Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hormones can exert significant protective effects on autoimmune diseases by activating immunoregulatory mechanisms. One of the possible mechanisms of hormonal protection might be through the anti-inflammatory effects of the TGF-beta molecule. The present study investigated the changes in expression of two TGF-beta isoforms, TGF-beta1 and TGF-beta3, in C57BL/6 and TCR transgenic (T/R+) B10.PL mice that manifested or were protected against clinical signs of experimental autoimmune encephalomyelitis (EAE) with 17beta-estradiol (E2) treatment. We here demonstrate an inverse relationship between expression of TGF-beta1 that is enhanced in mice with EAE, and TGF-beta3 that is enhanced in E2-protected mice. The differential expression of TGF-beta isoforms was observed in spinal cord tissue but not spleen. Additionally TGF-beta1 expression was evident both in whole spinal cord tissue and mononuclear cells isolated from inflamed tissue, in contrast to TGF-beta3 that was only detected in spinal cord tissue but not in mononuclear cells. Further studies revealed that CD3 and especially MAC-1 positive cells were the main source of TGF-beta1 in the mononuclear CNS population. Of crucial importance, the TGF-beta3 isoform displayed anti-proliferative properties towards encephalitogenic cells in vitro. We propose that the TGF-beta1 and TGF-beta3 isoforms play opposing roles in the expression of EAE.
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PMID:Opposing roles for TGF-beta1 and TGF-beta3 isoforms in experimental autoimmune encephalomyelitis. 1469 59

Experimental allergic encephalomyelitis (EAE) and multiple sclerosis (MS) are characterized by strong sexual dimorphisms, many of which may be due to genetically controlled sex hormone effects on the immune system, the central nervous system (CNS), or both. In the present study we used 487 gonadectomized and 376 intact age-matched F(2) mice generated through crosses of B10.S/SgMcdJ and SJL/J mice to assess the role of adult gonadal hormones in regulating clinical and histopathological quantitative traits (QT) associated with EAE in the context of genetic heterogeneity. We found that gonadectomy resulted in different effects, depending on the QT and the sex of the mouse. Ovariectomized mice on average had lower cumulative clinical disease scores, shorter duration of clinical signs, and increased peak disease scores. This trend was accompanied by a significant increase in the incidence of acute, progressive EAE which is more frequently seen in intact and orchiectomized males. Although spinal cord (SC) inflammation was the better predictor of clinical signs of EAE in both sexes, ovariectomized females had considerable reductions in nearly all histopathological QT in both the brain and SC. Orchiectomy resulted in modestly significant increases in disease severity and peak score and earlier onset of clinical signs. With the exception of SC demyelination and lesion scores, orchiectomy had no effect on histopathological QT. Importantly, gonadectomy reduced but did not completely abolish any of the sexually dimorphic clinical QT seen in intact mice. It did however, lead to a significant sexual dimorphism in incidence and severity not seen in intact mice. For histopathological QT, no sexual dimorphism was detected for brain lesions in either intact or gonadectomized mice. In contrast, SC histopathological QT exhibited significant sexual dimorphisms, which were impacted by gonadectomy. The results from this study indicate that within the context of genetic heterogeneity, circulating gonadal hormones influence both clinical and histopathological QT in this model of MS, but they do not solely account for the sexual dimorphisms seen in these traits. Thus, additional mechanisms must play a role in regulating gender differences in autoimmune disease of the CNS.
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PMID:Adult gonadal hormones selectively regulate sexually dimorphic quantitative traits observed in experimental allergic encephalomyelitis. 1469 30

Nasal installation or oral feeding of antigens can alter the subsequent immune response in animals and humans. Most mucosal treatments with antigens tend to down-regulate disease, inducing full tolerance or immune deviation; however, priming has also been reported. We evaluated the course of experimental autoimmune encephalomyelitis (EAE) in (SJL x B10.PL)F1 mice after nasal instillation of myelin basic protein. There was a tendency towards exacerbation of subsequent disease in animals if they were nasally exposed to gpMBP during the neonatal period (first week of life), compared to exposure during adulthood. Later, at 11 months of age, this tendency to exacerbate disappeared. Our results suggest that mucosal exposure during early life may regularly modulate the anti-self immune response upwards in individuals genetically predisposed to autoimmune diseases.
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PMID:Nasal instillation of gpMBP can exacerbate murine EAE: effect of mucosal priming is an age-dependent phenomenon. 1470 9

