Pathological manifestations in lymphatic filariasis correlate with lack of inhibitory properties of IgG4 antibodies on IgE-activated granulocytes
Identifieur interne : 000151 ( Pmc/Checkpoint ); précédent : 000150; suivant : 000152Pathological manifestations in lymphatic filariasis correlate with lack of inhibitory properties of IgG4 antibodies on IgE-activated granulocytes
Auteurs : Ulrich F. Prodjinotho [Allemagne] ; Charlotte Von Horn [Allemagne] ; Alex Y. Debrah [Ghana] ; Linda Batsa Debrah [Ghana] ; Anna Albers [Allemagne] ; Laura E. Layland [Allemagne] ; Achim Hoerauf [Allemagne] ; Tomabu Adjobimey [Allemagne, Bénin]Source :
- PLoS Neglected Tropical Diseases [ 1935-2727 ] ; 2017.
Abstract
Helminth parasites are known to be efficient modulators of their host’s immune system. To guarantee their own survival, they induce alongside the classical Th2 a strong regulatory response with high levels of anti-inflammatory cytokines and elevated plasma levels of IgG4. This particular antibody was shown in different models to exhibit immunosuppressive properties. How IgG4 affects the etiopathology of lymphatic filariasis (LF) is however not well characterized. Here we investigate the impact of plasma and affinity-purified IgG/IgG4 fractions from endemic normals (EN) and LF infected pathology patients (CP), asymptomatic microfilaraemic (Mf+) and amicrofilaraemic (Mf-) individuals on IgE/IL3 activated granulocytes. The activation and degranulation states were investigated by monitoring the expression of CD63/HLADR and the release of granule contents (neutrophil elastase (NE), eosinophil cationic protein (ECP) and histamine) respectively by flow cytometry and ELISA. We could show that the activation of granulocytes was inhibited in the presence of plasma from EN and Mf+ individuals whereas those of Mf- and CP presented no effect. This inhibitory capacity was impaired upon depletion of IgG in Mf+ individuals but persisted in IgG-depleted plasma from EN, where it strongly correlated with the expression of IgA. In addition, IgA-depleted fractions failed to suppress granulocyte activation. Strikingly, affinity-purified IgG4 antibodies from EN, Mf+ and Mf- individuals bound granulocytes and inhibited activation and the release of ECP, NE and histamine. In contrast, IgG4 from CP could not bind granulocytes and presented no suppressive capacity. Reduction of both the affinity to, and the suppressive properties of anti-inflammatory IgG4 on granulocytes was reached only when FcγRI and II were blocked simultaneously. These data indicate that IgG4 antibodies from Mf+, Mf- and EN, in contrast to those of CP, natively exhibit FcγRI/II-dependent suppressive properties on granulocytes. Our findings suggest that quantitative and qualitative alterations in IgG4 molecules are associated with the different clinical phenotypes in LF endemic regions.
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DOI: 10.1371/journal.pntd.0005777
PubMed: 28742098
PubMed Central: 5542694
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Prodjinotho</name><affiliation wicri:level="3"><nlm:aff id="aff001"><addr-line>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Von Horn, Charlotte" sort="Von Horn, Charlotte" uniqKey="Von Horn C" first="Charlotte" last="Von Horn">Charlotte Von Horn</name><affiliation wicri:level="3"><nlm:aff id="aff001"><addr-line>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Debrah, Alex Y" sort="Debrah, Alex Y" uniqKey="Debrah A" first="Alex Y." last="Debrah">Alex Y. Debrah</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR), Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea>Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR), Kwame Nkrumah University of Science and Technology, Kumasi</wicri:regionArea><wicri:noRegion>Kumasi</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Faculty of Allied Health Sciences and School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea>Faculty of Allied Health Sciences and School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi</wicri:regionArea><wicri:noRegion>Kumasi</wicri:noRegion></affiliation></author><author><name sortKey="Batsa Debrah, Linda" sort="Batsa Debrah, Linda" uniqKey="Batsa Debrah L" first="Linda" last="Batsa Debrah">Linda Batsa Debrah</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR), Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea>Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR), Kwame Nkrumah University of Science and Technology, Kumasi</wicri:regionArea><wicri:noRegion>Kumasi</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Department