical picture was vague and inconclusive and consisted of several months of headaches, irritability, clumsiness, and personality change. Physical examinations were noncontributory. Laboratory investigation revealed no other cause of the demyelination. All of the patients have done well without any treatment, with a disappearance of symptomatology. The white-matter lesions on MRI scan in these children may indicate subtle exposure to a myelinolytic antigen. It has been suggested that such an exposure may create a state of complete or partial resistance to the encephalitogenic potential of the next infection or immunization. With complete resistance, the patient remains healthy and with partial resistance progressive demyelination results. Verification of these findings by others would suggest a possible benefit of a multicenter study of such patients, with virological, HLA testing, and long-term follow-up, in understanding the etiopathogenesis of multiple sclerosis.
Acute Disease↗
The significance of western equine encephalomyelitis viral infections in Aedes trivittatus (Diptera: Culicidae) in Iowa. I. Variation in susceptibility of Aedes trivittatus to experimental infection with three strains of western equine encephalomyelitis virus.
F1 pregnancy obtained from field-collected Aedes trivittatus were evaluated for susceptibility to infection with western equine encephalomyelitis (WEE) virus by intrathoracic inoculation and by oral imbibition of virus-blood suspensions through a membrane. Mosquitoes were uniformly susceptible to infection by intrathoracic inoculation of three strains of WEE virus, but minimum infective doses varied as much as 2,000 to 12,000-fold between strains by membrane feeding. Dose-response data obtained by membrane feeding also indicated that field strains of A. trivittatus were quite heterogeneous in their susceptibility to WEE virus since some individual mosquitoes could be infected by ingestion of low virus concentrations while others could not be infected by a 20,000-fold increase in virus concentration. Moreover, A. trivittatus showed a greater affinity for a WEE viral strain isolated from this species than for a WEE viral strain isolated from Culex tarsalis, even though the site, date of collection, and passage history of these isolates were identical. Field strains of A. trivittatus were relatively refractory to oral infection with WEE virus.
Aedes↗