Septin‐5 and ‐7‐IgGs: Neurologic, Serologic, and Pathophysiologic Characteristics
Background and Objectives We sought to determine clinical significance of neuronal septin autoimmunity and evaluate for potential IgG effects. Methods Septin‐IgGs were detected by indirect immunofluorescence assays (IFAs; mouse tissue and cell based) or Western blot. IgG binding to (and internalizat...
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| Veröffentlicht in: | Annals of neurology 2022-12, Vol.92 (6), p.1090-1101 |
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| creator | Hinson, Shannon R. Honorat, Josephe A. Grund, Ethan M. Clarkson, Benjamin D. Miske, Ramona Scharf, Madeleine Zivelonghi, Cecilia Al‐Lozi, Muhammad Taher Bucelli, Robert C. Budhram, Adrian Cho, Tracey Choi, Ellie Grell, Jacquelyn Lopez‐Chiriboga, Alfonso Sebastian Levin, Marc Merati, Melody Montalvo, Mayra Pittock, Sean J. Wilson, Michael R. Howe, Charles L. McKeon, Andrew |
| description | Background and Objectives
We sought to determine clinical significance of neuronal septin autoimmunity and evaluate for potential IgG effects.
Methods
Septin‐IgGs were detected by indirect immunofluorescence assays (IFAs; mouse tissue and cell based) or Western blot. IgG binding to (and internalization of) extracellular septin epitopes were evaluated for by live rat hippocampal neuron assay. The impact of purified patient IgGs on murine cortical neuron function was determined by recording extracellular field potentials in a multielectrode array platform.
Results
Septin‐IgGs were identified in 23 patients. All 8 patients with septin‐5‐IgG detected had cerebellar ataxia, and 7 had prominent eye movement disorders. One of 2 patients with co‐existing septin‐7‐IgG had additional psychiatric phenotype (apathy, emotional blunting, and poor insight). Fifteen patients had septin‐7 autoimmunity, without septin‐5‐IgG detected. Disorders included encephalopathy (11; 2 patients with accompanying myelopathy, and 2 were relapsing), myelopathy (3), and episodic ataxia (1). Psychiatric symptoms (≥1 of agitation, apathy, catatonia, disorganized thinking, and paranoia) were prominent in 6 of 11 patients with encephalopathic symptoms. Eight of 10 patients with data available (from 23 total) improved after immunotherapy, and a further 2 patients improved spontaneously. Staining of plasma membranes of live hippocampal neurons produced by patient IgGs (subclasses 1 and 2) colocalized with pre‐ and post‐synaptic markers. Decreased spiking and bursting behavior in mixed cultures of murine glutamatergic and GABAergic cortical neurons produced by patient IgGs were attributable to neither antigenic crosslinking and internalization nor complement activation.
Interpretation
Septin‐IgGs are predictive of distinct treatment‐responsive autoimmune central nervous system (CNS) disorders. Live neuron binding and induced electrophysiologic effects by patient IgGs may support septin‐specific pathophysiology. ANN NEUROL 2022;92:1090–1101 |
