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)

The development of autoimmune disease is accompanied by the acquired recognition of new self-determinants, a process commonly referred to as determinant spreading. In this study, we addressed the question of whether determinant spreading is pathogenic for progression of chronic-relapsing experimental autoimmune encephalomyelitis (EAE), a disease with many similarities to multiple sclerosis (MS). Our approach involved a systematic epitope mapping of responses to myelin proteolipid protein (PLP) as well as assaying responses to known encephalitogenic determinants of myelin basic protein (MBP 87-89) and myelin oligodendrocyte glycoprotein (MOG 92-106) at various times after induction of EAE in (SWR X SJL)F1 mice immunized with PLP 139-151. We found that the order in which new determinants are recognized during the course of disease follows a predictable sequential pattern. At monthly intervals after immunization with p139-151, responses to PLP 249-273, MBP 87-99, and PLP 137-198 were sequentially accumulated in al mice examined. Three lines of evidence showed that determinant spreading is pathogenic for disease progression: (a) spreading determinants mediate passive transfer of acute EAE in naive (SWR X SJL)F1 recipients; (b) an invariant relationship exists between the development of relapse/progression and the spreading of recognition to new immunodominant encephalitogenic determinants; and (c) after EAE onset, the induction of peptide-specific tolerance to spreading but not to nonspreading encephalitogenic determinants prevents subsequent progression of EAE. Thus, the predictability of acquired self-determinant recognition provides a basis for sequential determinant-specific therapeutic intervention after onset of the autoimmune disease process.
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PMID:A predictable sequential determinant spreading cascade invariably accompanies progression of experimental autoimmune encephalomyelitis: a basis for peptide-specific therapy after onset of clinical disease. 866 34

129/Sv mice are resistant to induction of experimental autoimmune encephalomyelitis (EAE) induced with myelin oligodendrocyte glycoprotein peptide (MOG35-55). Mice of this strain lacking the gene coding for the ligand-binding chain of the IFN-gamma receptor develop EAE with high morbidity and mortality. Spleen cells from sensitized IFN-gammaR-/- mice proliferated extensively when stimulated with MOG peptide in culture and produced high levels of IFN-gamma and TNF but no detectable IL-4. Transfer of spleen cells from sensitized IFN-gammaR-/- mice produced EAE in both IFN-gammaR+/+ and IFN-gammaR-/- recipients. Disease was severe in IFN-gammaR-/- recipients and mortality high (77%). Surviving mice remained moribund until termination of the experiments. IFN-gammaR+/+ recipients developed disease of equal severity, but with no mortality, and recovered significantly. These results indicate that IFN-gamma is not essential for the generation or function of anti-MOG35-55 effector cells but does play an important role in down-regulating EAE at both the effector and induction phase of disease.
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PMID:IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. 887 15

The nature of the autoimmune T cell response to myelin oligodendrocyte glycoprotein (MOG), recently recognized as a potential target antigen in multiple sclerosis (MS), has not yet been characterized, in contrast to the T cell reactivity to other potential target antigens in MS such as myelin basic protein and proteolipid protein. Here, we show that the encephalitogenicity of the recombinant Ig-like domain of human MOG is associated, in H-2 b mice, with an immunodominant T cell reactivity against a single region of MOG spanning amino acids 35-55, accounting for the previously reported strong encephalitogenic activity of pMOG 35-55. A single injection of pMOG 35-55 with or without administration of pertussis toxin was sufficient to induce severe clinical experimental autoimmune encephalomyelitis (EAE) in H-2 b mice. Encephalitogenic pMOG 35-55-specific T cell lines derived from C3H.SW (V beta b) mice were diverse in their TCR V beta gene usage (V beta 1, V beta 6, V beta 8 and V beta 15), although V beta 8.2 was most predominantly expressed (48%). However, V beta 8 + T cells may only be part of the encephalitogenic MOG-specific T cell repertoire in H-2 b mice, as demonstrated by the susceptibility of C57L (V beta a) mice to disease induced by pMOG 35-55. Encephalitogenic T cell lines from V beta a mice were also diverse in their TCR V beta gene usage (V beta 1, V beta 2, V beta 6, V beta 14 and V beta 16). Such a heterogeneous TCT V beta gene expression by pMOG 35-55/I-A b-reactive T cells from both V beta a and V beta b H-2 b mice suggested multiple epitopes within pMOG 35-55. Analysis of the pattern of reactivity by pMOG 35-55-reactive T cells to a set of truncated peptides was not commensurate with independent nested epitopes, but revealed a requirement for recognition of a core sequence, YRSPFSRVV (pMOG 40-48). However, optimal stimulation was obtained with longer peptides, with each additional amino acid flanking either the N or the C terminus differentially increasing the stimulatory capacity of pMOG 40-48. Nonetheless, pMOG 40-48 was the minimal encephalitogenic epitope for both V beta a and V beta b mice. Thus, the T cell reactivity against the immunodominant encephalitogenic region of MOG is characterized by a diverse V beta gene usage and a requirement for the same core epitope. This pattern of reactivity may favor epitope-directed, rather than TCR-targeted, approaches to immunospecific therapy for MOG-related autoimmune disease.
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PMID:Delineation of the minimal encephalitogenic epitope within the immunodominant region of myelin oligodendrocyte glycoprotein: diverse V beta gene usage by T cells recognizing the core epitope encephalitogenic for T cell receptor V beta b and T cell receptor V beta a H-2b mice. 889 62

