title: Circulating CXCR5+PD-1+ICOS+ Follicular T Helper Cells Are Increased Close to the Diagnosis of Type 1 Diabetes in Children With Multiple Autoantibodies.
abstract: Although type 1 diabetes (T1D) is primarily perceived as a T cell-driven autoimmune disease, islet autoantibodies are the best currently available biomarker for autoimmunity and disease risk. These antibodies are produced by autoreactive B cells, the activation of which is largely dependent on the function of CD4+CXCR5+follicular T helper cells (Tfh). In this study, we have comprehensively characterized the Tfh- as well as B-cell compartments in a large cohort of children with newly diagnosed T1D or at different stages of preclinical T1D. We demonstrate that the frequency of CXCR5+PD-1+ICOS+-activated circulating Tfh cells is increased both in children with newly diagnosed T1D and in autoantibody-positive at-risk children with impaired glucose tolerance. Interestingly, this increase was only evident in children positive for two or more biochemical autoantibodies. No alterations in the circulating B-cell compartment were observed in children with either prediabetes or diabetes. Our results demonstrate that Tfh activation is detectable in the peripheral blood close to the presentation of clinical T1D but only in a subgroup of children identifiable by positivity for multiple autoantibodies. These findings suggest a role for Tfh cells in the pathogenesis of human T1D and carry important implications for targeting Tfh cells and/or B cells therapeutically.
authors.affiliation: Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Tyyne
authors.initials: T
authors.lastname: Viisanen
authors.affiliation: Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Emmi-Leena
authors.initials: EL
authors.lastname: Ihantola
authors.affiliation: Department of Pediatrics, Turku University Hospital and University of Turku, Turku, Finland.
authors.forename: Kirsti
authors.initials: K
authors.lastname: Näntö-Salonen
authors.affiliation: School of Medicine, University of Tampere and Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Hyöty
authors.affiliation: School of Medicine, University of Tampere and Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland.
authors.forename: Noora
authors.initials: N
authors.lastname: Nurminen
authors.affiliation: Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland.
authors.forename: Jenni
authors.initials: J
authors.lastname: Selvenius
authors.affiliation: Department of Medicine, Kuopio University Hospital, Kuopio, Finland.|Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Auni
authors.initials: A
authors.lastname: Juutilainen
authors.affiliation: Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Moilanen
authors.affiliation: Institute of Public Health and Clinical Nutrition, University of Eastern Finland and Clinical Nutrition and Obesity Center, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Pihlajamäki
authors.affiliation: Department of Pediatrics, Medical Research Center, PEDEGO Research Unit, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Riitta
authors.initials: R
authors.lastname: Veijola
authors.affiliation: Department of Physiology, Institute of Biomedicine, University of Turku, and Department of Pediatrics, Turku University Hospital, Turku, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Toppari
authors.affiliation: Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland.|Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.|Folkhälsan Research Centre, Helsinki, Finland.
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
authors.affiliation: Immunogenetics Laboratory, University of Turku, Turku, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.affiliation: Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland tuure.kinnunen@uef.fi.
authors.forename: Tuure
authors.initials: T
authors.lastname: Kinnunen
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D018920:Coculture Techniques; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D018149:Glucose Intolerance / Q000276:immunology*; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism; D007378:Interleukins / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D008297:Male; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D001323:Autoantibodies; C095085:CXCR5 protein, human; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D007378:Interleukins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D054380:Receptors, CXCR5; D000098546:Interleukin-21