{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T16:01:26Z","timestamp":1792425686230,"version":"4.5.0"},"reference-count":72,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2021,10,30]],"date-time":"2021-10-30T00:00:00Z","timestamp":1635552000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 NS110949"],"award-info":[{"award-number":["R01 NS110949"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,5,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Neuromyelitis optica is an autoimmune inflammatory disorder targeting aquaporin-4 water channels in CNS astrocytes. Histopathological descriptions of astrocytic lesions reported in neuromyelitis optica so far have emphasized a characteristic loss of aquaporin-4, with deposition of IgG and complement and lysis of astrocytes, but sublytic reactions have been underappreciated.<\/jats:p>\n               <jats:p>We performed a multi-modality study of 23 neuromyelitis optica autopsy cases (clinically and\/or pathologically confirmed; 337 tissue blocks). By evaluating astrocytic morphology, immunohistochemistry and AQP4 RNA transcripts, and their associations with demyelinating activity, we documented a spectrum of astrocytopathy in addition to complement deposition, microglial reaction, granulocyte infiltration and regenerating activity.<\/jats:p>\n               <jats:p>Within advanced demyelinating lesions, and in periplaque areas, there was remarkable hypertrophic astrogliosis, more subtle than astrocytic lysis. A degenerative component was suggested by \u2018dystrophic\u2019 morphology, cytoplasmic vacuolation, Rosenthal fibres and associated stress protein markers. The abundance of AQP4 mRNA transcripts in sublytic reactive astrocytes devoid of aquaporin-4 protein supported in vivo restoration following IgG-induced aquaporin-4 endocytosis\/degradation. Astrocytic alterations extending beyond demyelinating lesions speak to astrocytopathy being an early and primary event in the evolving neuromyelitis optica lesion. Focal astrocytopathy observed without aquaporin-4 loss or lytic complement component deposition verifies that astrocytic reactions in neuromyelitis optica are not solely dependent on IgG-mediated aquaporin-4 loss or lysis by complement or by IgG-dependent leucocyte mediators.<\/jats:p>\n               <jats:p>We conclude that neuromyelitis optica reflects a global astrocytopathy, initiated by binding of IgG to aquaporin-4 and not simply definable by demyelination and astrocytic lysis. The spectrum of astrocytic morphological changes in neuromyelitis optica attests to the complexity of factors influencing the range of astrocytic physiological responses to a targeted attack by aquaporin-4-specific IgG. Sublytic astrocytic reactions are no doubt an important determinant of the lesion\u2019s evolution and potential for repair. Pharmacological manipulation of the astrocytic stress response may offer new avenues for therapeutic intervention.<\/jats:p>","DOI":"10.1093\/brain\/awab394","type":"journal-article","created":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T11:13:27Z","timestamp":1635333207000},"page":"1379-1390","source":"Crossref","is-referenced-by-count":52,"title":["Spectrum of sublytic astrocytopathy in neuromyelitis optica"],"prefix":"10.1093","volume":"145","author":[{"given":"Yong","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanda A","family":"Lennon","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph E","family":"Parisi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogdan","family":"Popescu","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, Saskatoon SK S7N 5E5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Vasquez","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6140-5584","authenticated-orcid":false,"given":"Sean J","family":"Pittock","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles L","family":"Howe","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia F","family":"Lucchinetti","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,10,30]]},"reference":[{"issue":"1","key":"2022052416115350200_awab394-B1","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/bpa.12099","article-title":"The pathology of an autoimmune astrocytopathy: Lessons learned from neuromyelitis optica","volume":"24","author":"Lucchinetti","year":"2014","journal-title":"Brain Pathol"},{"issue":"9","key":"2022052416115350200_awab394-B2","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/S1474-4422(07)70216-8","article-title":"The spectrum of neuromyelitis optica","volume":"6","author":"Wingerchuk","year":"2007","journal-title":"Lancet Neurol"},{"issue":"Pt 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