A possible role for humoral immunity in the pathogenesis of Parkinson's disease
Identifieur interne : 000974 ( Main/Corpus ); précédent : 000973; suivant : 000975A possible role for humoral immunity in the pathogenesis of Parkinson's disease
Auteurs : Carolyn F. Orr ; Dominic B. Rowe ; Yoshikuni Mizuno ; Hideo Mori ; Glenda M. HallidaySource :
- Brain [ 0006-8950 ] ; 2005-11.
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- KwdEn :
Abstract
The pathogenesis of idiopathic Parkinson's disease is unknown, but nigral degeneration and depigmentation are associated with microglial inflammation and anti-inflammatory medications appear to protect against the disease. The possibility that humoral immunity may play a role in initiating or regulating the inflammation has been suggested by experimental studies triggering dopamine cell death using a variety of transfer strategies and the observation of CD8+ T lymphocytes and complement in the nigra in Parkinson's disease. We analysed the association between degeneration and humoral immune markers in brain tissue of patients with idiopathic (n = 13) or genetic (n = 2 with α-synuclein and n = 1 with parkin mutations) Parkinson's disease and controls without neurological disease (n = 12) to determine the humoral immune involvement in Parkinson's disease. Formalin-fixed tissue samples from the substantia nigra and primary visual cortex for comparison were stained for α-synuclein, major histocompatibility complex II (HLA), immunoglobulin M (IgM), immunoglobulin G (IgG), IgG subclasses 1–4 and IgG receptors FcγR I–III. Antigen retrieval and both single immunoperoxidase and double immunofluorescence procedures were employed to determine the cell types involved and their pattern and semiquantitative densities. Significant dopamine neuron loss occurred in all patients with Parkinson's disease, negatively correlating with disease duration (r = −0.76, P = 0.002). Although all patients had increased inflammatory HLA immunopositive microglia, the degree of inflammation was similar throughout the disease (r = 0.08, P = 0.82). All patients with Parkinson's disease had IgG binding on dopamine neurons but not IgM binding. Lewy bodies were strongly immunolabelled with IgG. A mean 30 ± 12% of dopamine nigral neurons were immunoreactive for IgG in Parkinson's disease with the proportion of IgG immunopositive neurons negatively correlating with the degree of cell loss in the substantia nigra (r = −0.67, P < 0.0001) and positively correlating with the number of HLA immunopositive microglia (r = 0.51, P = 0.01). Most neuronal IgG was the IgG1 subclass with some IgG3 and less IgG2 also found in the damaged substantia nigra. The high affinity activating IgG receptor, FcγRI, was expressed on nearby activated microglia. The low affinity activating IgG receptor, FcγRIII was expressed on cells morphologically resembling lymphocytes, whereas immunoreactivity for the inhibitory IgG receptor FcγRII was absent in all cases. This pattern of humoral immune reactivity is consistent with an immune activation of microglia leading to the targeting of dopamine nigral neurons for destruction in both idiopathic and genetic cases of Parkinson's disease.