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system that has been extensively studied as a model for the human demyelinating disease multiple sclerosis (MS). Here we describe the characteristics of a novel form of EAE developed in a nonhuman primate. In Callithrix jacchus marmosets (C. jacchus), immunization with whole brain white matter induces a primary demyelinating disease with a relapsing-remitting chronic course, closely resembling human MS. In these animals, the MS-like lesion results from a complex immune response requiring both disease-inducing T lymphocytes and pathogenic antibody. T lymphocytes reactive against myelin basic protein are capable of mediating the inflammatory component of marmoset EAE. Demyelination, on the other hand, is antibody mediated. The quantitatively minor myelin protein myelin oligodendrocyte glycoprotein (MOG) is an important antigen in this system, as immunization against MOG, or passive transfer of anti-MOG antibodies, reproduces the core features of the disease induced with whole white matter. Advantages of the C. jacchus model of EAE for the study of MS include the clinical and pathologic similarity between the two conditions, the natural bone marrow chimerism in C. jacchus permitting adoptive transfer of T lymphocytes between siblings, and the similarity of immune and nervous system genes and proteins between human and nonhuman primates. A diverse immune response to multiple myelin antigens appears to be responsible for the MS-like lesion in C. jacchus, a finding that parallels emerging concepts of the pathogenesis of human MS.
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PMID:Allergic Encephalomyelitis in Common Marmosets: Pathogenesis of a Multiple Sclerosis-like Lesion 895 53

Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS) characterized by primary demyelination, is believed to result from an autoimmune attack against myelin components. In view of their ability to induce experimental autoimmune encephalomyelitis (EAE), an animal model for MS, the quantitatively major malign proteins--myelin basic protein (MBP) and proteolipid protein (PLP)--have been extensively studied as the relevant primary antigens in MS, and therapeutic approaches have been targeted to counteract autoimmune reactivity to MBP and PLP. Accordingly, copolymer 1, a random synthetic amino acid copolymer crossreactive with MBP and highly protective against the induction of EAE with MBP or PLP, is not being extensively tested in clinical studies as a therapeutic agent for MS. However, increasing evidence suggests that autoimmune reactivity against other CNS-specific myelin proteins could also be involved in the pathogenesis of MS. In this context, we have demonstrated that peripheral blood lymphocytes from patients with MS respond predominantly to myelin oligodendrocyte glycoprotein (MOG) rather than to MBP or PLP, suggesting an important role for cell reactivity against MOG in the pathogenesis of MS. We have demonstrated that T-cell reactivity in MOG can also be pathogenic by inducing neurological disease in H-2u and H-2b mice with the same peptide of MOG, pMOG 35-55. Most interestingly, the expression of the disease differed with the different MHC backgrounds. Induction of a differentially expressed disease in different strains of mice with the same myelin antigen makes this new model particularly relevant to MS, where different expression of the disease is seen in different patients. Therefore, notwithstanding the importance of the autoimmune reactivity to MBP and PLP in MS, the potentially pathogenic autoimmune reactivity to MOG must now also be taken into consideration in therapeutic approaches to MS. In this context, we have investigated the possible effect of copolymer 1 treatment on autoimmune reactivity to MOG and on the development of EAE induced by MOG. Copolymer 1 was found to inhibit the binding of MOG peptides to MHC molecules, as well as the proliferation of MOG-reactive T cells, in a dose-dependent manner. In parallel, injection of copolymer 1 concomitantly with the encephalitogenic MOG peptide exerted a strong protective effect against the development of EAE. These preliminary data on the effect of copolymer 1 on the autoimmune response to MOG in mice indicate that copolymer 1 may also be effective in cases of MS where the autoimmune response to MOG prevails, and should therefore be further investigated in this context.
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PMID:The autoimmune reactivity to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis is potentially pathogenic: effect of copolymer 1 on MOG-induced disease. 896 16

