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1. Immunomodulatory Effects of Rhinovirus and Enterovirus Infections During the First Year of Life

Author

Terhi Ruohtula, Anita Kondrashova, Jussi Lehtonen, Sami Oikarinen, Anu-Maaria Hämäläinen, Onni Niemelä, Aleksandr Peet, Vallo Tillmann, Janne K. Nieminen, Jorma Ilonen, Mikael Knip, Outi Vaarala, Heikki Hyöty, the DIABIMMUNE Study Group, Taina Härkönen, Samppa Ryhänen, Heli Siljander, Katriina Koski, Matti Koski, Janne Nieminen, Anne Ormisson, Valentina Ulich, Elena Kuzmicheva, Sergei Mokurov, Svetlana Markova, Svetlana Pylova, Marina Isakova, Elena Shakurova, Vladimir Petrov, Natalya V. Dorshakova, Tatyana Karapetyan, Tatyana Varlamova, Minna Kiviniemi, Kristi Alnek, Helis Janson, Raivo Uibo, Tiit Salum, Erika von Mutius, Juliane Weber, Helena Ahlfors, Henna Kallionpää, Essi Laajala, Riitta Lahesmaa, Harri Lähdesmäki, Robert Moulder, Hanna Honkanen, Hermie J. M. Harmsen, Marcus C. De Goffau, Gjalt Welling, Kirsi Alahuhta, Suvi M. Virtanen, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Microbes in Health and Disease (MHD), Tampere University, BioMediTech, Clinical Medicine, Seinäjoen keskussairaala VA, Department of Clinical Microbiology, Health Sciences, Department of Paediatrics, Clinicum, University of Helsinki, HUS Children and Adolescents, Children's Hospital, and Helsinki University Hospital Area

Subjects
0301 basic medicine, Male, Chemokine, regulatory T cell, type 1 diabetes, medicine.medical_treatment, medicine.disease_cause, Feces, T-Lymphocyte Subsets, 3123 Gynaecology and paediatrics, cytokine, Immunology and Allergy, Picornaviridae Infections/immunology, Rhinovirus/immunology, Forkhead Transcription Factors/genetics, Original Research, 11832 Microbiology and virology, education.field_of_study, biology, enterovirus, Age Factors, Cytokines/metabolism, FOXP3, Forkhead Transcription Factors, T-Lymphocyte Subsets/immunology, 3. Good health, Host-Pathogen Interactions/immunology, medicine.anatomical_structure, Cytokine, rhinovirus, Host-Pathogen Interactions, Cytokines, Female, Rhinovirus, Feces/virology, lcsh:Immunologic diseases. Allergy, Regulatory T cell, Enterovirus/immunology, 030106 microbiology, Immunology, Population, chemical and pharmacologic phenomena, Proinflammatory cytokine, Immunomodulation, 03 medical and health sciences, Enterovirus Infections, medicine, Humans, education, Picornaviridae Infections, business.industry, Infant, Newborn, Infant, Newborn, 3141 Health care science, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, Enterovirus Infections/immunology, biology.protein, Enterovirus, 3111 Biomedicine, business, lcsh:RC581-607, Biomarkers
Abstract

Early childhood infections have been implicated in the development of immune-mediated diseases, such as allergies, asthma, and type 1 diabetes. We set out to investigate the immunomodulatory effects of early viral infections experienced before the age of one year on the peripheral regulatory T cell population (Treg) and circulating cytokines in a birth-cohort study of Estonian and Finnish infants. We show here a temporal association of virus infection with the expression of FOXP3 in regulatory T cells. Infants with rhinovirus infection during the preceding 30 days had a higher FOXP3 expression in Treg cells and decreased levels of several cytokines related to Th1 and Th2 responses in comparison to the children without infections. In contrast, FOXP3 expression was significantly decreased in highly activated (CD4+CD127-/loCD25+FOXP3high) regulatory T cells (TregFOXP3high) in the infants who had enterovirus infection during the preceding 30 or 60 days. After enterovirus infections, the cytokine profile showed an upregulation of Th1- and Th17-related cytokines and a decreased activation of CCL22, which is a chemokine derived from dendritic cells and associated with Th2 deviation. Our results reveal that immunoregulatory mechanisms are up-regulated after rhinovirus infections, while enterovirus infections are associated with activation of proinflammatory pathways and decreased immune regulation. publishedVersion

Published
2021
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2. Exploring the risk factors for differences in the cumulative incidence of coeliac disease in two neighboring countries : the prospective DIABIMMUNE study