| doi_str_mv | 10.1002/ana.26482 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9672904</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2736590479</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4432-5f51e109704a073ff85e6f06e86068296fe0e79494983a6dfdb6f0f4abe2f8323</originalsourceid><addsrcrecordid>eNp1kd9qFDEUh0Ox2LV60ReQAW8UnPbk70y8EJZF20KpQpVehuzsyW7K7GRNZpS98xH6jH0SU6cuVZAQcsj5-DiHHyFHFI4pADuxnT1mStRsj0yo5LSsmdBPyAS4EqWkXByQZyndAIBWFJ6SA65A8pqxCbm-wk3vu7uft7Kw3aLIRZXv-fI0vSsucYihDUvfvC2ucFfec59tvwqb1Tb58beYrWy0TY_Rp9436TnZd7ZN-OLhPSRfP374MjsrLz6dns-mF2UjBGeldJIiBV2BsFBx52qJyoHCWoGqmVYOASst8qm5VQu3mOe2E3aOzNWc8UPyfvRuhvkaFw12fbSt2US_tnFrgvXm707nV2YZvhutKqZBZMHrB0EM3wZMvVn71GDb2g7DkAyr8nRcaqEy-uof9CYMscvrZYormXWVztSbkWpiSCmi2w1DwdzHZXJc5ndcmX35ePod-SefDJyMwA_f4vb_JjO9nI7KX_QCoPg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2736590479</pqid></control><display><type>article</type><title>Septin‐5 and ‐7‐IgGs: Neurologic, Serologic, and Pathophysiologic Characteristics</title><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><creator>Hinson, Shannon R. ; Honorat, Josephe A. ; Grund, Ethan M. ; Clarkson, Benjamin D. ; Miske, Ramona ; Scharf, Madeleine ; Zivelonghi, Cecilia ; Al‐Lozi, Muhammad Taher ; Bucelli, Robert C. ; Budhram, Adrian ; Cho, Tracey ; Choi, Ellie ; Grell, Jacquelyn ; Lopez‐Chiriboga, Alfonso Sebastian ; Levin, Marc ; Merati, Melody ; Montalvo, Mayra ; Pittock, Sean J. ; Wilson, Michael R. ; Howe, Charles L. ; McKeon, Andrew</creator><creatorcontrib>Hinson, Shannon R. ; Honorat, Josephe A. ; Grund, Ethan M. ; Clarkson, Benjamin D. ; Miske, Ramona ; Scharf, Madeleine ; Zivelonghi, Cecilia ; Al‐Lozi, Muhammad Taher ; Bucelli, Robert C. ; Budhram, Adrian ; Cho, Tracey ; Choi, Ellie ; Grell, Jacquelyn ; Lopez‐Chiriboga, Alfonso Sebastian ; Levin, Marc ; Merati, Melody ; Montalvo, Mayra ; Pittock, Sean J. ; Wilson, Michael R. ; Howe, Charles L. ; McKeon, Andrew</creatorcontrib><description>Background and Objectives
We sought to determine clinical significance of neuronal septin autoimmunity and evaluate for potential IgG effects.
Methods
Septin‐IgGs were detected by indirect immunofluorescence assays (IFAs; mouse tissue and cell based) or Western blot. IgG binding to (and internalization of) extracellular septin epitopes were evaluated for by live rat hippocampal neuron assay. The impact of purified patient IgGs on murine cortical neuron function was determined by recording extracellular field potentials in a multielectrode array platform.
Results
Septin‐IgGs were identified in 23 patients. All 8 patients with septin‐5‐IgG detected had cerebellar ataxia, and 7 had prominent eye movement disorders. One of 2 patients with co‐existing septin‐7‐IgG had additional psychiatric phenotype (apathy, emotional blunting, and poor insight). Fifteen patients had septin‐7 autoimmunity, without septin‐5‐IgG detected. Disorders included encephalopathy (11; 2 patients with accompanying myelopathy, and 2 were relapsing), myelopathy (3), and episodic ataxia (1). Psychiatric symptoms (≥1 of agitation, apathy, catatonia, disorganized thinking, and paranoia) were prominent in 6 of 11 patients with encephalopathic symptoms. Eight of 10 patients with data available (from 23 total) improved after immunotherapy, and a further 2 patients improved spontaneously. Staining of plasma membranes of live hippocampal neurons produced by patient IgGs (subclasses 1 and 2) colocalized with pre‐ and post‐synaptic markers. Decreased spiking and bursting behavior in mixed cultures of murine glutamatergic and GABAergic cortical neurons produced by patient IgGs were attributable to neither antigenic crosslinking and internalization nor complement activation.