We describe the generation of mice that express a transgenic T cell receptor (TCR) (5B6) specific for the encephalitogenic myelin proteolipid protein (PLP) peptide 139-151, on the experimental autoimmune encephalomyelitis-resistant (EAE-resistant) B10.S background. Despite harboring a high frequency of self-reactive T cells, 5B6 transgenic mice on the B10.S background rarely develop spontaneous EAE, which is in striking contrast to 5B6 transgenic mice on the EAE-susceptible SJL background. The relative resistance to spontaneous EAE in transgenic B10.S mice is not due to deletion or anergy of T cells, but appears to be controlled by APCs. Analysis of APCs revealed a lower activation state and a lower T cell-activating capacity for APCs from B10.S mice than for those from EAE-susceptible SJL mice. When APCs in 5B6 transgenic B10.S mice were activated, for example, via TLR9 or TLR4, T cell tolerance was broken, resulting in EAE. Our findings demonstrate that activation of APCs via innate immune receptors can break self tolerance and trigger the development of autoimmunity even in a genetically resistant strain. These findings suggest that the development of autoimmune diseases such as multiple sclerosis is determined at least partly by the endogenous activation state of APCs.
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PMID:Activation of antigen-presenting cells by microbial products breaks self tolerance and induces autoimmune disease. 1505 5

Multiple sclerosis (MS) is more prevalent in women than men. We evaluated seven different mouse strains commonly used in the study of autoimmune diseases, for sex differences in the disease course of experimental autoimmune encephalomyelitis (EAE). Greater severity of EAE was observed in the female SJL immunized with two different peptides of myelin proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG) as well as in the female ASW relative to males. Female NZW mice showed a greater incidence of EAE than males. However, male B10.PL and PL/J mice showed more severe disease than females. No sex differences were noted in the C57BL/6 or NOD strains.
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PMID:Sex differences in experimental autoimmune encephalomyelitis in multiple murine strains. 1508 Dec 49

Experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) is a well-established animal model of multiple sclerosis (MS) in rodents. It reflects the wide spectrum of disease pathology and serves as a valuable tool for studying the pathogenesis and for testing new therapies of MS. In order to identify genes responsible for resistance to and modulation of the disease, we compared the mRNA expression profile of more than 12,000 genes by DNA microarray technique in lymph nodes of the highly EAE-susceptible mouse strain C57Bl/6 (B6) and the resistant strain C57Bl/10.S (B10). The disease onset in B6 mice was day 15. We identified 84 genes that were up-regulated more than two-fold in B10 mice compared to vehicle-treated controls, whereas only two genes were up-regulated in B6 mice after 7 and 15 days post-immunization (p.i.), respectively. We were able to match five up-regulated genes in B10 mice to known quantitative trait loci (QTLs), which control for EAE susceptibility. Only 17, respectively 5, genes were down-regulated at both time points in B10 and B6 mice. Tests for immunoreactivity to MOG (T cell proliferation and interferon-gamma (IFN-gamma) secretion) revealed no stronger immune response in B6 compared to B10 mice supporting the hypothesis of an immunosuppressive effect as a target to prevent EAE in the B10 mice. We conclude that resistance to EAE (and possibly to MS) is an active process mediated by multiple genes up-regulated in peripheral lymphatic organs of resistant animals. Thus, monitoring of the expression of these new candidate genes may serve as a tool for the disease progression and the pharmaceutical treatment.
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PMID:Gene-expression profiling of the early stages of MOG-induced EAE proves EAE-resistance as an active process. 1514 14

Estrogens and estrogen-receptor signaling function in establishing and regulating the female immune system and it is becoming increasingly evident that they may play a similar role in males. We report that B10.PL/SnJ male mice with a disrupted estrogen receptor-1 (alpha) gene (Esr1(-/-)) develop less severe clinical experimental allergic encephalomyelitis (EAE) compared to either Esr1(+/-) or wild-type (Esr1(+/+)) controls when immunized with myelin basic protein peptide Ac1-11 (MBP(Ac1-11)). In contrast, the disease course in B10.PL/SnJ male mice with a disrupted estrogen receptor-2 (beta) gene (Esr2(-/-)) does not differ from that of wild-type (Esr2(+/+)) mice. However, Esr2(+/-) mice do develop more severe clinical disease with an earlier onset indicating that heterosis at Esr2 plays a significant role in regulating EAE in males. No significant differences in central nervous system histopathology or MBP(Ac1-11)-specific T-cell responses as assessed by proliferation and interleukin-2 production were observed as a function of either Esr1 or Esr2 genotype. An analysis of cytokine/chemokine secretion by MBP(Ac1-11)-specific T cells revealed unique Esr1 and Esr2 genotype-dependent regulation. Interferon-gamma secretion was found to be negatively regulated by Esr1 whereas interleukin-6 and tumor necrosis factor-alpha secretion exhibited classical Esr2 gene dose responses. Interestingly, MCP-1 displayed distinctively unique patterns of genotype-dependent regulation by Esr1 and Esr2. The contribution of the hematopoietic and nonhematopoietic cellular compartments associated with the heterotic effect at Esr2 in regulating the severity of clinical EAE was identified using reciprocal hematopoietic radiation bone marrow chimeras generated between male wild-type and Esr2(+/-) mice. Wild-type --> Esr2(+/-) mice exhibited EAE equivalent in severity to that seen in Esr2(+/-) --> Esr2(+/-) control constructs; both of which were more severe than the clinical signs observed in Esr2(+/-) --> wild-type and wild-type --> wild-type mice. These results indicate that the heterotic effect at Esr2 is a function of the nonhematopoietic compartment.
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PMID:Estrogen receptor-1 (Esr1) and -2 (Esr2) regulate the severity of clinical experimental allergic encephalomyelitis in male mice. 1516 28

