Multiple sclerosis

Hafler, David A.

doi:10.1172/jci200421357

Cited by 109 publications

(108 citation statements)

References 87 publications

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“…Several lines of evidence support an early role of autoreactive CD4 ϩ CNS myelin-specific T cells (1,2). In addition, there is epitope spreading such that T cell responses are directed against multiple different myelin antigens (5).…”

Section: Ultiple Sclerosis (Ms) Is An Immune-mediated Disorder Inmentioning

confidence: 99%

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The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain

Rus

Pardo

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

172

167

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Section: Ultiple Sclerosis (Ms) Is An Immune-mediated Disorder Inmentioning

confidence: 99%

“…which inflammatory cells from the peripheral blood (PB) migrate to the CNS and cause demyelination and subsequent axonal degeneration (1)(2)(3)(4). Several lines of evidence support an early role of autoreactive CD4 ϩ CNS myelin-specific T cells (1,2).…”

Section: Ultiple Sclerosis (Ms) Is An Immune-mediated Disorder Inmentioning

confidence: 99%

The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain

Rus

Pardo

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

172

167

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“…A poor understanding of the etiology of MS has complicated the development of effective therapeutics (2). Despite strong evidence for the contribution of T cell responses to manifestations of autoimmunity in the central nervous system (CNS) of patients with MS (3,4), recent findings encouraged investigators to search also for B cell-mediated contributions to the MS pathogenesis (5,6).…”

mentioning

confidence: 99%

“…Moreover, highresolution microscopic analysis detected myelin-specific autoantibodies in the regions of demyelination plaques in human MS and a MS-like disease of marmosets, suggesting their direct contribution to myelin destruction (9). Although the mechanism of the autoantibody role in MS pathogenesis is unknown (2), autoantibodies to myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) were proposed as biomarkers for clinical prognosis of MS (10). Similar immunoglobulins were also found in mice with induced experimental allergic encephalomyelitis (EAE), which is an animal model of MS (11).…”

mentioning

confidence: 99%

Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen

Пономаренко

Durova

Vorobiev

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

174

236

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Autoantibody-mediated tissue destruction is among the main features of organ-specific autoimmunity. This report describes ''an antibody enzyme'' (abzyme) contribution to the site-specific degradation of a neural antigen. We detected proteolytic activity toward myelin basic protein (MBP) in the fraction of antibodies purified from the sera of humans with multiple sclerosis (MS) and mice with induced experimental allergic encephalomyelitis. Chromatography and zymography data demonstrated that the proteolytic activity of this preparation was exclusively associated with the antibodies. No activity was found in the IgG fraction of healthy donors. The human and murine abzymes efficiently cleaved MBP but not other protein substrates tested. The sites of MBP cleavage determined by mass spectrometry were localized within immunodominant regions of MBP. The abzymes could also cleave recombinant substrates containing encephalytogenic MBP 85-101 peptide. An established MS therapeutic Copaxone appeared to be a specific abzyme inhibitor. Thus, the discovered epitope-specific antibodymediated degradation of MBP suggests a mechanistic explanation of the slow development of neurodegeneration associated with MS.

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“…characterized by the perivascular infiltration of inflammatory mononuclear cells (1). Although the etiology of MS is unknown, evidence from human patients (2)(3)(4) and an animal model of MS, experimental autoimmune encephalomyelitis (EAE) (5-7), supports a major pathogenic role for autoreactive myelin-specific CD4 ϩ T cells, which are a logical target for clinical therapies.…”

mentioning

confidence: 99%

Differential induction of IgE-mediated anaphylaxis after soluble vs. cell-bound tolerogenic peptide therapy of autoimmune encephalomyelitis

Smith

Eagar

Strominger

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

100

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The ability of different forms of myelin peptides to induce tolerance for the treatment of preestablished murine experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, was evaluated. i.v. administration of myelin peptidepulsed, ethylene carbodiimide-fixed syngeneic splenocytes, but not soluble myelin peptide monomers or oligomers, proved exceedingly effective at treating preestablished EAE, resulting in amelioration of disease progression. In addition to the lack of therapeutic efficacy of soluble peptide and peptide oligomer, administering them i.v. after the onset of clinical symptoms in many but not all peptide-induced EAE models led to a rapid-onset anaphylactic reaction characterized by respiratory distress, erythema, decreased body temperature, unresponsiveness, and, often, death. By using anti-IgE antibody treatments and mice with targeted mutations of the Fc␥RIII ␣-chain or the common ␥-chain of Fc RI and Fc␥RI͞III, we demonstrate that IgE crosslinking of Fc RI appears to be necessary and sufficient for myelin peptide-induced anaphylaxis. The implications of these findings to myelin peptide͞ protein tolerance strategies for the treatment of multiple sclerosis are discussed.myelin ͉ tolerance M ultiple sclerosis (MS) is a CNS-demyelinating disease characterized by the perivascular infiltration of inflammatory mononuclear cells (1). Although the etiology of MS is unknown, evidence from human patients (2-4) and an animal model of MS, experimental autoimmune encephalomyelitis (EAE) (5-7), supports a major pathogenic role for autoreactive myelin-specific CD4 ϩ T cells, which are a logical target for clinical therapies. Two protocols that have shown promise in inducing antigen-specific immune tolerance for the prevention and͞or treatment of EAE are the i.v. injection of soluble protein, peptide, or peptide oligomers (8-10) and the i.v. injection of myelin proteins or peptides chemically coupled to syngeneic splenocytes [antigen-coupled splenocytes (Ag-SP)] (11). We performed a side-by-side comparison of these two tolerance protocols in preventing EAE induction and ameliorating ongoing EAE. We found that i.v. injection of soluble peptide monomer was not particularly effective when administered at any time point tested, and a soluble peptide oligomer was only fully effective when administered after immunization (day ϩ7) but before the onset of clinical symptoms of EAE. In contrast, i.v. administration of Ag-SP proved effective at preventing the onset of clinical symptoms and treating preestablished disease. In addition, an unexpected result of the administration of soluble peptide and peptide oligomer after the onset of clinical symptoms in many, but not all, peptide-induced EAE models was a rapid-onset anaphylactic reaction characterized by respiratory distress, erythema, decreased body temperature, unresponsiveness, and often death. This result is especially alarming given the proposed use of peptide-based tolerance therapies for the treatment of autoimmune diseases.Anaphylaxis i...

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Multiple sclerosis

Cited by 109 publications

References 87 publications

The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain

The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain

Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen

Differential induction of IgE-mediated anaphylaxis after soluble vs. cell-bound tolerogenic peptide therapy of autoimmune encephalomyelitis

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