Interpretation
Septin‐IgGs are predictive of distinct treatment‐responsive autoimmune central nervous system (CNS) disorders. Live neuron binding and induced electrophysiologic effects by patient IgGs may support septin‐specific pathophysiology. ANN NEUROL 2022;92:1090–1101</description><identifier>ISSN: 0364-5134</identifier><identifier>EISSN: 1531-8249</identifier><identifier>DOI: 10.1002/ana.26482</identifier><identifier>PMID: 36053822</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley & Sons, Inc</publisher><subject>Animal tissues ; Animals ; Antigens ; Apathy ; Ataxia ; Autoimmunity ; Binding ; Brain Diseases ; Catatonia ; Central nervous system ; Central nervous system diseases ; Cerebellar ataxia ; Cerebellum ; Complement activation ; Crosslinking ; Disorders ; Emotional behavior ; Encephalopathy ; Epitopes ; Eye movements ; Firing pattern ; Glutamatergic transmission ; Hippocampus ; Immunofluorescence ; Immunoglobulin G ; Immunoglobulin G - metabolism ; Immunotherapy ; Internalization ; Mice ; Movement disorders ; Neurons ; Neurons - metabolism ; Patients ; Phenotypes ; Plasma membranes ; Rats ; Septin ; Septins - metabolism ; Signs and symptoms ; Spinal cord ; Spinal Cord Diseases ; γ-Aminobutyric acid</subject><ispartof>Annals of neurology, 2022-12, Vol.92 (6), p.1090-1101</ispartof><rights>2022 American Neurological Association.</rights><rights>2022 American Neurological Association</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4432-5f51e109704a073ff85e6f06e86068296fe0e79494983a6dfdb6f0f4abe2f8323</citedby><cites>FETCH-LOGICAL-c4432-5f51e109704a073ff85e6f06e86068296fe0e79494983a6dfdb6f0f4abe2f8323</cites><orcidid>0000-0003-2054-3486 ; 0000-0001-6856-8143 ; 0000-0002-8705-5084 ; 0000-0001-5653-5600 ; 0000-0002-6140-5584 ; 0000-0002-9166-9820</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fana.26482$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fana.26482$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,776,780,881,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36053822$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hinson, Shannon R.</creatorcontrib><creatorcontrib>Honorat, Josephe A.</creatorcontrib><creatorcontrib>Grund, Ethan M.</creatorcontrib><creatorcontrib>Clarkson, Benjamin D.</creatorcontrib><creatorcontrib>Miske, Ramona</creatorcontrib><creatorcontrib>Scharf, Madeleine</creatorcontrib><creatorcontrib>Zivelonghi, Cecilia</creatorcontrib><creatorcontrib>Al‐Lozi, Muhammad Taher</creatorcontrib><creatorcontrib>Bucelli, Robert C.</creatorcontrib><creatorcontrib>Budhram, Adrian</creatorcontrib><creatorcontrib>Cho, Tracey</creatorcontrib><creatorcontrib>Choi, Ellie</creatorcontrib><creatorcontrib>Grell, Jacquelyn</creatorcontrib><creatorcontrib>Lopez‐Chiriboga, Alfonso Sebastian</creatorcontrib><creatorcontrib>Levin, Marc</creatorcontrib><creatorcontrib>Merati, Melody</creatorcontrib><creatorcontrib>Montalvo, Mayra</creatorcontrib><creatorcontrib>Pittock, Sean J.</creatorcontrib><creatorcontrib>Wilson, Michael R.</creatorcontrib><creatorcontrib>Howe, Charles L.</creatorcontrib><creatorcontrib>McKeon, Andrew</creatorcontrib><title>Septin‐5 and ‐7‐IgGs: Neurologic, Serologic, and Pathophysiologic Characteristics</title><title>Annals of neurology</title><addtitle>Ann Neurol</addtitle><description>Background and Objectives
We sought to determine clinical significance of neuronal septin autoimmunity and evaluate for potential IgG effects.
Methods
Septin‐IgGs were detected by indirect immunofluorescence assays (IFAs; mouse tissue and cell based) or Western blot. IgG binding to (and internalization of) extracellular septin epitopes were evaluated for by live rat hippocampal neuron assay. The impact of purified patient IgGs on murine cortical neuron function was determined by recording extracellular field potentials in a multielectrode array platform.
Results
Septin‐IgGs were identified in 23 patients. All 8 patients with septin‐5‐IgG detected had cerebellar ataxia, and 7 had prominent eye movement disorders. One of 2 patients with co‐existing septin‐7‐IgG had additional psychiatric phenotype (apathy, emotional blunting, and poor insight). Fifteen patients had septin‐7 autoimmunity, without septin‐5‐IgG detected. Disorders included encephalopathy (11; 2 patients with accompanying myelopathy, and 2 were relapsing), myelopathy (3), and episodic ataxia (1). Psychiatric symptoms (≥1 of agitation, apathy, catatonia, disorganized thinking, and paranoia) were prominent in 6 of 11 patients with encephalopathic symptoms. Eight of 10 patients with data available (from 23 total) improved after immunotherapy, and a further 2 patients improved spontaneously. Staining of plasma membranes of live hippocampal neurons produced by patient IgGs (subclasses 1 and 2) colocalized with pre‐ and post‐synaptic markers. Decreased spiking and bursting behavior in mixed cultures of murine glutamatergic and GABAergic cortical neurons produced by patient IgGs were attributable to neither antigenic crosslinking and internalization nor complement activation.