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DOI: 10.1093/brain/awh625
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Halliday</name><affiliation><mods:affiliation>Prince of Wales Medical Research Institute, University of New South Wales, Randwick,</mods:affiliation></affiliation><affiliation><mods:affiliation>Prince of Wales Medical Research Institute, University of New South Wales, Randwick,</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Brain</title><title level="j" type="abbrev">Brain</title><idno type="ISSN">0006-8950</idno><idno type="eISSN">1460-2156</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2005-11">2005-11</date><biblScope unit="volume">128</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="2665">2665</biblScope><biblScope unit="page" to="2674">2674</biblScope></imprint><idno type="ISSN">0006-8950</idno></series><idno type="istex">45F42263D90032254FDBC8391187FCC25C2D894E</idno><idno type="DOI">10.1093/brain/awh625</idno><idno type="local">awh625</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0006-8950</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>IgG = immunoglobulin G</term><term>IgM = immunoglobulin M</term><term>Parkinson's disease</term><term>SN = substantia nigra pars compacta</term><term>humoral immunity</term><term>microglia</term><term>neuropathology</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The pathogenesis of idiopathic Parkinson's disease is unknown, but nigral degeneration and depigmentation are associated with microglial inflammation and anti-inflammatory medications appear to protect against the disease. The possibility that humoral immunity may play a role in initiating or regulating the inflammation has been suggested by experimental studies triggering dopamine cell death using a variety of transfer strategies and the observation of CD8+ T lymphocytes and complement in the nigra in Parkinson's disease. We analysed the association between degeneration and humoral immune markers in brain tissue of patients with idiopathic (n = 13) or genetic (n = 2 with α-synuclein and n = 1 with parkin mutations) Parkinson's disease and controls without neurological disease (n = 12) to determine the humoral immune involvement in Parkinson's disease. Formalin-fixed tissue samples from the substantia nigra and primary visual cortex for comparison were stained for α-synuclein, major histocompatibility complex II (HLA), immunoglobulin M (IgM), immunoglobulin G (IgG), IgG subclasses 1–4 and IgG receptors FcγR I–III. Antigen retrieval and both single immunoperoxidase and double immunofluorescence procedures were employed to determine the cell types involved and their pattern and semiquantitative densities. Significant dopamine neuron loss occurred in all patients with Parkinson's disease, negatively correlating with disease duration (r = −0.76, P = 0.002). Although all patients had increased inflammatory HLA immunopositive microglia, the degree of inflammation was similar throughout the disease (r = 0.08, P = 0.82). All patients with Parkinson's disease had IgG binding on dopamine neurons but not IgM binding. Lewy bodies were strongly immunolabelled with IgG. A mean 30 ± 12% of dopamine nigral neurons were immunoreactive for IgG in Parkinson's disease with the proportion of IgG immunopositive neurons negatively correlating with the degree of cell loss in the substantia nigra (r = −0.67, P < 0.0001) and positively correlating with the number of HLA immunopositive microglia (r = 0.51, P = 0.01). Most neuronal IgG was the IgG1 subclass with some IgG3 and less IgG2 also found in the damaged substantia nigra. The high affinity activating IgG receptor, FcγRI, was expressed on nearby activated microglia. The low affinity activating IgG receptor, FcγRIII was expressed on cells morphologically resembling lymphocytes, whereas immunoreactivity for the inhibitory IgG receptor FcγRII was absent in all cases. This pattern of humoral immune reactivity is consistent with an immune activation of microglia leading to the targeting of dopamine nigral neurons for destruction in both idiopathic and genetic cases of Parkinson's disease.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Carolyn F. 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Rowe</name><affiliations><json:string>Department of Neurology, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia and</json:string><json:string>Prince of Wales Medical Research Institute, University of New South Wales, Randwick,</json:string></affiliations></json:item><json:item><name>Yoshikuni Mizuno</name><affiliations><json:string>Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan</json:string><json:string>Prince of Wales Medical Research Institute, University of New South Wales, Randwick,</json:string></affiliations></json:item><json:item><name>Hideo Mori</name><affiliations><json:string>Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan</json:string><json:string>Prince of Wales Medical Research Institute, University of New South Wales, Randwick,</json:string></affiliations></json:item><json:item><name>Glenda M. 