Copolymer 1 is a synthetic amino acid copolymer, effective in suppression of experimental allergic encephalomyelitis (EAE) induced in a variety of species. Copolymer 1 can suppress both acute and chronic relapsing EAE induced by either whole brain homogenate or the purified encephalitogens myelin basic protein (MBP) and proteolipid protein (PLP). Thus, the suppressive effect of copolymer 1 in EAE is a general phenomenon and is not restricted to a certain species, the disease type, or the encephalitogen used for EAE induction. The suppressive activity of copolymer 1 is, however, limited to EAE, and copolymer 1 has no nonspecific immunological activity. On the other hand, a marked degree of immunological cross-reactivity in both the cellular and humoral immune responses was demonstrated between MBP and copolymer 1. This cross-reactivity may be the underlying mechanism for the specific suppressive effect of copolymer 1 in EAE. In vivo and in vitro studies using both murine and human cell cultures suggest that the mechanism for copolymer 1 activity in EAE and multiple sclerosis involves, as an initial step, the binding of copolymer 1 to the major histocompatibility complex class II molecules on antigen-presenting cells. Following this step, two pathways may be activated: (1) induction of antigen-specific suppressor T cells by determinants shared between MBP and copolymer 1, or (2) competition with MBP and other myelin-associated antigens, PLP and myelin oligodendrocyte glycoprotein, for the activation of effector T cells. These two mechanisms can act either separately or in concert to interfere in the autoimmune processes that lead to the neurological damage in EAE and multiple sclerosis.
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PMID:New insights into the mechanism of action of copolymer 1 in experimental allergic encephalomyelitis and multiple sclerosis. 896 19

Recent studies on autoimmune encephalomyelitis and neuritis reveal that many different antigens of the central (CNS) and peripheral nervous system may become targets of an encephalitogenic T-cell response. The aim of this study was to determine the influence of T-cell specificity on the pathology of autoimmune-mediated inflammation in the nervous system. Autoimmune encephalomyelitis was induced by the adoptive transfer of CD4+ T-line cells specific for either myelin basic protein, myelin oligodendrocyte glycoprotein (MOG), myelin-associated glycoprotein, S100 beta, or glial fibrillary acidic protein. The severity of the inflammatory response was antigen- and dose-dependent. With the exception of MOG-specific T-line cells, all autoreactive T-cell lines induced inflammation in the CNS and peripheral nervous system. In the myelin-basic-protein-mediated model, the spinal cord was most severely affected with only minor inflammation in the forebrain. In contrast, both MOG- and myelin-associated-glycoprotein-specific T cells induced a far higher density of lesions in the periventricular and cerebellar white matter. S100 beta- and glial-fibrillary-acidic-protein-specific T cells mediated particularly severe inflammation in the gray matter. In addition to these topographic differences, antigen specificity also influenced the extent of both parenchymal inflammation and macrophage activation in the CNS. However, irrespective of the specificity or number of T cells transferred, the major neuropathologic correlate with disease severity was the absolute number of activated macrophages recruited into the CNS parenchyma (r = 0.9; p < 0.0001). This study suggests that differences in lesion distribution in multiple sclerosis patients may reflect differences in the antigen specificity of an encephalitogenic T-cell response.
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PMID:Experimental autoimmune encephalomyelitis: the antigen specificity of T lymphocytes determines the topography of lesions in the central and peripheral nervous system. 912 Nov 18

