A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica

Claudia F Lucchinetti, Raul N. Mandler, Dorian McGavern, Wolfgang Bruck, Gerald Gleich, Richard M. Ransohoff, Corinna Trebst, Brian G Weinshenker, Dean Marko Wingerchuk, Joseph E Parisi, Hans Lassmann

Research output: Contribution to journalArticle

864 Citations (Scopus)

Abstract

Devic's disease [neuromyelitis optica (NMO)] is an idiopathic inflammatory demyelinating disease of the CNS, characterized by attacks of optic neuritis and myelitis. The mechanisms that result in selective localization of inflammatory demyelinating lesions to the optic nerves and spinal cord are unknown. Serological and clinical evidence of B cell autoimmunity has been observed in a high proportion of patients with NMO. The purpose of this study was to investigate the importance of humoral mechanisms, including complement activation, in producing the necrotizing demyelination seen in the spinal cord and optic nerves. Eighty-two lesions were examined from nine autopsy cases of clinically confirmed Devic's disease. Demyelinating activity in the lesions was immunocytochemically classified as early active (21 lesions), late active (18 lesions), inactive (35 lesions) or remyelinating (eight lesions) by examining the antigenic profile of myelin degradation products within macrophages. The pathology of the lesions was analysed using a broad spectrum of immunological and neurobiological markers, and lesions were defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction and the immunopathological evidence of complement activation. The pathology was identical in all nine patients. Extensive demyelination was present across multiple spinal cord levels, associated with cavitation, necrosis and acute axonal pathology (spheroids), in both grey and white matter. There was a pronounced loss of oligodendrocytes within the lesions. The inflammatory infiltrates in active lesions were characterized by extensive macrophage infiltration associated with large numbers of perivascular granulocytes and eosinophils and rare CD3+ and CD8+ T cells. There was a pronounced perivascular deposition of immunoglobulins (mainly IgM) and complement C9neo antigen in active lesions associated with prominent vascular fibrosis and hyalinization in both active and inactive lesions. The extent of complement activation, eosinophilic infiltration and vascular fibrosis observed in the Devic NMO cases is more prominent compared with that in prototypic multiple sclerosis, and supports a role for humoral immunity in the pathogenesis of NMO. Based on this study, future therapeutic strategies designed to limit the deleterious effects of complement activation, eosinophil degranulation and neutrophil/macrophage/microglial activation are worthy of further investigation.

Original languageEnglish (US)
Pages (from-to)1450-1461
Number of pages12
JournalBrain
Volume125
Issue number7
StatePublished - 2002

Fingerprint

Neuromyelitis Optica
Complement Activation
Demyelinating Diseases
Spinal Cord
Oligodendroglia
Pathology
Optic Nerve
Eosinophils
Blood Vessels
Fibrosis
Macrophages
Myelitis
Myelin Proteins
Spinal Nerves
Optic Neuritis
Geography
Macrophage Activation
Humoral Immunity
Myelin Sheath
Autoimmunity

Keywords

  • Devic's syndrome
  • Eosinophils
  • Humoral immunity
  • Neuromyelitis optica
  • Neuropathology

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Lucchinetti, C. F., Mandler, R. N., McGavern, D., Bruck, W., Gleich, G., Ransohoff, R. M., ... Lassmann, H. (2002). A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica. Brain, 125(7), 1450-1461.

A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica. / Lucchinetti, Claudia F; Mandler, Raul N.; McGavern, Dorian; Bruck, Wolfgang; Gleich, Gerald; Ransohoff, Richard M.; Trebst, Corinna; Weinshenker, Brian G; Wingerchuk, Dean Marko; Parisi, Joseph E; Lassmann, Hans.

In: Brain, Vol. 125, No. 7, 2002, p. 1450-1461.

