UMLS:C0004364 - FACTA Search

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Query: UMLS:C0004364 (autoimmune disease)
24,845 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Definition of the immune process that causes demyelination in multiple sclerosis is essential to determine the feasibility of Ag-directed immunotherapy. Using the nonhuman primate, Callithrix jacchus jacchus (common marmoset), we show that immunization with myelin basic protein and proteolipid protein determinants results in clinical disease with significant demyelination. Demyelination was associated with spreading to myelin oligodendrocyte glycoprotein (MOG) determinants that generated anti-MOG serum Abs and Ig deposition in central nervous system white matter lesions. These data associate intermolecular "determinant spreading" with clinical autoimmune disease in primates and raise important issues for the pathogenesis and treatment of multiple sclerosis.
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PMID:Determinant spreading associated with demyelination in a nonhuman primate model of multiple sclerosis. 997 19

Experimental autoimmune encephalomyelitis (EAE) induced by active immunization with the myelin oligodendrocyte glycoprotein (MOG) is an Ab-mediated, T cell-dependent autoimmune disease that replicates the inflammatory demyelinating pathology of multiple sclerosis. We report that disease susceptibility and severity are determined by MHC and MHC-linked effects on the MOG-specific B cell response that mediate severe clinical EAE in the EAE-resistant Brown Norway (BN) rat. Immunization with the extracellular domain of MOG in CFA induced fulminant clinical disease associated with widespread demyelination and with an inflammatory infiltrate containing large numbers of polymorphonuclear cells and eosinophils within 10 days of immunization. To analyze the effects of the MHC (RT1 system) we compared BN (RT1 n) rats with Lewis (LEW) (RT1 l) and two reciprocal MHC congenic strains, LEW.1N (RT1n) and BN.1L (RT1 l). This comparison revealed that disease severity and clinical course were strongly influenced by the MHC haplotype that modulated the pathogenic MOG-specific autoantibody response. The intra-MHC recombinant congenic strain LEW.1R38 demonstrated that gene loci located both within the centromeric segment of the MHC containing classical class I and class II genes and within the telomeric RT1.M region containing the MOG gene are involved in determining Ab production and disease susceptibility. This study indicates that the current T cell-centered interpretation of MHC-mediated effects on disease susceptibility must be reassessed in multiple sclerosis and other autoimmune diseases in which autoantibody is involved in disease pathogenesis.
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PMID:Myelin oligodendrocyte glycoprotein induces experimental autoimmune encephalomyelitis in the "resistant" Brown Norway rat: disease susceptibility is determined by MHC and MHC-linked effects on the B cell response. 1038 97

The bm12 mutation in the class II I-A(b)molecule can profoundly influence experimental autoimmune disease, enhancing the development of systemic lupus erythematosus-like syndromes in NZB.H-2(bm12)mice or, conversely, abolishing the susceptibility of C57BL/6J (H-2(b)) mice to the induction of experimental autoimmune myasthenia gravis. We have studied the effect of this mutation on experimental autoimmune encephalomyelitis (EAE), induced in H-2(b)mice by myelin oligodendrocyte glycoprotein (MOG), and recently showed that MOG 35-55 peptide (pMOG 35-55), which represents the immunodominant encephalitogenic region for H-2(b)mice, is also a strong encephalitogen for H-2(bm12)mice. Nevertheless, although the differences in fine epitope specificity and TCR-Vbeta gene usage between encephalitogenic pMOG 35-55-specific T cells from H-2(b)and H-2(bm12)mice were subtle, H-2(bm12)and H-2(b)antigen presenting cells failed to effectively cross-present pMOG 35-55 non-syngeneically to I-A(b)/pMOG 33-55- and I-A(bm12)/pMOG 35-55-specific T cells, respectively. In the present study, we show that the abrogation of the response to pMOG 35-55 by the Th1 encephalitogenic pMOG 35-55-specific T cells upon non-syngeneic cross-presentation is neither due to a cytokine shift to a Th2 pattern, nor a result of anergy induction. Therefore, we suggest that presentation of pMOG 35-55 to I-A(b)/pMOG 35-55-specific T cells via the bm12 class II MHC molecule resulted in ineffective stimulation, similar to a weak agonistic effect.
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PMID:Effect of the bm12 class II mutation on proliferative and cytokine responses of encephalitogenic T cells in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis. 1044 Nov 62