The lymphotoxin (LT)/tumor necrosis factor (TNF) family has been implicated in the neurologic inflammatory diseases multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). To determine the role of individual family members in EAE, C57BL/6 mice, LT-alpha-deficient (LT-alpha-/- mice), or LT-beta-deficient (LT-beta-/- mice), and their wild-type (WT) littermates were immunized with rat myelin oligodendrocyte glycoprotein (MOG) peptide 35-55. C57BL/6 and WT mice developed chronic, sustained paralytic disease with average maximum clinical scores of 3.5 and disease indices (a measure of day of onset and sustained disease scores) ranging from 367 to 663 with central nervous system (CNS) inflammation and demyelination. LT-alpha-/- mice were primed so that their splenic lymphocytes proliferated in response to MOG 35-55 and the mice produced anti-MOG antibody. However, LT-alpha-/- mice were quite resistant to EAE with low average clinical scores (<1), an average disease index of 61, and the negligible CNS inflammation and demyelination. WT T cells transferred EAE to LT-alpha-/- recipients. LT-beta-/- mice were susceptible to EAE, though less than WT, with an average maximum clinical score of 1.9 and disease index of 312. These data implicate T cell production of LT-alpha in MOG EAE and support a major role for LT-alpha3, a minor role for the LT-alpha/beta complex, and by inference, no role for TNF-alpha.
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PMID:A critical role for lymphotoxin in experimental allergic encephalomyelitis. 933 62

Tumor necrosis factor (TNF)-dependent sites of action in the generation of autoimmune inflammation have been defined by targeted disruption of TNF in the C57BL/6 mouse strain. C57BL/6 mice are susceptible to an inflammatory, demyelinating form of experimental autoimmune encephalomyelitis (EAE) induced by the 35-55 peptide of myelin oligodendrocyte glycoprotein. Direct targeting of a strain in which EAE was inducible was necessary, as the location of the TNF gene renders segregation of the mutated allele from the original major histocompatibility complex by backcrossing virtually impossible. In this way a single gene effect was studied. We show here that TNF is obligatory for normal initiation of the neurological deficit, as demonstrated by a significant (6 d) delay in disease in its absence relative to wild-type (WT) mice. During this delay, comparable numbers of leukocytes were isolated from the perfused central nervous system (CNS) of WT and TNF-/- mice. However, in the TNF-/- mice, immunohistological analysis of CNS tissue indicated that leukocytes failed to form the typical mature perivascular cuffs observed in WT mice at this same time point. Severe EAE, including paralysis and widespread CNS perivascular inflammation, eventually developed without TNF. TNF-/- and WT mice recovered from the acute illness at the same time, such that the overall disease course in TNF-/- mice was only 60% of the course in control mice. Primary demyelination occurred in both WT and TNF-/- mice, although it was of variable magnitude. These results are consistent with the TNF dependence of processes controlling initial leukocyte movement within the CNS. Nevertheless, potent alternative mechanisms exist to mediate all other phases of EAE.
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PMID:Critical points of tumor necrosis factor action in central nervous system autoimmune inflammation defined by gene targeting. 934 16

In this report, we establish a regulatory role of natural killer (NK) cells in experimental autoimmune encephalomyelitis (EAE), a prototype T helper cell type 1 (Th1)-mediated disease. Active sensitization of C57BL/6 (B6) mice with the myelin oligodendrocyte glycoprotein (MOG)35-55 peptide induces a mild form of monophasic EAE. When mice were deprived of NK cells by antibody treatment before immunization, they developed a more serious form of EAE associated with relapse. Aggravation of EAE by NK cell deletion was also seen in beta 2-microglobulin-/- (beta 2m-/-) mice, indicating that NK cells can play a regulatory role in a manner independent of CD8+ T cells or NK1.1+ T cells (NK-T cells). The disease enhancement was associated with augmentation of T cell proliferation and production of Th1 cytokines in response to MOG35-55. EAE passively induced by the MOG35-55-specific T cell line was also enhanced by NK cell deletion in B6, beta 2m-/-, and recombination activation gene 2 (RAG-2)-/- mice, indicating that the regulation by NK cells can be independent of T, B, or NK-T cells. We further showed that NK cells inhibit T cell proliferation triggered by antigen or cytokine stimulation. Taken together, we conclude that NK cells are an important regulator for EAE in both induction and effector phases.
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PMID:Regulation of experimental autoimmune encephalomyelitis by natural killer (NK) cells. 936 28


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