of Clinical Microbiology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea>Department of Clinical Microbiology, Kwame Nkrumah University of Science and Technology, Kumasi</wicri:regionArea><wicri:noRegion>Kumasi</wicri:noRegion></affiliation></author><author><name sortKey="Albers, Anna" sort="Albers, Anna" uniqKey="Albers A" first="Anna" last="Albers">Anna Albers</name><affiliation wicri:level="3"><nlm:aff id="aff001"><addr-line>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Layland, Laura E" sort="Layland, Laura E" uniqKey="Layland L" first="Laura E." last="Layland">Laura E. Layland</name><affiliation wicri:level="3"><nlm:aff id="aff001"><addr-line>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Hoerauf, Achim" sort="Hoerauf, Achim" uniqKey="Hoerauf A" first="Achim" last="Hoerauf">Achim Hoerauf</name><affiliation wicri:level="3"><nlm:aff id="aff001"><addr-line>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="aff005"><addr-line>Bonn-Cologne Site, German Center for Infectious Disease Research (DZIF), Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Bonn-Cologne Site, German Center for Infectious Disease Research (DZIF), Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Adjobimey, Tomabu" sort="Adjobimey, Tomabu" uniqKey="Adjobimey T" first="Tomabu" last="Adjobimey">Tomabu Adjobimey</name><affiliation wicri:level="3"><nlm:aff id="aff001"><addr-line>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Faculté des Sciences et Techniques (FAST), Université d’Abomey-Calavi, Abomey-Calavi, Bénin</addr-line></nlm:aff><country xml:lang="fr">Bénin</country><wicri:regionArea>Faculté des Sciences et Techniques (FAST), Université d’Abomey-Calavi, Abomey-Calavi</wicri:regionArea><wicri:noRegion>Abomey-Calavi</wicri:noRegion></affiliation></author></analytic><series><title level="j">PLoS Neglected Tropical Diseases</title><idno type="ISSN">1935-2727</idno><idno type="eISSN">1935-2735</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Helminth parasites are known to be efficient modulators of their host’s immune system. To guarantee their own survival, they induce alongside the classical Th2 a strong regulatory response with high levels of anti-inflammatory cytokines and elevated plasma levels of IgG4. This particular antibody was shown in different models to exhibit immunosuppressive properties. How IgG4 affects the etiopathology of lymphatic filariasis (LF) is however not well characterized. Here we investigate the impact of plasma and affinity-purified IgG/IgG4 fractions from endemic normals (EN) and LF infected pathology patients (CP), asymptomatic microfilaraemic (Mf+) and amicrofilaraemic (Mf-) individuals on IgE/IL3 activated granulocytes. The activation and degranulation states were investigated by monitoring the expression of CD63/HLADR and the release of granule contents (neutrophil elastase (NE), eosinophil cationic protein (ECP) and histamine) respectively by flow cytometry and ELISA. We could show that the activation of granulocytes was inhibited in the presence of plasma from EN and Mf+ individuals whereas those of Mf- and CP presented no effect. This inhibitory capacity was impaired upon depletion of IgG in Mf+ individuals but persisted in IgG-depleted plasma from EN, where it strongly correlated with the expression of IgA. In addition, IgA-depleted fractions failed to suppress granulocyte activation. Strikingly, affinity-purified IgG4 antibodies from EN, Mf+ and Mf- individuals bound granulocytes and inhibited activation and the release of ECP, NE and histamine. In contrast, IgG4 from CP could not bind granulocytes and presented no suppressive capacity. Reduction of both the affinity to, and the suppressive properties of anti-inflammatory IgG4 on granulocytes was reached only when FcγRI and II were blocked simultaneously. These data indicate that IgG4 antibodies from Mf+, Mf- and EN, in contrast to those of CP, natively exhibit FcγRI/II-dependent suppressive properties on granulocytes. Our findings suggest that quantitative and qualitative alterations in IgG4 molecules are associated with the different clinical phenotypes in LF endemic regions.