Interpretation
Septin‐IgGs are predictive of distinct treatment‐responsive autoimmune central nervous system (CNS) disorders. Live neuron binding and induced electrophysiologic effects by patient IgGs may support septin‐specific pathophysiology. ANN NEUROL 2022;92:1090–1101</description><subject>Animal tissues</subject><subject>Animals</subject><subject>Antigens</subject><subject>Apathy</subject><subject>Ataxia</subject><subject>Autoimmunity</subject><subject>Binding</subject><subject>Brain Diseases</subject><subject>Catatonia</subject><subject>Central nervous system</subject><subject>Central nervous system diseases</subject><subject>Cerebellar ataxia</subject><subject>Cerebellum</subject><subject>Complement activation</subject><subject>Crosslinking</subject><subject>Disorders</subject><subject>Emotional behavior</subject><subject>Encephalopathy</subject><subject>Epitopes</subject><subject>Eye movements</subject><subject>Firing pattern</subject><subject>Glutamatergic transmission</subject><subject>Hippocampus</subject><subject>Immunofluorescence</subject><subject>Immunoglobulin G</subject><subject>Immunoglobulin G - metabolism</subject><subject>Immunotherapy</subject><subject>Internalization</subject><subject>Mice</subject><subject>Movement disorders</subject><subject>Neurons</subject><subject>Neurons - metabolism</subject><subject>Patients</subject><subject>Phenotypes</subject><subject>Plasma membranes</subject><subject>Rats</subject><subject>Septin</subject><subject>Septins - metabolism</subject><subject>Signs and symptoms</subject><subject>Spinal cord</subject><subject>Spinal Cord Diseases</subject><subject>γ-Aminobutyric acid</subject><issn>0364-5134</issn><issn>1531-8249</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kd9qFDEUh0Ox2LV60ReQAW8UnPbk70y8EJZF20KpQpVehuzsyW7K7GRNZpS98xH6jH0SU6cuVZAQcsj5-DiHHyFHFI4pADuxnT1mStRsj0yo5LSsmdBPyAS4EqWkXByQZyndAIBWFJ6SA65A8pqxCbm-wk3vu7uft7Kw3aLIRZXv-fI0vSsucYihDUvfvC2ucFfec59tvwqb1Tb58beYrWy0TY_Rp9436TnZd7ZN-OLhPSRfP374MjsrLz6dns-mF2UjBGeldJIiBV2BsFBx52qJyoHCWoGqmVYOASst8qm5VQu3mOe2E3aOzNWc8UPyfvRuhvkaFw12fbSt2US_tnFrgvXm707nV2YZvhutKqZBZMHrB0EM3wZMvVn71GDb2g7DkAyr8nRcaqEy-uof9CYMscvrZYormXWVztSbkWpiSCmi2w1DwdzHZXJc5ndcmX35ePod-SefDJyMwA_f4vb_JjO9nI7KX_QCoPg</recordid><startdate>202212</startdate><enddate>202212</enddate><creator>Hinson, Shannon R.</creator><creator>Honorat, Josephe A.</creator><creator>Grund, Ethan M.</creator><creator>Clarkson, Benjamin D.</creator><creator>Miske, Ramona</creator><creator>Scharf, Madeleine</creator><creator>Zivelonghi, Cecilia</creator><creator>Al‐Lozi, Muhammad Taher</creator><creator>Bucelli, Robert C.</creator><creator>Budhram, Adrian</creator><creator>Cho, Tracey</creator><creator>Choi, Ellie</creator><creator>Grell, Jacquelyn</creator><creator>Lopez‐Chiriboga, Alfonso Sebastian</creator><creator>Levin, Marc</creator><creator>Merati, Melody</creator><creator>Montalvo, Mayra</creator><creator>Pittock, Sean J.</creator><creator>Wilson, Michael R.</creator><creator>Howe, Charles L.</creator><creator>McKeon, Andrew</creator><general>John Wiley & Sons, Inc</general><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7U7</scope><scope>C1K</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2054-3486</orcidid><orcidid>https://orcid.org/0000-0001-6856-8143</orcidid><orcidid>https://orcid.org/0000-0002-8705-5084</orcidid><orcidid>https://orcid.org/0000-0001-5653-5600</orcidid><orcidid>https://orcid.org/0000-0002-6140-5584</orcidid><orcidid>https://orcid.org/0000-0002-9166-9820</orcidid></search><sort><creationdate>202212</creationdate><title>Septin‐5 and ‐7‐IgGs: Neurologic, Serologic, and Pathophysiologic Characteristics</title><author>Hinson, Shannon R. ; Honorat, Josephe A. ; Grund, Ethan M. ; Clarkson, Benjamin D. ; Miske, Ramona ; Scharf, Madeleine ; Zivelonghi, Cecilia ; Al‐Lozi, Muhammad Taher ; Bucelli, Robert