Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis

Shanu F. Roemer, Joseph E Parisi, Vanda A Lennon, Eduardo E. Benarroch, Hans Lassmann, Wolfgang Bruck, Raul N. Mandler, Brian G Weinshenker, Sean J Pittock, Dean Marko Wingerchuk, Claudia F Lucchinetti

Research output: Contribution to journalArticle

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Abstract

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that typically affects optic nerves and spinal cord. Its pathogenic relationship to multiple sclerosis (MS) is uncertain. Unlike MS, NMO lesions are characterized by deposits of IgG and IgM co-localizing with products of complement activation in a vasculocentric pattern around thickened hyalinized blood vessels, suggesting a pathogenic role for humoral immunity targeting an antigen in the perivascular space. A recently identified specific serum autoantibody biomarker, NMO-IgG, targets aquaporin-4 (AQP4), the most abundant water channel protein in the CNS, which is highly concentrated in astrocytic foot processes. We analysed and compared patterns of AQP4 immunoreactivity in CNS tissues of nine patients with NMO, 13 with MS, nine with infarcts and five normal controls. In normal brain, optic nerve and spinal cord, the distribution of AQP4 expression resembles the vasculocentric pattern of immune complex deposition observed in NMO lesions. In contrast to MS lesions, which exhibit stage-dependent loss of AQP4, all NMO lesions demonstrate a striking loss of AQP4 regardless of the stage of demyelinating activity, extent of tissue necrosis, or site of CNS involvement. We identified a novel NMO lesion in the spinal cord and medullary tegmentum extending into the area postrema, characterized by AQP4 loss in foci that were inflammatory and oedematous, but neither demyelinated nor necrotic. Foci of AQP4 loss coincided with sites of intense vasculocentric immune complex deposition. These findings strongly support a role for a complement activating AQP4-specific autoantibody as the initiator of the NMO lesion, and further distinguish NMO from MS.

Original languageEnglish (US)
Pages (from-to)1194-1205
Number of pages12
JournalBrain
Volume130
Issue number5
DOIs
StatePublished - May 2007

Fingerprint

Aquaporin 4
Neuromyelitis Optica
Multiple Sclerosis
Spinal Cord
Optic Nerve
Antigen-Antibody Complex
Autoantibodies
Immunoglobulin G
Area Postrema
Aquaporins
Complement Activation
Demyelinating Diseases
Humoral Immunity
Immunoglobulin M
Blood Vessels
Foot
Necrosis
Biomarkers
Antigens

Keywords

  • Aquaporin-4
  • Astrocyte
  • Blood-brain barrier
  • Demyelination
  • Multiple sclerosis
  • Neuromyelitis optica

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. / Roemer, Shanu F.; Parisi, Joseph E; Lennon, Vanda A; Benarroch, Eduardo E.; Lassmann, Hans; Bruck, Wolfgang; Mandler, Raul N.; Weinshenker, Brian G; Pittock, Sean J; Wingerchuk, Dean Marko; Lucchinetti, Claudia F.

In: Brain, Vol. 130, No. 5, 05.2007, p. 1194-1205.

Research output: Contribution to journalArticle

Roemer, Shanu F. ; Parisi, Joseph E ; Lennon, Vanda A ; Benarroch, Eduardo E. ; Lassmann, Hans ; Bruck, Wolfgang ; Mandler, Raul N. ; Weinshenker, Brian G ; Pittock, Sean J ; Wingerchuk, Dean Marko ; Lucchinetti, Claudia F. / Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. In: Brain. 2007 ; Vol. 130, No. 5. pp. 1194-1205.
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abstract = "Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that typically affects optic nerves and spinal cord. Its pathogenic relationship to multiple sclerosis (MS) is uncertain. Unlike MS, NMO lesions are characterized by deposits of IgG and IgM co-localizing with products of complement activation in a vasculocentric pattern around thickened hyalinized blood vessels, suggesting a pathogenic role for humoral immunity targeting an antigen in the perivascular space. A recently identified specific serum autoantibody biomarker, NMO-IgG, targets aquaporin-4 (AQP4), the most abundant water channel protein in the CNS, which is highly concentrated in astrocytic foot processes. We analysed and compared patterns of AQP4 immunoreactivity in CNS tissues of nine patients with NMO, 13 with MS, nine with infarcts and five normal controls. In normal brain, optic nerve and spinal cord, the distribution of AQP4 expression resembles the vasculocentric pattern of immune complex deposition observed in NMO lesions. In contrast to MS lesions, which exhibit stage-dependent loss of AQP4, all NMO lesions demonstrate a striking loss of AQP4 regardless of the stage of demyelinating activity, extent of tissue necrosis, or site of CNS involvement. We identified a novel NMO lesion in the spinal cord and medullary tegmentum extending into the area postrema, characterized by AQP4 loss in foci that were inflammatory and oedematous, but neither demyelinated nor necrotic. Foci of AQP4 loss coincided with sites of intense vasculocentric immune complex deposition. These findings strongly support a role for a complement activating AQP4-specific autoantibody as the initiator of the NMO lesion, and further distinguish NMO from MS.",
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author = "Roemer, {Shanu F.} and Parisi, {Joseph E} and Lennon, {Vanda A} and Benarroch, {Eduardo E.} and Hans Lassmann and Wolfgang Bruck and Mandler, {Raul N.} and Weinshenker, {Brian G} and Pittock, {Sean J} and Wingerchuk, {Dean Marko} and Lucchinetti, {Claudia F}",
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T1 - Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis