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease of the CNS, which has long been used as an animal model for human multiple sclerosis. Development of autoimmune disease requires coordinated expression of a number of genes that are involved in the activation and effector functions of inflammatory cells. These include genes that encode costimulatory molecules, cytokines, chemokines, and adhesion molecules. Activation of these genes is regulated at the transcriptional level by several families of transcription factors. One of these is the NF-kappa B family, which is present in a variety of cell types and becomes highly activated at sites of inflammation. To test the roles of NF-kappa B in the development of autoimmune diseases, we studied EAE in mice deficient in one of the NF-kappa B isoforms, i.e., NF-kappa B1 (p50). We found that NF-kappa B1-deficient mice were significantly resistant to EAE induced by myelin oligodendrocyte glycoprotein. The resistance was primarily evidenced by a decrease in disease incidence, clinical score, and the degree of CNS inflammation. Furthermore, we established that the resistance to EAE in NF-kappa B1-deficient mice was associated with a deficiency of myelin oligodendrocyte glycoprotein-specific T cells to differentiate into either Th1- or Th2-type effector cells in vivo. These results strongly suggest that NF-kappa B1 plays crucial roles in the activation and differentiation of autoreactive T cells in vivo and that blocking NF-kappa B function can be an effective means to prevent autoimmune encephalomyelitis.
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PMID:Experimental autoimmune encephalomyelitis in NF-kappa B-deficient mice:roles of NF-kappa B in the activation and differentiation of autoreactive T cells. 1045 42

Experimental allergic encephalomyelitis (EAE) is a T(h)1-type cell-mediated autoimmune disease induced by immunization with myelin proteins and mediated by CD4(+) T cells. Although susceptibility to EAE is dependent largely on MHC background, the B10.S strain is resistant to induction of EAE despite sharing the I-A(s) MHC locus with the susceptible SJL strain. Furthermore, NOD mice which spontaneously develop diabetes are susceptible to EAE induction with myelin oligodendrocyte glycoprotein (MOG) 35-55, whereas a MHC congenic strain, III, which also expresses I-A(g7) MHC haplotype does not develop diabetes and is also resistant to EAE induction. We induced EAE in these four strains of mice with MOG peptides 92-106 (for I-A(s) strains) and 35-55 (for I-A(g7) strains) in complete Freund's adjuvant. In the susceptible strains (SJL and NOD) in vitro, there are high levels of IFN-gamma production, whereas the resistant strains (B10.S or III) secreted primarily IL-4/IL-10 and transforming growth factor (TGF)-beta, and had decreased levels of IFN-gamma. When brains from susceptible and resistant mice were examined by immunohistochemical methods for cytokine expression, the brains from resistant mice showed fewer infiltrates which predominantly expressed IL-4 and IL-10 and/or TGF-beta. Brains from NOD and SJL with EAE showed mainly IL-2 and IFN-gamma positive cells. Thus, resistance to MOG induced EAE in B10.S and III mouse strains is related to non-MHC genes and is associated with an altered balance of pro- and anti-inflammatory cytokines both in lymphoid tissue and in the brain following immunization with myelin antigens.
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PMID:Genetic susceptibility or resistance to autoimmune encephalomyelitis in MHC congenic mice is associated with differential production of pro- and anti-inflammatory cytokines. 1046 78

