title: Splenic TFH expansion participates in B-cell differentiation and antiplatelet-antibody production during immune thrombocytopenia.
abstract: Antiplatelet-antibody-producing B cells play a key role in immune thrombocytopenia (ITP) pathogenesis; however, little is known about T-cell dysregulations that support B-cell differentiation. During the past decade, T follicular helper cells (TFHs) have been characterized as the main T-cell subset within secondary lymphoid organs that promotes B-cell differentiation leading to antibody class-switch recombination and secretion. Herein, we characterized TFHs within the spleen of 8 controls and 13 ITP patients. We show that human splenic TFHs are the main producers of interleukin (IL)-21, express CD40 ligand (CD154), and are located within the germinal center of secondary follicles. Compared with controls, splenic TFH frequency is higher in ITP patients and correlates with germinal center and plasma cell percentages that are also increased. In vitro, IL-21 stimulation combined with an anti-CD40 agonist antibody led to the differentiation of splenic B cells into plasma cells and to the secretion of antiplatelet antibodies in ITP patients. Overall, these results point out the involvement of TFH in ITP pathophysiology and the potential interest of IL-21 and CD40 as therapeutic targets in ITP.
authors.affiliation: Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands; Centre de Recherche INSERM 1098, University of Bourgogne/Franche-Comté, Fédération Hospitalo-Universitaire Integrated Center for Research in Inflammatory Diseases, Bourgogne, France; Department of Internal Medicine and Clinical Immunology, Competence Center for Autoimmune Cytopenia, University Hospital, Dijon, France;
authors.forename: Sylvain
authors.initials: S
authors.lastname: Audia
authors.affiliation: Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands;
authors.forename: Marzia
authors.initials: M
authors.lastname: Rossato
authors.affiliation: Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands;
authors.forename: Kim
authors.initials: K
authors.lastname: Santegoets
authors.affiliation: Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands;
authors.forename: Sanne
authors.initials: S
authors.lastname: Spijkers
authors.affiliation: Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands;
authors.forename: Catharina
authors.initials: C
authors.lastname: Wichers
authors.affiliation: Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands;
authors.forename: Cornelis
authors.initials: C
authors.lastname: Bekker
authors.affiliation: Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands;
authors.forename: Andries
authors.initials: A
authors.lastname: Bloem
authors.affiliation: Bioceros, Utrecht, The Netherlands; and.
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands;
authors.forename: Thijs
authors.initials: T
authors.lastname: Flinsenberg
authors.affiliation: Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands;
authors.forename: Ewoud
authors.initials: E
authors.lastname: Compeer
authors.affiliation: Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands;
authors.forename: Theo
authors.initials: T
authors.lastname: van den Broek
authors.affiliation: Department of Surgery and.
authors.forename: Olivier
authors.initials: O
authors.lastname: Facy
authors.affiliation: Department of Surgery and.
authors.forename: Pablo
authors.initials: P
authors.lastname: Ortega-Deballon
authors.affiliation: Department of Internal Medicine and Clinical Immunology, Competence Center for Autoimmune Cytopenia, University Hospital, Dijon, France;
authors.forename: Sabine
authors.initials: S
authors.lastname: Berthier
authors.affiliation: Department of Internal Medicine and Clinical Immunology, Competence Center for Autoimmune Cytopenia, University Hospital, Dijon, France;
authors.forename: Vanessa
authors.initials: V
authors.lastname: Leguy-Seguin
authors.affiliation: Centre de Recherche INSERM 1098, University of Bourgogne/Franche-Comté, Fédération Hospitalo-Universitaire Integrated Center for Research in Inflammatory Diseases, Bourgogne, France; Department of Pathology, University Hospital, Dijon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Martin
authors.affiliation: Centre de Recherche INSERM 1098, University of Bourgogne/Franche-Comté, Fédération Hospitalo-Universitaire Integrated Center for Research in Inflammatory Diseases, Bourgogne, France;
authors.forename: Marion
authors.initials: M
authors.lastname: Ciudad
authors.affiliation: Centre de Recherche INSERM 1098, University of Bourgogne/Franche-Comté, Fédération Hospitalo-Universitaire Integrated Center for Research in Inflammatory Diseases, Bourgogne, France;
authors.forename: Maxime
authors.initials: M
authors.lastname: Samson
authors.affiliation: Centre de Recherche INSERM 1098, University of Bourgogne/Franche-Comté, Fédération Hospitalo-Universitaire Integrated Center for Research in Inflammatory Diseases, Bourgogne, France;
authors.forename: Malika
authors.initials: M
authors.lastname: Trad
authors.affiliation: Department of Internal Medicine and Clinical Immunology, Competence Center for Autoimmune Cytopenia, University Hospital, Dijon, France;
authors.forename: Bernard
authors.initials: B
authors.lastname: Lorcerie
authors.affiliation: Centre de Recherche INSERM 1098, University of Bourgogne/Franche-Comté, Fédération Hospitalo-Universitaire Integrated Center for Research in Inflammatory Diseases, Bourgogne, France;
authors.forename: Nona
authors.initials: N
authors.lastname: Janikashvili
authors.affiliation: Centre de Recherche INSERM 1098, University of Bourgogne/Franche-Comté, Fédération Hospitalo-Universitaire Integrated Center for Research in Inflammatory Diseases, Bourgogne, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Saas
authors.affiliation: Centre de Recherche INSERM 1098, University of Bourgogne/Franche-Comté, Fédération Hospitalo-Universitaire Integrated Center for Research in Inflammatory Diseases, Bourgogne, France; Department of Internal Medicine and Clinical Immunology, Competence Center for Autoimmune Cytopenia, University Hospital, Dijon, France;
authors.forename: Bernard
authors.initials: B
authors.lastname: Bonnotte
authors.affiliation: Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands;
authors.forename: Timothy R D J
authors.initials: TR
authors.lastname: Radstake
mesh_terms: D000328:Adult; D000368:Aged; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology*; D015703:Antigens, CD / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D001792:Blood Platelets / Q000187:drug effects / Q000276:immunology*; D023201:CD40 Ligand / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D018858:Germinal Center / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D007378:Interleukins / Q000494:pharmacology; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010950:Plasma Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000276:immunology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000473:pathology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D015703:Antigens, CD; D007074:Immunoglobulin G; D007378:Interleukins; D012333:RNA, Messenger; D023201:CD40 Ligand; D000098546:Interleukin-21