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The possibility that humoral immunity may play a role in initiating or regulating the inflammation has been suggested by experimental studies triggering dopamine cell death using a variety of transfer strategies and the observation of CD8+ T lymphocytes and complement in the nigra in Parkinson's disease. We analysed the association between degeneration and humoral immune markers in brain tissue of patients with idiopathic (n = 13) or genetic (n = 2 with α-synuclein and n = 1 with parkin mutations) Parkinson's disease and controls without neurological disease (n = 12) to determine the humoral immune involvement in Parkinson's disease. Formalin-fixed tissue samples from the substantia nigra and primary visual cortex for comparison were stained for α-synuclein, major histocompatibility complex II (HLA), immunoglobulin M (IgM), immunoglobulin G (IgG), IgG subclasses 1–4 and IgG receptors FcγR I–III. Antigen retrieval and both single immunoperoxidase and double immunofluorescence procedures were employed to determine the cell types involved and their pattern and semiquantitative densities. Significant dopamine neuron loss occurred in all patients with Parkinson's disease, negatively correlating with disease duration (r = −0.76, P = 0.002). Although all patients had increased inflammatory HLA immunopositive microglia, the degree of inflammation was similar throughout the disease (r = 0.08, P = 0.82). All patients with Parkinson's disease had IgG binding on dopamine neurons but not IgM binding. Lewy bodies were strongly immunolabelled with IgG. A mean 30 ± 12% of dopamine nigral neurons were immunoreactive for IgG in Parkinson's disease with the proportion of IgG immunopositive neurons negatively correlating with the degree of cell loss in the substantia nigra (r = −0.67, P > 0.0001) and positively correlating with the number of HLA immunopositive microglia (r = 0.51, P = 0.01). Most neuronal IgG was the IgG1 subclass with some IgG3 and less IgG2 also found in the damaged substantia nigra. The high affinity activating IgG receptor, FcγRI, was expressed on nearby activated microglia. The low affinity activating IgG receptor, FcγRIII was expressed on cells morphologically resembling lymphocytes, whereas immunoreactivity for the inhibitory IgG receptor FcγRII was absent in all cases. This pattern of humoral immune reactivity is consistent with an immune activation of microglia leading to the targeting of dopamine nigral neurons for destruction in both idiopathic and genetic cases of Parkinson's disease.</abstract><qualityIndicators><score>8.5</score><pdfVersion>1.4</pdfVersion><pdfPageSize>612.288 x 790.87 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>8</keywordCount><abstractCharCount>2761</abstractCharCount><pdfWordCount>6183</pdfWordCount><pdfCharCount>40175</pdfCharCount><pdfPageCount>10</pdfPageCount><abstractWordCount>404</abstractWordCount></qualityIndicators><title>A possible role for humoral immunity in the pathogenesis of Parkinson's disease</title><genre><json:string>research-article</json:string></genre><host><volume>128</volume><pages><last>2674</last><first>2665</first></pages><issn><json:string>0006-8950</json:string></issn><issue>11</issue><genre></genre><language><json:string>unknown</json:string></language><eissn><json:string>1460-2156</json:string></eissn><title>Brain</title></host><categories><wos><json:string>CLINICAL NEUROLOGY</json:string><json:string>NEUROSCIENCES</json:string></wos></categories><publicationDate>2005</publicationDate><copyrightDate>2005</copyrightDate><doi><json:string>10.1093/brain/awh625</json:string></doi><id>45F42263D90032254FDBC8391187FCC25C2D894E</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/45F42263D90032254FDBC8391187FCC25C2D894E/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/45F42263D90032254FDBC8391187FCC25C2D894E/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/45F42263D90032254FDBC8391187FCC25C2D894E/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">A possible role for humoral immunity in the pathogenesis of Parkinson's disease</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Oxford University Press</publisher><availability><p>OUP</p></availability><date>2005-10-11</date></publicationStmt><notesStmt><note>Correspondence to: Professor G. M. Halliday, PhD, Prince of Wales Medical Research Institute, University of New South Wales, Randwick, Sydney, NSW 2031, Australia E-mail: g.halliday@unsw.edu.au</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">A possible role for humoral immunity in the pathogenesis of Parkinson's disease</title><author><persName><forename type="first">Carolyn F.