Research output: Contribution to journalArticle

Lucchinetti, CF, Mandler, RN, McGavern, D, Bruck, W, Gleich, G, Ransohoff, RM, Trebst, C, Weinshenker, BG, Wingerchuk, DM, Parisi, JE & Lassmann, H 2002, 'A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica', Brain, vol. 125, no. 7, pp. 1450-1461.
Lucchinetti CF, Mandler RN, McGavern D, Bruck W, Gleich G, Ransohoff RM et al. A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica. Brain. 2002;125(7):1450-1461.
Lucchinetti, Claudia F ; Mandler, Raul N. ; McGavern, Dorian ; Bruck, Wolfgang ; Gleich, Gerald ; Ransohoff, Richard M. ; Trebst, Corinna ; Weinshenker, Brian G ; Wingerchuk, Dean Marko ; Parisi, Joseph E ; Lassmann, Hans. / A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica. In: Brain. 2002 ; Vol. 125, No. 7. pp. 1450-1461.
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abstract = "Devic's disease [neuromyelitis optica (NMO)] is an idiopathic inflammatory demyelinating disease of the CNS, characterized by attacks of optic neuritis and myelitis. The mechanisms that result in selective localization of inflammatory demyelinating lesions to the optic nerves and spinal cord are unknown. Serological and clinical evidence of B cell autoimmunity has been observed in a high proportion of patients with NMO. The purpose of this study was to investigate the importance of humoral mechanisms, including complement activation, in producing the necrotizing demyelination seen in the spinal cord and optic nerves. Eighty-two lesions were examined from nine autopsy cases of clinically confirmed Devic's disease. Demyelinating activity in the lesions was immunocytochemically classified as early active (21 lesions), late active (18 lesions), inactive (35 lesions) or remyelinating (eight lesions) by examining the antigenic profile of myelin degradation products within macrophages. The pathology of the lesions was analysed using a broad spectrum of immunological and neurobiological markers, and lesions were defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction and the immunopathological evidence of complement activation. The pathology was identical in all nine patients. Extensive demyelination was present across multiple spinal cord levels, associated with cavitation, necrosis and acute axonal pathology (spheroids), in both grey and white matter. There was a pronounced loss of oligodendrocytes within the lesions. The inflammatory infiltrates in active lesions were characterized by extensive macrophage infiltration associated with large numbers of perivascular granulocytes and eosinophils and rare CD3+ and CD8+ T cells. There was a pronounced perivascular deposition of immunoglobulins (mainly IgM) and complement C9neo antigen in active lesions associated with prominent vascular fibrosis and hyalinization in both active and inactive lesions. The extent of complement activation, eosinophilic infiltration and vascular fibrosis observed in the Devic NMO cases is more prominent compared with that in prototypic multiple sclerosis, and supports a role for humoral immunity in the pathogenesis of NMO. Based on this study, future therapeutic strategies designed to limit the deleterious effects of complement activation, eosinophil degranulation and neutrophil/macrophage/microglial activation are worthy of further investigation.",
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AU - Gleich, Gerald

AU - Ransohoff, Richard M.

AU - Trebst, Corinna

AU - Weinshenker, Brian G

AU - Wingerchuk, Dean Marko

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AU - Lassmann, Hans

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N2 - Devic's disease [neuromyelitis optica (NMO)] is an idiopathic inflammatory demyelinating disease of the CNS, characterized by attacks of optic neuritis and myelitis. The mechanisms that result in selective localization of inflammatory demyelinating lesions to the optic nerves and spinal cord are unknown. Serological and clinical evidence of B cell autoimmunity has been observed in a high proportion of patients with NMO. The purpose of this study was to investigate the importance of humoral mechanisms, including complement activation, in producing the necrotizing demyelination seen in the spinal cord and optic nerves. Eighty-two lesions were examined from nine autopsy cases of clinically confirmed Devic's disease. Demyelinating activity in the lesions was immunocytochemically classified as early active (21 lesions), late active (18 lesions), inactive (35 lesions) or remyelinating (eight lesions) by examining the antigenic profile of myelin degradation products within macrophages. The pathology of the lesions was analysed using a broad spectrum of immunological and neurobiological markers, and lesions were defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction and the immunopathological evidence of complement activation. The pathology was identical in all nine patients. Extensive demyelination was present across multiple spinal cord levels, associated with cavitation, necrosis and acute axonal pathology (spheroids), in both grey and white matter. There was a pronounced loss of oligodendrocytes within the lesions. The inflammatory infiltrates in active lesions were characterized by extensive macrophage infiltration associated with large numbers of perivascular granulocytes and eosinophils and rare CD3+ and CD8+ T cells. There was a pronounced perivascular deposition of immunoglobulins (mainly IgM) and complement C9neo antigen in active lesions associated with prominent vascular fibrosis and hyalinization in both active and inactive lesions. The extent of complement activation, eosinophilic infiltration and vascular fibrosis observed in the Devic NMO cases is more prominent compared with that in prototypic multiple sclerosis, and supports a role for humoral immunity in the pathogenesis of NMO. Based on this study, future therapeutic strategies designed to limit the deleterious effects of complement activation, eosinophil degranulation and neutrophil/macrophage/microglial activation are worthy of further investigation.

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