Autoimmunity in neuromyelitis optica and opticospinal multiple sclerosis

Astrocytopathy as a common denominator in demyelinating disorders

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Abstract

Neuromyelitis optica (NMO) selectively affects the optic nerves and spinal cord. In Asians, multiple sclerosis (MS) is rare; however, when it appears, the selective and severe involvement of the optic nerves and spinal cord is characteristic. This form, termed opticospinal multiple sclerosis (OSMS), has similar features to the relapsing form of NMO in Westerners. The discovery that NMO-IgG, an NMO-specific IgG, targets aquaporin-4 (AQP4), suggested that NMO is a distinct disease entity with a fundamentally different etiology from MS. Because NMO-IgG is present in 30-60% of OSMS patients, OSMS in Asians is suggested to be the same entity as NMO. Pathologically, perivascular immune complex (IgM, IgG and C9neo) deposition and extensive loss of AQP4 in active lesions are reported hallmarks of NMO. However, we found that some autopsied NMO cases showed selective AQP4 loss while others showed preservation of AQP4, despite extensive tissue destruction. Vasculocentric deposition of complement and immunoglobulin was detected only in NMO patients, with less than 30% of actively demyelinating lesions showing AQP4 loss. Such heterogeneity of AQP4 expression and immunoglobulin deposition suggests a heterogeneous disease process in NMO. We recently reported that AQP4 was extensively lost in glial fibrillary acidic protein-positive hypertrophic astrocytes, both in demyelinated and myelinated layers of actively demyelinating lesions in Baló's disease, a variant of MS. We also found that in some acute MS lesions, AQP4 was lost extensively far beyond the areas of myelin loss. Active demyelinating lesions involved perivascular lymphocyte cuffings, consisting mainly of T cells in Baló's disease and MS, while the same was true for approximately half of the active lesions in NMO. This review proposes that anti-AQP4 antibody-dependent AQP4 loss occurs in some NMO patients while antibody-independent AQP4 astrocytopathy can occur in heterogeneous demyelinating conditions, including Baló's disease, NMO and MS. The latter may be mediated by T cells and other cell-mediated mechanisms, and should be tested in future experimental studies.

Original languageEnglish
Pages (from-to)69-77
Number of pages9
JournalJournal of the Neurological Sciences
Volume311
Issue number1-2
DOIs
Publication statusPublished - Dec 15 2011

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Neuromyelitis Optica
Aquaporin 4
Demyelinating Diseases
Autoimmunity
Multiple Sclerosis
Immunoglobulin G
Optic Nerve
Opticospinal Multiple Sclerosis
Immunoglobulins
Spinal Cord
T-Lymphocytes
Antibodies
Glial Fibrillary Acidic Protein
Myelin Sheath
Antigen-Antibody Complex

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Cite this

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title = "Autoimmunity in neuromyelitis optica and opticospinal multiple sclerosis: Astrocytopathy as a common denominator in demyelinating disorders",
abstract = "Neuromyelitis optica (NMO) selectively affects the optic nerves and spinal cord. In Asians, multiple sclerosis (MS) is rare; however, when it appears, the selective and severe involvement of the optic nerves and spinal cord is characteristic. This form, termed opticospinal multiple sclerosis (OSMS), has similar features to the relapsing form of NMO in Westerners. The discovery that NMO-IgG, an NMO-specific IgG, targets aquaporin-4 (AQP4), suggested that NMO is a distinct disease entity with a fundamentally different etiology from MS. Because NMO-IgG is present in 30-60{\%} of OSMS patients, OSMS in Asians is suggested to be the same entity as NMO. Pathologically, perivascular immune complex (IgM, IgG and C9neo) deposition and extensive loss of AQP4 in active lesions are reported hallmarks of NMO. However, we found that some autopsied NMO cases showed selective AQP4 loss while others showed preservation of AQP4, despite extensive tissue destruction. Vasculocentric deposition of complement and immunoglobulin was detected only in NMO patients, with less than 30{\%} of actively demyelinating lesions showing AQP4 loss. Such heterogeneity of AQP4 expression and immunoglobulin deposition suggests a heterogeneous disease process in NMO. We recently reported that AQP4 was extensively lost in glial fibrillary acidic protein-positive hypertrophic astrocytes, both in demyelinated and myelinated layers of actively demyelinating lesions in Bal{\'o}'s disease, a variant of MS. We also found that in some acute MS lesions, AQP4 was lost extensively far beyond the areas of myelin loss. Active demyelinating lesions involved perivascular lymphocyte cuffings, consisting mainly of T cells in Bal{\'o}'s disease and MS, while the same was true for approximately half of the active lesions in NMO. This review proposes that anti-AQP4 antibody-dependent AQP4 loss occurs in some NMO patients while antibody-independent AQP4 astrocytopathy can occur in heterogeneous demyelinating conditions, including Bal{\'o}'s disease, NMO and MS. The latter may be mediated by T cells and other cell-mediated mechanisms, and should be tested in future experimental studies.",
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