C. ; Budhram, Adrian ; Cho, Tracey ; Choi, Ellie ; Grell, Jacquelyn ; Lopez‐Chiriboga, Alfonso Sebastian ; Levin, Marc ; Merati, Melody ; Montalvo, Mayra ; Pittock, Sean J. ; Wilson, Michael R. ; Howe, Charles L. ; McKeon, Andrew</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4432-5f51e109704a073ff85e6f06e86068296fe0e79494983a6dfdb6f0f4abe2f8323</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animal tissues</topic><topic>Animals</topic><topic>Antigens</topic><topic>Apathy</topic><topic>Ataxia</topic><topic>Autoimmunity</topic><topic>Binding</topic><topic>Brain Diseases</topic><topic>Catatonia</topic><topic>Central nervous system</topic><topic>Central nervous system diseases</topic><topic>Cerebellar ataxia</topic><topic>Cerebellum</topic><topic>Complement activation</topic><topic>Crosslinking</topic><topic>Disorders</topic><topic>Emotional behavior</topic><topic>Encephalopathy</topic><topic>Epitopes</topic><topic>Eye movements</topic><topic>Firing pattern</topic><topic>Glutamatergic transmission</topic><topic>Hippocampus</topic><topic>Immunofluorescence</topic><topic>Immunoglobulin G</topic><topic>Immunoglobulin G - metabolism</topic><topic>Immunotherapy</topic><topic>Internalization</topic><topic>Mice</topic><topic>Movement disorders</topic><topic>Neurons</topic><topic>Neurons - metabolism</topic><topic>Patients</topic><topic>Phenotypes</topic><topic>Plasma membranes</topic><topic>Rats</topic><topic>Septin</topic><topic>Septins - metabolism</topic><topic>Signs and symptoms</topic><topic>Spinal cord</topic><topic>Spinal Cord Diseases</topic><topic>γ-Aminobutyric acid</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hinson, Shannon R.</creatorcontrib><creatorcontrib>Honorat, Josephe A.</creatorcontrib><creatorcontrib>Grund, Ethan M.</creatorcontrib><creatorcontrib>Clarkson, Benjamin D.</creatorcontrib><creatorcontrib>Miske, Ramona</creatorcontrib><creatorcontrib>Scharf, Madeleine</creatorcontrib><creatorcontrib>Zivelonghi, Cecilia</creatorcontrib><creatorcontrib>Al‐Lozi, Muhammad Taher</creatorcontrib><creatorcontrib>Bucelli, Robert C.</creatorcontrib><creatorcontrib>Budhram, Adrian</creatorcontrib><creatorcontrib>Cho, Tracey</creatorcontrib><creatorcontrib>Choi, Ellie</creatorcontrib><creatorcontrib>Grell, Jacquelyn</creatorcontrib><creatorcontrib>Lopez‐Chiriboga, Alfonso Sebastian</creatorcontrib><creatorcontrib>Levin, Marc</creatorcontrib><creatorcontrib>Merati, Melody</creatorcontrib><creatorcontrib>Montalvo, Mayra</creatorcontrib><creatorcontrib>Pittock, Sean J.</creatorcontrib><creatorcontrib>Wilson, Michael R.</creatorcontrib><creatorcontrib>Howe, Charles L.</creatorcontrib><creatorcontrib>McKeon, Andrew</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Annals of neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hinson, Shannon R.</au><au>Honorat, Josephe A.</au><au>Grund, Ethan M.</au><au>Clarkson, Benjamin D.</au><au>Miske, Ramona</au><au>Scharf, Madeleine</au><au>Zivelonghi, Cecilia</au><au>Al‐Lozi, Muhammad Taher</au><au>Bucelli, Robert C.</au><au>Budhram, Adrian</au><au>Cho, Tracey</au><au>Choi, Ellie</au><au>Grell, Jacquelyn</au><au>Lopez‐Chiriboga, Alfonso Sebastian</au><au>Levin, Marc</au><au>Merati, Melody</au><au>Montalvo, Mayra</au><au>Pittock, Sean J.</au><au>Wilson, Michael R.</au><au>Howe, Charles L.</au><au>McKeon, Andrew</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Septin‐5 and ‐7‐IgGs: Neurologic, Serologic, and Pathophysiologic Characteristics</atitle><jtitle>Annals of neurology</jtitle><addtitle>Ann Neurol</addtitle><date>2022-12</date><risdate>2022</risdate><volume>92</volume><issue>6</issue><spage>1090</spage><epage>1101</epage><pages>1090-1101</pages><issn>0364-5134</issn><eissn>1531-8249</eissn><abstract>Background and Objectives
We sought to determine clinical significance of neuronal septin autoimmunity and evaluate for potential IgG effects.