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Hoerauf, A" uniqKey="Hoerauf A">A Hoerauf</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Disease, Gbd" uniqKey="Disease G">GBD Disease</name></author><author><name sortKey="Injury, I" uniqKey="Injury I">I Injury</name></author><author><name sortKey="Prevalence, C" uniqKey="Prevalence C">C Prevalence</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Maizels, Rm" uniqKey="Maizels R">RM Maizels</name></author><author><name sortKey="Yazdanbakhsh, M" uniqKey="Yazdanbakhsh M">M Yazdanbakhsh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Babu, S" uniqKey="Babu S">S Babu</name></author><author><name sortKey="Bhat, Sq" uniqKey="Bhat S">SQ Bhat</name></author><author><name sortKey="Pavan Kumar, N" uniqKey="Pavan Kumar N">N Pavan Kumar</name></author><author><name sortKey="Lipira, Ab" uniqKey="Lipira A">AB Lipira</name></author><author><name sortKey="Kumar, S" uniqKey="Kumar S">S Kumar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Debrah, Ay" uniqKey="Debrah A">AY Debrah</name></author><author><name sortKey="Mand, S" uniqKey="Mand S">S Mand</name></author><author><name sortKey="Specht, S" uniqKey="Specht S">S Specht</name></author><author><name sortKey="Marfo Debrekyei, Y" uniqKey="Marfo Debrekyei Y">Y Marfo-Debrekyei</name></author><author><name sortKey="Batsa, L" uniqKey="Batsa L">L Batsa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hussain, R" uniqKey="Hussain R">R Hussain</name></author><author><name sortKey="Ottesen, Ea" uniqKey="Ottesen E">EA 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Negl Trop Dis</journal-id><journal-id journal-id-type="iso-abbrev">PLoS Negl Trop Dis</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosntds</journal-id><journal-title-group><journal-title>PLoS Neglected Tropical Diseases</journal-title></journal-title-group><issn pub-type="ppub">1935-2727</issn><issn pub-type="epub">1935-2735</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28742098</article-id><article-id pub-id-type="pmc">5542694</article-id><article-id pub-id-type="doi">10.1371/journal.pntd.0005777</article-id><article-id pub-id-type="publisher-id">PNTD-D-17-00059</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Cellular Types</subject><subj-group><subject>Animal Cells</subject><subj-group><subject>Blood Cells</subject><subj-group><subject>White Blood Cells</subject><subj-group><subject>Granulocytes</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Cellular Types</subject><subj-group><subject>Animal Cells</subject><subj-group><subject>Immune Cells</subject><subj-group><subject>White Blood Cells</subject><subj-group><subject>Granulocytes</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune Cells</subject><subj-group><subject>White Blood Cells</subject><subj-group><subject>Granulocytes</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune Cells</subject><subj-group><subject>White Blood Cells</subject><subj-group><subject>Granulocytes</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Body Fluids</subject><subj-group><subject>Blood</subject><subj-group><subject>Blood Plasma</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Body Fluids</subject><subj-group><subject>Blood</subject><subj-group><subject>Blood Plasma</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Physiology</subject><subj-group><subject>Body Fluids</subject><subj-group><subject>Blood</subject><subj-group><subject>Blood Plasma</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Physiology</subject><subj-group><subject>Body Fluids</subject><subj-group><subject>Blood</subject><subj-group><subject>Blood Plasma</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject><subj-group><subject>Immunologic Techniques</subject><subj-group><subject>Immunoassays</subject><subj-group><subject>Enzyme-Linked Immunoassays</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Neurochemistry</subject><subj-group><subject>Neurotransmitters</subject><subj-group><subject>Biogenic Amines</subject><subj-group><subject>Histamine</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Neuroscience</subject><subj-group><subject>Neurochemistry</subject><subj-group><subject>Neurotransmitters</subject><subj-group><subject>Biogenic Amines</subject><subj-group><subject>Histamine</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Physical Sciences</subject><subj-group><subject>Chemistry</subject><subj-group><subject>Chemical Compounds</subject><subj-group><subject>Organic Compounds</subject><subj-group><subject>Histamine</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Physical Sciences</subject><subj-group><subject>Chemistry</subject><subj-group><subject>Organic Chemistry</subject><subj-group><subject>Organic Compounds</subject><subj-group><subject>Histamine</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Organisms</subject><subj-group><subject>Animals</subject><subj-group><subject>Invertebrates</subject><subj-group><subject>Nematoda</subject><subj-group><subject>Brugia</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Cellular