Linkage analysis and congenic mapping in NOD mice have identified a susceptibility locus for type 1 diabetes, Idd5.1 on mouse chromosome 1, which includes the Ctla4 and Icos genes. Besides type 1 diabetes, numerous autoimmune diseases have been mapped to a syntenic region on human chromosome 2q33. In this study we determined how the costimulatory molecules encoded by these genes contribute to the immunopathogenesis of experimental autoimmune encephalomyelitis (EAE). When we compared levels of expression of costimulatory molecules on T cells, we found higher ICOS and lower full-length CTLA-4 expression on activated NOD T cells compared with C57BL/6 (B6) and C57BL/10 (B10) T cells. Using NOD.B10 Idd5 congenic strains, we determined that a 2.1-Mb region controls the observed expression differences of ICOS. Although Idd5.1 congenic mice are resistant to diabetes, we found them more susceptible to myelin oligodendrocyte glycoprotein 35-55-induced EAE compared with NOD mice. Our data demonstrate that higher ICOS expression correlates with more IL-10 production by NOD-derived T cells, and this may be responsible for the less severe EAE in NOD mice compared with Idd5.1 congenic mice. Paradoxically, alleles at the Idd5.1 locus have opposite effects on two autoimmune diseases, diabetes and EAE. This may reflect differential roles for costimulatory pathways in inducing autoimmune responses depending upon the origin (tissue) of the target Ag.
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PMID:The diabetes susceptibility locus Idd5.1 on mouse chromosome 1 regulates ICOS expression and modulates murine experimental autoimmune encephalomyelitis. 1521 Jul 70

The Ncf1 gene was recently identified as a strong regulator of severe arthritis in rat. This finding was surprising, because the disease-promoting allele mediated a lower level of reactive oxygen species in NADPH oxidase-expressing cells. We have now investigated a splice mutation of the Ncf1 gene in B10.Q mice, causing a truncated and nonfunctional Ncf1 protein. We found that the mutated Ncf1 led to a more severe and chronic relapsing collagen-induced arthritis. Enhanced IgG and delayed-type hypersensitivity responses against type II collagen were seen, indicating increased activity of autoreactive T cells. Interestingly, female Ncf1-mutated mice spontaneously developed severe arthritis during the postpartum period. The arthritis was accompanied by an increased antibody response to type II collagen, with the same fine specificity as in collagen-induced arthritis. The enhancing effect of the mutated Ncf1 could also be shown to be more general in that it enhanced myelin oligodendrocyte glycoprotein protein-induced experimental autoimmune encephalomyelitis, a model for multiple sclerosis. These results show that Ncf1, a gene important for oxidative burst, regulates the susceptibility and severity of both arthritis and encephalomyelitis and modulates, directly or indirectly, the level of T cell-dependent autoimmune responses.
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PMID:Enhanced autoimmunity, arthritis, and encephalomyelitis in mice with a reduced oxidative burst due to a mutation in the Ncf1 gene. 1531 Aug 53

SJL mice are highly susceptible to experimental autoimmune encephalomyelitis (EAE) induced with myelin proteolipid protein (PLP) peptide 139-151, whereas H-2 congenic B10.S mice are resistant. Immunodominance and susceptibility to EAE are associated with a high precursor frequency of PLP 139-151-specific T cells in the naive repertoire of SJL mice. To understand the mechanism of EAE resistance in B10.S mice, we determined the precursor frequency of PLP 139-151-reactive T cells in both strains by using IAs/PLP 139-151 tetramers. SJL and B10.S mice had similar frequencies of tetramer-reactive T cells in the naive peripheral repertoire. However, in SJL mice, the majority of PLP 139-151 tetramer-positive cells were in the CD4+CD25- population, whereas there were more tetramer-positive cells in the CD4+CD25+ population of B10.S mice. Depletion of CD4+CD25+ cells in vivo facilitated the expansion of PLP 139-151-reactive cells with production of T helper 1 cytokines in EAE-resistant B10.S mice. Furthermore, anti-CD25 Ab treatment before immunization resulted in EAE induction in these otherwise resistant mice. These data indicate an important role for autoantigen-specific CD4+CD25+ cells in genetic resistance to autoimmunity.
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PMID:Myelin proteolipid protein-specific CD4+CD25+ regulatory cells mediate genetic resistance to experimental autoimmune encephalomyelitis. 1549 18


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