Methods
Septin‐IgGs were detected by indirect immunofluorescence assays (IFAs; mouse tissue and cell based) or Western blot. IgG binding to (and internalization of) extracellular septin epitopes were evaluated for by live rat hippocampal neuron assay. The impact of purified patient IgGs on murine cortical neuron function was determined by recording extracellular field potentials in a multielectrode array platform.
Results
Septin‐IgGs were identified in 23 patients. All 8 patients with septin‐5‐IgG detected had cerebellar ataxia, and 7 had prominent eye movement disorders. One of 2 patients with co‐existing septin‐7‐IgG had additional psychiatric phenotype (apathy, emotional blunting, and poor insight). Fifteen patients had septin‐7 autoimmunity, without septin‐5‐IgG detected. Disorders included encephalopathy (11; 2 patients with accompanying myelopathy, and 2 were relapsing), myelopathy (3), and episodic ataxia (1). Psychiatric symptoms (≥1 of agitation, apathy, catatonia, disorganized thinking, and paranoia) were prominent in 6 of 11 patients with encephalopathic symptoms. Eight of 10 patients with data available (from 23 total) improved after immunotherapy, and a further 2 patients improved spontaneously. Staining of plasma membranes of live hippocampal neurons produced by patient IgGs (subclasses 1 and 2) colocalized with pre‐ and post‐synaptic markers. Decreased spiking and bursting behavior in mixed cultures of murine glutamatergic and GABAergic cortical neurons produced by patient IgGs were attributable to neither antigenic crosslinking and internalization nor complement activation.
Interpretation
Septin‐IgGs are predictive of distinct treatment‐responsive autoimmune central nervous system (CNS) disorders. Live neuron binding and induced electrophysiologic effects by patient IgGs may support septin‐specific pathophysiology. ANN NEUROL 2022;92:1090–1101</abstract><cop>Hoboken, USA</cop><pub>John Wiley & Sons, Inc</pub><pmid>36053822</pmid><doi>10.1002/ana.26482</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-2054-3486</orcidid><orcidid>https://orcid.org/0000-0001-6856-8143</orcidid><orcidid>https://orcid.org/0000-0002-8705-5084</orcidid><orcidid>https://orcid.org/0000-0001-5653-5600</orcidid><orcidid>https://orcid.org/0000-0002-6140-5584</orcidid><orcidid>https://orcid.org/0000-0002-9166-9820</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Annals of neurology, 2022-12, Vol.92 (6), p.1090-1101 |
| issn | 0364-5134 1531-8249 |
| language | eng |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Animal tissues Animals Antigens Apathy Ataxia Autoimmunity Binding Brain Diseases Catatonia Central nervous system Central nervous system diseases Cerebellar ataxia Cerebellum Complement activation Crosslinking Disorders Emotional behavior Encephalopathy Epitopes Eye movements Firing pattern Glutamatergic transmission Hippocampus Immunofluorescence Immunoglobulin G Immunoglobulin G - metabolism Immunotherapy Internalization Mice Movement disorders Neurons Neurons - metabolism Patients Phenotypes Plasma membranes Rats Septin Septins - metabolism Signs and symptoms Spinal cord Spinal Cord Diseases γ-Aminobutyric acid |
| title | Septin‐5 and ‐7‐IgGs: Neurologic, Serologic, and Pathophysiologic Characteristics |
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