Types</subject><subj-group><subject>Animal Cells</subject><subj-group><subject>Blood Cells</subject><subj-group><subject>White Blood Cells</subject><subj-group><subject>Eosinophils</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Cellular Types</subject><subj-group><subject>Animal Cells</subject><subj-group><subject>Immune Cells</subject><subj-group><subject>White Blood Cells</subject><subj-group><subject>Eosinophils</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune Cells</subject><subj-group><subject>White Blood Cells</subject><subj-group><subject>Eosinophils</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune Cells</subject><subj-group><subject>White Blood Cells</subject><subj-group><subject>Eosinophils</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Cellular Types</subject><subj-group><subject>Animal Cells</subject><subj-group><subject>Blood Cells</subject><subj-group><subject>White Blood Cells</subject><subj-group><subject>Neutrophils</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Cellular Types</subject><subj-group><subject>Animal Cells</subject><subj-group><subject>Immune Cells</subject><subj-group><subject>White Blood Cells</subject><subj-group><subject>Neutrophils</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune Cells</subject><subj-group><subject>White Blood Cells</subject><subj-group><subject>Neutrophils</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune Cells</subject><subj-group><subject>White Blood Cells</subject><subj-group><subject>Neutrophils</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Proteins</subject><subj-group><subject>Plasma Proteins</subject></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Pathological manifestations in lymphatic filariasis correlate with lack of inhibitory properties of IgG4 antibodies on IgE-activated granulocytes</article-title><alt-title alt-title-type="running-head">Anti-inflammatory properties of IgG4 in lymphatic filariasis</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Prodjinotho</surname><given-names>Ulrich F.</given-names></name><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Visualization</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>von Horn</surname><given-names>Charlotte</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Visualization</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Debrah</surname><given-names>Alex Y.</given-names></name><role content-type="http://credit.casrai.org/">Resources</role><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Batsa Debrah</surname><given-names>Linda</given-names></name><role content-type="http://credit.casrai.org/">Resources</role><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="aff" rid="aff004"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Albers</surname><given-names>Anna</given-names></name><role content-type="http://credit.casrai.org/">Resources</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Layland</surname><given-names>Laura E.</given-names></name><role content-type="http://credit.casrai.org/">Funding acquisition</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Hoerauf</surname><given-names>Achim</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Funding acquisition</role><role content-type="http://credit.casrai.org/">Project administration</role><role content-type="http://credit.casrai.org/">Supervision</role><role content-type="http://credit.casrai.org/">Validation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff005"><sup>5</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-4353-2897</contrib-id><name><surname>Adjobimey</surname><given-names>Tomabu</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Funding acquisition</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Project administration</role><role content-type="http://credit.casrai.org/">Supervision</role><role content-type="http://credit.casrai.org/">Visualization</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff006"><sup>6</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany</addr-line></aff><aff id="aff002"><label>2</label><addr-line>Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR), Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></aff><aff id="aff003"><label>3</label><addr-line>Faculty of Allied Health Sciences and School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></aff><aff id="aff004"><label>4</label><addr-line>Department of Clinical Microbiology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></aff><aff id="aff005"><label>5</label><addr-line>Bonn-Cologne Site, German Center for Infectious Disease Research (DZIF), Bonn, Germany</addr-line></aff><aff id="aff006"><label>6</label><addr-line>Faculté des Sciences et Techniques (FAST), Université d’Abomey-Calavi, Abomey-Calavi, Bénin</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Mitre</surname><given-names>Edward</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>Uniformed Services University of the Health Sciences, UNITED STATES</addr-line></aff><author-notes><fn fn-type="COI-statement" id="coi001"><p>The authors have declared that no competing interests exist.