</forename><surname>Orr</surname></persName><affiliation>Prince of Wales Medical Research Institute, University of New South Wales, Randwick,</affiliation><affiliation>Prince of Wales Medical Research Institute, University of New South Wales, Randwick,</affiliation></author><author><persName><forename type="first">Dominic B.</forename><surname>Rowe</surname></persName><affiliation>Department of Neurology, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia and</affiliation><affiliation>Prince of Wales Medical Research Institute, University of New South Wales, Randwick,</affiliation></author><author><persName><forename type="first">Yoshikuni</forename><surname>Mizuno</surname></persName><affiliation>Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan</affiliation><affiliation>Prince of Wales Medical Research Institute, University of New South Wales, Randwick,</affiliation></author><author><persName><forename type="first">Hideo</forename><surname>Mori</surname></persName><affiliation>Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan</affiliation><affiliation>Prince of Wales Medical Research Institute, University of New South Wales, Randwick,</affiliation></author><author><persName><forename type="first">Glenda M.</forename><surname>Halliday</surname></persName><affiliation>Prince of Wales Medical Research Institute, University of New South Wales, Randwick,</affiliation><affiliation>Prince of Wales Medical Research Institute, University of New South Wales, Randwick,</affiliation></author></analytic><monogr><title level="j">Brain</title><title level="j" type="abbrev">Brain</title><idno type="pISSN">0006-8950</idno><idno type="eISSN">1460-2156</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2005-11"></date><biblScope unit="volume">128</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="2665">2665</biblScope><biblScope unit="page" to="2674">2674</biblScope></imprint></monogr><idno type="istex">45F42263D90032254FDBC8391187FCC25C2D894E</idno><idno type="DOI">10.1093/brain/awh625</idno><idno type="local">awh625</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2005-10-11</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>The pathogenesis of idiopathic Parkinson's disease is unknown, but nigral degeneration and depigmentation are associated with microglial inflammation and anti-inflammatory medications appear to protect against the disease. The possibility that humoral immunity may play a role in initiating or regulating the inflammation has been suggested by experimental studies triggering dopamine cell death using a variety of transfer strategies and the observation of CD8+ T lymphocytes and complement in the nigra in Parkinson's disease. We analysed the association between degeneration and humoral immune markers in brain tissue of patients with idiopathic (n = 13) or genetic (n = 2 with α-synuclein and n = 1 with parkin mutations) Parkinson's disease and controls without neurological disease (n = 12) to determine the humoral immune involvement in Parkinson's disease. Formalin-fixed tissue samples from the substantia nigra and primary visual cortex for comparison were stained for α-synuclein, major histocompatibility complex II (HLA), immunoglobulin M (IgM), immunoglobulin G (IgG), IgG subclasses 1–4 and IgG receptors FcγR I–III. Antigen retrieval and both single immunoperoxidase and double immunofluorescence procedures were employed to determine the cell types involved and their pattern and semiquantitative densities. Significant dopamine neuron loss occurred in all patients with Parkinson's disease, negatively correlating with disease duration (r = −0.76, P = 0.002). Although all patients had increased inflammatory HLA immunopositive microglia, the degree of inflammation was similar throughout the disease (r = 0.08, P = 0.82). All patients with Parkinson's disease had IgG binding on dopamine neurons but not IgM binding. Lewy bodies were strongly immunolabelled with IgG. A mean 30 ± 12% of dopamine nigral neurons were immunoreactive for IgG in Parkinson's disease with the proportion of IgG immunopositive neurons negatively correlating with the degree of cell loss in the substantia nigra (r = −0.67, P < 0.0001) and positively correlating with the number of HLA immunopositive microglia (r = 0.51, P = 0.01). Most neuronal IgG was the IgG1 subclass with some IgG3 and less IgG2 also found in the damaged substantia nigra. The high affinity activating IgG receptor, FcγRI, was expressed on nearby activated microglia. The low affinity activating IgG receptor, FcγRIII was expressed on cells morphologically resembling lymphocytes, whereas immunoreactivity for the inhibitory IgG receptor FcγRII was absent in all cases. This pattern of humoral immune reactivity is consistent with an immune activation of microglia leading to the targeting of dopamine nigral neurons for destruction in both idiopathic and genetic cases of Parkinson's disease.