AU - Roemer, Shanu F.

AU - Parisi, Joseph E

AU - Lennon, Vanda A

AU - Benarroch, Eduardo E.

AU - Lassmann, Hans

AU - Bruck, Wolfgang

AU - Mandler, Raul N.

AU - Weinshenker, Brian G

AU - Pittock, Sean J

AU - Wingerchuk, Dean Marko

AU - Lucchinetti, Claudia F

PY - 2007/5

Y1 - 2007/5

N2 - Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that typically affects optic nerves and spinal cord. Its pathogenic relationship to multiple sclerosis (MS) is uncertain. Unlike MS, NMO lesions are characterized by deposits of IgG and IgM co-localizing with products of complement activation in a vasculocentric pattern around thickened hyalinized blood vessels, suggesting a pathogenic role for humoral immunity targeting an antigen in the perivascular space. A recently identified specific serum autoantibody biomarker, NMO-IgG, targets aquaporin-4 (AQP4), the most abundant water channel protein in the CNS, which is highly concentrated in astrocytic foot processes. We analysed and compared patterns of AQP4 immunoreactivity in CNS tissues of nine patients with NMO, 13 with MS, nine with infarcts and five normal controls. In normal brain, optic nerve and spinal cord, the distribution of AQP4 expression resembles the vasculocentric pattern of immune complex deposition observed in NMO lesions. In contrast to MS lesions, which exhibit stage-dependent loss of AQP4, all NMO lesions demonstrate a striking loss of AQP4 regardless of the stage of demyelinating activity, extent of tissue necrosis, or site of CNS involvement. We identified a novel NMO lesion in the spinal cord and medullary tegmentum extending into the area postrema, characterized by AQP4 loss in foci that were inflammatory and oedematous, but neither demyelinated nor necrotic. Foci of AQP4 loss coincided with sites of intense vasculocentric immune complex deposition. These findings strongly support a role for a complement activating AQP4-specific autoantibody as the initiator of the NMO lesion, and further distinguish NMO from MS.

AB - Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that typically affects optic nerves and spinal cord. Its pathogenic relationship to multiple sclerosis (MS) is uncertain. Unlike MS, NMO lesions are characterized by deposits of IgG and IgM co-localizing with products of complement activation in a vasculocentric pattern around thickened hyalinized blood vessels, suggesting a pathogenic role for humoral immunity targeting an antigen in the perivascular space. A recently identified specific serum autoantibody biomarker, NMO-IgG, targets aquaporin-4 (AQP4), the most abundant water channel protein in the CNS, which is highly concentrated in astrocytic foot processes. We analysed and compared patterns of AQP4 immunoreactivity in CNS tissues of nine patients with NMO, 13 with MS, nine with infarcts and five normal controls. In normal brain, optic nerve and spinal cord, the distribution of AQP4 expression resembles the vasculocentric pattern of immune complex deposition observed in NMO lesions. In contrast to MS lesions, which exhibit stage-dependent loss of AQP4, all NMO lesions demonstrate a striking loss of AQP4 regardless of the stage of demyelinating activity, extent of tissue necrosis, or site of CNS involvement. We identified a novel NMO lesion in the spinal cord and medullary tegmentum extending into the area postrema, characterized by AQP4 loss in foci that were inflammatory and oedematous, but neither demyelinated nor necrotic. Foci of AQP4 loss coincided with sites of intense vasculocentric immune complex deposition. These findings strongly support a role for a complement activating AQP4-specific autoantibody as the initiator of the NMO lesion, and further distinguish NMO from MS.

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