The importance of B7 costimulation in regulating T cell expansion and peripheral tolerance suggests that it may also play a significant regulatory role in the development of autoimmune disease. It is unclear whether B7 costimulation is involved only in the expansion of autoreactive T cells in the periphery, or if it is also required for effector activation of autoreactive T cells in the target organ for mediating tissue injury and propagating autoimmune disease. In this study, the role of B7-CD28 costimulation and the relative importance of B7 costimulators for the induction and effector phases of experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) peptide were examined. Wild-type, B7-1/B7-2-deficient mice, or CD28-deficient C57BL/6 mice were immunized with MOG 35-55 peptide. Mice lacking both B7-1 and B7-2 or CD28 showed no or minimal clinical signs of EAE and markedly reduced inflammatory infiltrates in the brain and spinal cord. However, mice lacking either B7-1 or B7-2 alone developed clinical and pathologic EAE that was comparable to EAE in wild-type mice, indicating overlapping functions for B7-1 and B7-2. Resistance to EAE was not due to a lack of induction of T helper type 1 (Th1) cytokines, since T cells from B7-1/B7-2(-/-) mice show reduced proliferative responses, but greater interferon gamma production compared with T cells from wild-type mice. To study the role of B7 molecules in the effector phase of the disease, MOG 35-55-specific T lines were adoptively transferred into the B7-1/B7-2(-/-) and wild-type mice. Clinical and histologic EAE were markedly reduced in B7-1/B7-2(-/-) compared with wild-type recipient mice. These results demonstrate that B7 costimulation has critical roles not only in the initial activation and expansion of MOG-reactive T cells, but also in the effector phase of encephalitogenic T cell activation within the central nervous system.
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PMID:Studies in B7-deficient mice reveal a critical role for B7 costimulation in both induction and effector phases of experimental autoimmune encephalomyelitis. 1047 57

The mechanisms of chronic disease and recovery from relapses in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, are unknown. Deletion of myelin-specific lymphocytes by apoptosis may play a role in termination of the inflammatory response. One pathway of apoptosis is the passive cell death or "cell death by neglect" pathway, which is under the control of the Bcl family of genes. To investigate the role of passive cell death pathway in EAE, we used mice with transgenic expression of the long form of the bcl-x gene (Bcl-x(L)) targeted to the T-cell lineage. We found that mice transgenic for Bcl-x(L) have an earlier onset and a more chronic form of EAE induced by myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 compared with wild-type littermate mice. This was not due to an expanded autoreactive cell repertoire. Primed peripheral lymphocytes from Bcl-x(L) transgenic mice showed increased proliferation and cytokine production to MOG peptide in vitro compared with lymphocytes from wild-type animals. Immunohistologic studies demonstrated increased cellular infiltrates, immunoglobulin precipitation, and demyelination in the Bcl-x(L) transgenic central nervous system (CNS) compared with controls. There was also a decreased number of apoptotic cells in the CNS of Bcl-x(L) transgenic mice when compared with littermates at all time points tested. This is the first report of an autoimmune disease model in Bcl-x(L) transgenic mice. Our data indicate that the passive cell death pathway is important in the pathogenesis of chronic EAE. These findings have implications for understanding the pathogenesis of multiple sclerosis and other autoimmune diseases.
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PMID:Role of passive T-cell death in chronic experimental autoimmune encephalomyelitis. 1077 55

Injection of autoantigens in IFA has been one of the most effective ways of preventing experimental, T cell-mediated, autoimmune disease in mice. The mechanism that underlies this protection has, however, remained controversial, with clonal deletion, induction of suppressor cells or of type 2 immunity being implicated at one time or another. Using high resolution enzyme-linked immunospot (ELISPOT) analysis, we have revisited this paradigm. As models of autoimmunity against sequestered and readily accessible autoantigens, we studied experimental allergic encephalomyelitis, induced by myelin oligodendrocyte glycoprotein, proteolipid protein, myelin basic protein, and renal tubular Ag-induced interstitial nephritis. We showed that the injection of each of these Ags in IFA was immunogenic and CD4 memory cells producing IL-2, IL-4, and IL-5, but essentially no IFN-gamma. IgG1, but not IgG2a, autoantibodies were produced. The engaged T cells were not classic Th2 cells in that IL-4 and IL-5 were produced by different cells. The IFA-induced violation of self tolerance, including the deposition of specific autoantibodies in the respective target organs, occurred in the absence of detectable pathology. Exhaustion of the pool of naive precursor cells was shown to be one mechanism of the IFA-induced tolerance. In addition, while the IFA-primed T cells acted as suppressor cells, in that they adoptively transferred disease protection, they did not interfere with the emergence of a type 1 T cell response in the adoptive host. Both active and passive tolerance mechanisms, therefore, contribute to autoantigen:IFA-induced protection from autoimmune disease.
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PMID:Revisiting tolerance induced by autoantigen in incomplete Freund's adjuvant. 1082 Feb 55