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>KWD</head><item><term>Parkinson's disease</term></item><item><term>microglia</term></item><item><term>humoral immunity</term></item><item><term>neuropathology</term></item></list></keywords></textClass><textClass xml:lang="en"><keywords scheme="keyword"><list><head>ABR</head><item><term>IgG = immunoglobulin G</term></item><item><term>IgM = immunoglobulin M</term></item><item><term>SN = substantia nigra pars compacta</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2005-10-11">Created</change><change when="2005-11">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/45F42263D90032254FDBC8391187FCC25C2D894E/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="US-ASCII"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article xml:lang="en" article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">brain</journal-id><journal-id journal-id-type="nlm-ta">Brain</journal-id><journal-id journal-id-type="publisher-id">brainj</journal-id><journal-title>Brain</journal-title><abbrev-journal-title abbrev-type="publisher">Brain</abbrev-journal-title><issn pub-type="ppub">0006-8950</issn><issn pub-type="epub">1460-2156</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="other">awh625</article-id><article-id pub-id-type="doi">10.1093/brain/awh625</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Articles</subject></subj-group></article-categories><title-group><article-title>A possible role for humoral immunity in the pathogenesis of Parkinson's disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Orr</surname><given-names>Carolyn F.</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Rowe</surname><given-names>Dominic B.</given-names></name><xref rid="AFF2">2</xref></contrib><contrib contrib-type="author"><name><surname>Mizuno</surname><given-names>Yoshikuni</given-names></name><xref rid="AFF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Mori</surname><given-names>Hideo</given-names></name><xref rid="AFF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Halliday</surname><given-names>Glenda M.</given-names></name><xref rid="AFF1">1</xref></contrib><aff><target target-type="aff" id="AFF1"></target><label>1</label>Prince of Wales Medical Research Institute, University of New South Wales, Randwick, <target target-type="aff" id="AFF2"></target><label>2</label>Department of Neurology, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia and <target target-type="aff" id="AFF3"></target><label>3</label>Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan</aff></contrib-group><author-notes><corresp>Correspondence to: Professor G. M. Halliday, PhD, Prince of Wales Medical Research Institute, University of New South Wales, Randwick, Sydney, NSW 2031, Australia E-mail: <ext-link xlink:href="g.halliday@unsw.edu.au" ext-link-type="email">g.halliday@unsw.edu.au</ext-link></corresp></author-notes><pub-date pub-type="ppub"><month>November</month><year>2005</year></pub-date><pub-date pub-type="epub"><day>11</day><month>10</month><year>2005</year></pub-date><volume>128</volume><issue>11</issue><fpage>2665</fpage><lpage>2674</lpage><history><date date-type="accepted"><day>1</day><month>8</month><year>2005</year></date><date date-type="received"><day>3</day><month>9</month><year>2004</year></date><date date-type="rev-recd"><day>30</day><month>7</month><year>2005</year></date></history><copyright-statement>© The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2005</copyright-year><abstract xml:lang="en"><p>The pathogenesis of idiopathic Parkinson's disease is unknown, but nigral degeneration and depigmentation are associated with microglial inflammation and anti-inflammatory medications appear to protect against the disease. The possibility that humoral immunity may play a role in initiating or regulating the inflammation has been suggested by experimental studies triggering dopamine cell death using a variety of transfer strategies and the observation of CD8+ T lymphocytes and complement in the nigra in Parkinson's disease. We analysed the association between