</p></fn><corresp id="cor001">* E-mail: <email>Tomabu.Adjobimey@ukb.uni-bonn.de</email></corresp></author-notes><pub-date pub-type="epub"><day>24</day><month>7</month><year>2017</year></pub-date><pub-date pub-type="collection"><month>7</month><year>2017</year></pub-date><volume>11</volume><issue>7</issue><elocation-id>e0005777</elocation-id><history><date date-type="received"><day>16</day><month>1</month><year>2017</year></date><date date-type="accepted"><day>5</day><month>7</month><year>2017</year></date></history><permissions><copyright-statement>© 2017 Prodjinotho et al</copyright-statement><copyright-year>2017</copyright-year><copyright-holder>Prodjinotho et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="pntd.0005777.pdf"></self-uri><abstract><p>Helminth parasites are known to be efficient modulators of their host’s immune system. To guarantee their own survival, they induce alongside the classical Th2 a strong regulatory response with high levels of anti-inflammatory cytokines and elevated plasma levels of IgG4. This particular antibody was shown in different models to exhibit immunosuppressive properties. How IgG4 affects the etiopathology of lymphatic filariasis (LF) is however not well characterized. Here we investigate the impact of plasma and affinity-purified IgG/IgG4 fractions from endemic normals (EN) and LF infected pathology patients (CP), asymptomatic microfilaraemic (Mf+) and amicrofilaraemic (Mf-) individuals on IgE/IL3 activated granulocytes. The activation and degranulation states were investigated by monitoring the expression of CD63/HLADR and the release of granule contents (neutrophil elastase (NE), eosinophil cationic protein (ECP) and histamine) respectively by flow cytometry and ELISA. We could show that the activation of granulocytes was inhibited in the presence of plasma from EN and Mf+ individuals whereas those of Mf- and CP presented no effect. This inhibitory capacity was impaired upon depletion of IgG in Mf+ individuals but persisted in IgG-depleted plasma from EN, where it strongly correlated with the expression of IgA. In addition, IgA-depleted fractions failed to suppress granulocyte activation. Strikingly, affinity-purified IgG4 antibodies from EN, Mf+ and Mf- individuals bound granulocytes and inhibited activation and the release of ECP, NE and histamine. In contrast, IgG4 from CP could not bind granulocytes and presented no suppressive capacity. Reduction of both the affinity to, and the suppressive properties of anti-inflammatory IgG4 on granulocytes was reached only when FcγRI and II were blocked simultaneously. These data indicate that IgG4 antibodies from Mf+, Mf- and EN, in contrast to those of CP, natively exhibit FcγRI/II-dependent suppressive properties on granulocytes. Our findings suggest that quantitative and qualitative alterations in IgG4 molecules are associated with the different clinical phenotypes in LF endemic regions.</p></abstract><abstract abstract-type="summary"><title>Author summary</title><p>Lymphatic Filariasis, also known as elephantiasis, infects an estimated 39 million people in 73 tropical and sub-tropical countries. The most severe clinical manifestations of the disease include swelling of the scrotal area and lower limbs (hydrocele and lymphedema). It is well admitted that host immune reactivity plays a critical role in the pathogenesis of the disease. Previous investigations have linked the non-cytolytic antibody IgG4 to the hyporesponsive states in filarial infections. However, few data exist on how this antibody is involved in the pathogenesis of human filariasis. Here we investigated the role of this antibody in disease pathogenesis by comparing the effect of plasma, IgG and IgG4 fractions from the four clinical categories of individuals; chronic pathology individuals (CP), asymptomatic microfilaria positive (Mf+) and negative (Mf-) and uninfected endemic normal individuals (EN) on activated granulocytes. We could show that granulocyte activation was significantly inhibited in the presence of plasma from EN and Mf+ and that, affinity-purified IgG4 antibodies from EN, Mf+ and Mf- individuals inhibited granulocyte activation in a dose-dependent manner via the immune receptors FcγRI and FcγRII. Our data also reveal significant functional differences between IgG4 molecules from EN, Mf+, Mf- and CP.