Experimental autoimmune encephalomyelitis (EAE) induced by sensitization with myelin oligodendrocyte glycoprotein (MOG) is a T cell-dependent autoimmune disease that reproduces the inflammatory demyelinating pathology of multiple sclerosis. We report that an encephalitogenic T cell response to MOG can be either induced or alternatively suppressed as a consequence of immunological cross-reactivity, or "molecular mimicry" with the extracellular IgV-like domain of the milk protein butyrophilin (BTN). In the Dark Agouti rat, active immunization with native BTN triggers an inflammatory response in the CNS characterized by the formation of scattered meningeal and perivascular infiltrates of T cells and macrophages. We demonstrate that this pathology is mediated by a MHC class II-restricted T cell response that cross-reacts with the MOG peptide sequence 76-87, I GEG KVA LRIQ N (identities underlined). Conversely, molecular mimicry with BTN can be exploited to suppress disease activity in MOG-induced EAE. We demonstrate that not only is EAE mediated by the adoptive transfer of MOG74-90 T cell lines markedly ameliorated by i.v. treatment with the homologous BTN peptide, BTN74-90, but that this protective effect is also seen in actively induced disease following transmucosal (intranasal) administration of the peptide. These results identify a mechanism by which the consumption of milk products may modulate the pathogenic autoimmune response to MOG.
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PMID:Butyrophilin, a milk protein, modulates the encephalitogenic T cell response to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis. 1094 19

The well established and characterized animal model for the human demyelinating autoimmune disease multiple sclerosis (MS) is known as experimental autoimmune encephalomyelitis (EAE). EAE is clinically characterized by focal areas of inflammation and demyelination and an infiltrate composed of large numbers of lymphocytes and macrophages, often found in a perivascular localization but also throughout the central nervous system (CNS). Active immunization of mice with several different protein components of myelin, including myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG), are capable of eliciting an immune response resulting in the quintessential symptoms of EAE: ascending paralysis involving the tail and then the limbs. Depending on the mouse strain and myelin antigen utilized, the disease course can be acute or chronic relapsing, characterized by a rapid onset of hind limb weakness that commonly progresses to paralysis, followed by spontaneous remission starting 7-10 days after the initial appearance of symptoms. EAE can also be induced passively by the adoptive transfer of in vitro activated CD4+ T cell clones or lines, typically of the Th1 phenotype, into irradiated susceptible recipients. The mechanisms involved in the cellular pathogenesis leading to paralysis and demyelination have been extensively studied and are primarily mediated by CD4+ T cells of the Th1 phenotype, with specificity for myelin antigens. Following activation, Th1 CD4 T cells produce in abundance the inflammatory cytokines TNF-alpha, IFN-gamma and lymphotoxin alpha (LT-alpha, also know as TNF-beta). IFN-gamma production is highly correlated with encephalitogenicity and may contribute to disease by up-regulation of adhesion molecules on endothelial cells, facilitating migration of lymphocytes into the CNS; by induction of major histocompatibility complex (MHC) class I and MHC class II molecules on astrocytes, microglial cells and brain endothelium, facilitating antigen (Ag) presentation in the CNS; and by activation of macrophages, leading to production of nitric oxide, a potent cytotoxic molecule. TNF-alpha and LT-alpha are both members of the TNF family of molecules and cause cell death by apoptosis following interaction with their counter-receptors, the TNFR1 and TNFR2, leading to a cascade of proteolytic events culminating in the blebbing of the cytoplasmic membrane, nuclear condensation and DNA fragmentation. Consequently, the production of TNF-alpha and LT-alpha by Th1 clones has been correlated with encephalitogenic potential and antibodies (Abs) to both prevents EAE upon transfer of encephalitogenic clones. Even though substantial evidence exists for the role of inflammatory cytokines in the pathogenesis of EAE, other mechanisms of myelin destruction are thought to exist. To date, many reports have implicated a role for the cell death-inducing ligand pair Fas and Fas-ligand (FasL).
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PMID:Evidence that Fas and FasL contribute to the pathogenesis of experimental autoimmune encephalomyelitis. 1114 Apr 65

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