degeneration and humoral immune markers in brain tissue of patients with idiopathic (<italic>n</italic> = 13) or genetic (<italic>n</italic> = 2 with α-synuclein and <italic>n</italic> = 1 with parkin mutations) Parkinson's disease and controls without neurological disease (<italic>n</italic> = 12) to determine the humoral immune involvement in Parkinson's disease. Formalin-fixed tissue samples from the substantia nigra and primary visual cortex for comparison were stained for α-synuclein, major histocompatibility complex II (HLA), immunoglobulin M (IgM), immunoglobulin G (IgG), IgG subclasses 1–4 and IgG receptors FcγR I–III. Antigen retrieval and both single immunoperoxidase and double immunofluorescence procedures were employed to determine the cell types involved and their pattern and semiquantitative densities. Significant dopamine neuron loss occurred in all patients with Parkinson's disease, negatively correlating with disease duration (<italic>r</italic> = −0.76, <italic>P</italic> = 0.002). Although all patients had increased inflammatory HLA immunopositive microglia, the degree of inflammation was similar throughout the disease (<italic>r</italic> = 0.08, <italic>P</italic> = 0.82). All patients with Parkinson's disease had IgG binding on dopamine neurons but not IgM binding. Lewy bodies were strongly immunolabelled with IgG. A mean 30 ± 12% of dopamine nigral neurons were immunoreactive for IgG in Parkinson's disease with the proportion of IgG immunopositive neurons negatively correlating with the degree of cell loss in the substantia nigra (<italic>r</italic> = −0.67, <italic>P</italic> < 0.0001) and positively correlating with the number of HLA immunopositive microglia (<italic>r</italic> = 0.51, <italic>P</italic> = 0.01). Most neuronal IgG was the IgG1 subclass with some IgG3 and less IgG2 also found in the damaged substantia nigra. The high affinity activating IgG receptor, FcγRI, was expressed on nearby activated microglia. The low affinity activating IgG receptor, FcγRIII was expressed on cells morphologically resembling lymphocytes, whereas immunoreactivity for the inhibitory IgG receptor FcγRII was absent in all cases. This pattern of humoral immune reactivity is consistent with an immune activation of microglia leading to the targeting of dopamine nigral neurons for destruction in both idiopathic and genetic cases of Parkinson's disease.</p></abstract><kwd-group kwd-group-type="KWD" xml:lang="en"><kwd>Parkinson's disease</kwd><kwd>microglia</kwd><kwd>humoral immunity</kwd><kwd>neuropathology</kwd></kwd-group><kwd-group kwd-group-type="ABR" xml:lang="en"><kwd>IgG = immunoglobulin G</kwd><kwd>IgM = immunoglobulin M</kwd><kwd>SN = substantia nigra pars compacta</kwd></kwd-group><custom-meta-wrap><custom-meta><meta-name>hwp-legacy-fpage</meta-name><meta-value>2665</meta-value></custom-meta><custom-meta><meta-name>cover-date</meta-name><meta-value>November 2005</meta-value></custom-meta><custom-meta><meta-name>hwp-legacy-dochead</meta-name><meta-value>Original Article</meta-value></custom-meta></custom-meta-wrap></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>A possible role for humoral immunity in the pathogenesis of Parkinson's disease</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>A possible role for humoral immunity in the pathogenesis of Parkinson's disease</title></titleInfo><name type="personal"><namePart type="given">Carolyn F.</namePart><namePart type="family">Orr</namePart><affiliation>Prince of Wales Medical Research Institute, University of New South Wales, Randwick,</affiliation><affiliation>Prince of Wales Medical Research Institute, University of New South Wales, Randwick,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dominic B.</namePart><namePart type="family">Rowe</namePart><affiliation>Department of Neurology, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia and</affiliation><affiliation>Prince of Wales Medical Research Institute, University of New South Wales, Randwick,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yoshikuni</namePart><namePart type="family">Mizuno</namePart><affiliation>Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan</affiliation><affiliation>Prince of Wales Medical Research Institute, University of New South Wales, Randwick,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hideo</namePart><namePart type="family">Mori</namePart><affiliation>Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan</affiliation><affiliation>Prince of Wales Medical Research Institute, University of New South Wales, Randwick,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Glenda M.