</p></abstract><funding-group><award-group id="award001"><funding-source><institution>German Research Council (DFG)</institution></funding-source><award-id>DFG Ho2009/8-2</award-id><principal-award-recipient><name><surname>Hoerauf</surname><given-names>Achim</given-names></name></principal-award-recipient></award-group><award-group id="award002"><funding-source><institution>German Academic Exchange Service (DAAD)</institution></funding-source><principal-award-recipient><name><surname>Prodjinotho</surname><given-names>Ulrich F.</given-names></name></principal-award-recipient></award-group><award-group id="award003"><funding-source><institution>Excellence Cluster Immunosensation</institution></funding-source><award-id>DFG, EXC 1023</award-id><principal-award-recipient><name><surname>Hoerauf</surname><given-names>Achim</given-names></name></principal-award-recipient></award-group><award-group id="award004"><funding-source><institution>German Centre of Infectious Disease Research (DZIF)</institution></funding-source><principal-award-recipient><name><surname>Hoerauf</surname><given-names>Achim</given-names></name></principal-award-recipient></award-group><funding-statement>This study was supported by the German Research Council (DFG Ho2009/8-2). UFP received a Ph.D. scholarship from the German Academic Exchange Service (DAAD). AH is a member of the Excellence Cluster Immunosensation (DFG, EXC 1023) and of the German Centre of Infectious Disease Research (DZIF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><fig-count count="7"></fig-count><table-count count="1"></table-count><page-count count="25"></page-count></counts><custom-meta-group><custom-meta><meta-name>PLOS Publication Stage</meta-name><meta-value>vor-update-to-uncorrected-proof</meta-value></custom-meta><custom-meta><meta-name>Publication Update</meta-name><meta-value>2017-08-03</meta-value></custom-meta><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>All relevant data are within the paper and its Supporting Information files.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>All relevant data are within the paper and its Supporting Information files.</p></notes></front></pmc><affiliations><list><country><li>Allemagne</li><li>Bénin</li><li>Ghana</li></country><region><li>District de Cologne</li><li>Rhénanie-du-Nord-Westphalie</li></region><settlement><li>Bonn</li></settlement></list><tree><country name="Allemagne"><region name="Rhénanie-du-Nord-Westphalie"><name sortKey="Prodjinotho, Ulrich F" sort="Prodjinotho, Ulrich F" uniqKey="Prodjinotho U" first="Ulrich F." last="Prodjinotho">Ulrich F. Prodjinotho</name></region><name sortKey="Adjobimey, Tomabu" sort="Adjobimey, Tomabu" uniqKey="Adjobimey T" first="Tomabu" last="Adjobimey">Tomabu Adjobimey</name><name sortKey="Albers, Anna" sort="Albers, Anna" uniqKey="Albers A" first="Anna" last="Albers">Anna Albers</name><name sortKey="Hoerauf, Achim" sort="Hoerauf, Achim" uniqKey="Hoerauf A" first="Achim" last="Hoerauf">Achim Hoerauf</name><name sortKey="Hoerauf, Achim" sort="Hoerauf, Achim" uniqKey="Hoerauf A" first="Achim" last="Hoerauf">Achim Hoerauf</name><name sortKey="Layland, Laura E" sort="Layland, Laura E" uniqKey="Layland L" first="Laura E." last="Layland">Laura E. Layland</name><name sortKey="Von Horn, Charlotte" sort="Von Horn, Charlotte" uniqKey="Von Horn C" first="Charlotte" last="Von Horn">Charlotte Von Horn</name></country><country name="Ghana"><noRegion><name sortKey="Debrah, Alex Y" sort="Debrah, Alex Y" uniqKey="Debrah A" first="Alex Y." last="Debrah">Alex Y. Debrah</name></noRegion><name sortKey="Batsa Debrah, Linda" sort="Batsa Debrah, Linda" uniqKey="Batsa Debrah L" first="Linda" last="Batsa Debrah">Linda Batsa Debrah</name><name sortKey="Batsa Debrah, Linda" sort="Batsa Debrah, Linda" uniqKey="Batsa Debrah L" first="Linda" last="Batsa Debrah">Linda Batsa Debrah</name><name sortKey="Debrah, Alex Y" sort="Debrah, Alex Y" uniqKey="Debrah A" first="Alex Y." last="Debrah">Alex Y. Debrah</name></country><country name="Bénin"><noRegion><name sortKey="Adjobimey, Tomabu" sort="Adjobimey, Tomabu" uniqKey="Adjobimey T" first="Tomabu" last="Adjobimey">Tomabu Adjobimey</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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