</namePart><namePart type="family">Halliday</namePart><affiliation>Prince of Wales Medical Research Institute, University of New South Wales, Randwick,</affiliation><affiliation>Prince of Wales Medical Research Institute, University of New South Wales, Randwick,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2005-11</dateIssued><dateCreated encoding="w3cdtf">2005-10-11</dateCreated><copyrightDate encoding="w3cdtf">2005</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">The pathogenesis of idiopathic Parkinson's disease is unknown, but nigral degeneration and depigmentation are associated with microglial inflammation and anti-inflammatory medications appear to protect against the disease. The possibility that humoral immunity may play a role in initiating or regulating the inflammation has been suggested by experimental studies triggering dopamine cell death using a variety of transfer strategies and the observation of CD8+ T lymphocytes and complement in the nigra in Parkinson's disease. We analysed the association between degeneration and humoral immune markers in brain tissue of patients with idiopathic (n = 13) or genetic (n = 2 with α-synuclein and n = 1 with parkin mutations) Parkinson's disease and controls without neurological disease (n = 12) to determine the humoral immune involvement in Parkinson's disease. Formalin-fixed tissue samples from the substantia nigra and primary visual cortex for comparison were stained for α-synuclein, major histocompatibility complex II (HLA), immunoglobulin M (IgM), immunoglobulin G (IgG), IgG subclasses 1–4 and IgG receptors FcγR I–III. Antigen retrieval and both single immunoperoxidase and double immunofluorescence procedures were employed to determine the cell types involved and their pattern and semiquantitative densities. Significant dopamine neuron loss occurred in all patients with Parkinson's disease, negatively correlating with disease duration (r = −0.76, P = 0.002). Although all patients had increased inflammatory HLA immunopositive microglia, the degree of inflammation was similar throughout the disease (r = 0.08, P = 0.82). All patients with Parkinson's disease had IgG binding on dopamine neurons but not IgM binding. Lewy bodies were strongly immunolabelled with IgG. A mean 30 ± 12% of dopamine nigral neurons were immunoreactive for IgG in Parkinson's disease with the proportion of IgG immunopositive neurons negatively correlating with the degree of cell loss in the substantia nigra (r = −0.67, P < 0.0001) and positively correlating with the number of HLA immunopositive microglia (r = 0.51, P = 0.01). Most neuronal IgG was the IgG1 subclass with some IgG3 and less IgG2 also found in the damaged substantia nigra. The high affinity activating IgG receptor, FcγRI, was expressed on nearby activated microglia. The low affinity activating IgG receptor, FcγRIII was expressed on cells morphologically resembling lymphocytes, whereas immunoreactivity for the inhibitory IgG receptor FcγRII was absent in all cases. This pattern of humoral immune reactivity is consistent with an immune activation of microglia leading to the targeting of dopamine nigral neurons for destruction in both idiopathic and genetic cases of Parkinson's disease.</abstract><note type="author-notes">Correspondence to: Professor G. M. Halliday, PhD, Prince of Wales Medical Research Institute, University of New South Wales, Randwick, Sydney, NSW 2031, Australia E-mail: g.halliday@unsw.edu.au</note><subject lang="en"><genre>KWD</genre><topic>Parkinson's disease</topic><topic>microglia</topic><topic>humoral immunity</topic><topic>neuropathology</topic></subject><subject lang="en"><genre>ABR</genre><topic>IgG = immunoglobulin G</topic><topic>IgM = immunoglobulin M</topic><topic>SN = substantia nigra pars compacta</topic></subject><relatedItem type="host"><titleInfo><title>Brain</title></titleInfo><titleInfo type="abbreviated"><title>Brain</title></titleInfo><genre type="Journal">journal</genre><identifier type="ISSN">0006-8950</identifier><identifier type="eISSN">1460-2156</identifier><identifier type="PublisherID">brainj</identifier><identifier type="PublisherID-hwp">brain</identifier><identifier type="PublisherID-nlm-ta">Brain</identifier><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>128</number></detail><detail type="issue"><caption>no.</caption><number>11</number></detail><extent unit="pages"><start>2665</start><end>2674</end></extent></part></relatedItem><identifier type="istex">45F42263D90032254FDBC8391187FCC25C2D894E</identifier><identifier type="DOI">10.1093/brain/awh625</identifier><identifier type="local">awh625</identifier><accessCondition type="use and reproduction" contentType="copyright">© The Author (2005). 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