Author

Kärt Simre, Oivi Uibo, Aleksandr Peet, Vallo Tillmann, Pille Kool, Anu-Maaria Hämäläinen, Taina Härkönen, Heli Siljander, Suvi Virtanen, Jorma Ilonen, Mikael Knip, Raivo Uibo, Katriina Koski, Matti Koski, Samppa Ryhänen, Anne Ormisson, Valentina Ulich, Elena Kuzmicheva, Sergei Mokurov, Svetlana Markova, Svetlana Pylova, Marina Isakova, Elena Shakurova, Vladimir Petrov, Natalya V. Dorshakova, Tatyana Karapetyan, Tatyana Varlamova, Minna Kiviniemi, Kristi Alnek, Helis Janson, Erika von Mutius, Juliane Weber, Helena Ahlfors, Henna Kallionpää, Essi Laajala, Riitta Lahesmaa, Harri Lähdesmäki, Robert Moulder, Janne Nieminen, Terhi Ruohtula, Outi Vaarala, Hanna Honkanen, Heikki Hyöty, Anita Kondrashova, Sami Oikarinen, Hermie J.M. Harmsen, Marcus C. De Goffau, Gjal Welling, Kirsi Alahuhta, Suvi M. Virtanen, Children's Hospital, Clinicum, Diabetes and Obesity Research Program, Research Programs Unit, Mikael Knip / Principal Investigator, Lastentautien yksikkö, HUS Children and Adolescents, Microbes in Health and Disease (MHD), and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
Male, Pediatrics, Breastfeeding, CHILDHOOD, CHILDREN, Coeliac disease, 0302 clinical medicine, Risk Factors, 3123 Gynaecology and paediatrics, Medicine, Cumulative incidence, Prospective Studies, Prospective cohort study, Finland, Incidence (epidemiology), Incidence, Vaccination, Gastroenterology, NEWBORN-INFANTS, 3142 Public health care science, environmental and occupational health, 3. Good health, PREVALENCE, TIME, Breast Feeding, NATIONWIDE COHORT, Child, Preschool, Cohort, 030211 gastroenterology & hepatology, Female, Early infections, Estonia, medicine.medical_specialty, TRANSGLUTAMINASE ANTIBODIES, 03 medical and health sciences, 030225 pediatrics, Humans, PERMEABILITY, GLUTEN, Transglutaminases, Hepatology, business.industry, Case-control study, Infant, Newborn, HLA-DQ, Infant, ta3121, medicine.disease, Immunoglobulin A, Celiac Disease, Case-Control Studies, 3121 General medicine, internal medicine and other clinical medicine, business, Breast feeding, Early feeding
Abstract

Background: During the last several decades the prevalence of coeliac disease (CD) has increased worldwide. Aim: To compare the cumulative incidence of CD between Estonian and Finnish children and to identify the risk factors. Materials and methods: Children were recruited as part of the DIABIMMUNE Study. In the birth cohort (BC) 258 children from Estonia and 305 from Finland, and in the young children's cohort (YCC) 1363 and 1384 children were followed up, respectively. The diagnosis of CD was made in accordance with the ESPGHAN guidelines-the presence of IgA-tTG antibodies and small bowel villous atrophy. Results: During the study period 29 children developed CD. The cumulative incidence of CD was significantly higher in Finland (0.77% vs 0.27%; P = 0.01). No difference was seen between the children with CD and the controls in the duration of breastfeeding or the age at cereal introduction. The BC children with CD had had significantly more episodes of infections with fever by the age of 12 months compared to the controls (3.4 vs 1.4; P = 0.04). Conclusion: The 5-year cumulative incidence of childhood CD is significantly higher in Finland than in Estonia. Sequential infections early in life may increase the risk for developing CD. (C) 2016 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.

Published
2016

3. Th1/Th17 plasticity is a marker of advanced β cell autoimmunity and impaired glucose tolerance in humans

Author

Outi Vaarala, Kirsi Alahuhta, Linnea Reinert-Hartwall, Henna Kallionpää, Olli Simell, Natalya Dorshakova, Sami Oikarinen, Harri M. Salo, Robert Moulder, Sergei Mokurov, Riitta Veijola, Jorma Ilonen, Elena Kuzmicheva, Samppa J. Ryhänen, Juliane Weber, Suvi M. Virtanen, Vladimir Petrov, Matti Koski, Helis Janson, Helena Ahlfors, Terhi Ruohtula, Anu-Maaria Hämäläinen, Vallo Tillmann, Elena Shakurova, Janne Nieminen, Tatyana Varlamova, Hanna Honkanen, Janne K. Nieminen, Taina Härkönen, Tatyana Karapetyan, Erika von Mutius, Tiit Salum, Essi Laajala, Kristiina Luopajärvi, Jarno Honkanen, Heikki Hyöty, Riitta Lahesmaa, Katriina Koski, Marcus C. de Goffau, Aleksandr Peet, Raivo Uibo, Mikael Knip, Kristi Alnek, Marina Isakova, Svetlana Pylova, Harri Lähdesmäki, Hermie J. M. Harmsen, Gjalt W. Welling, Valentina Ulich, Svetlana Markova, Anne Ormisson, Anita Kondrashova, Minna Kiviniemi, Microbes in Health and Disease (MHD), and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
Male, Immunology, Cell, Autoimmunity, medicine.disease_cause, T-Lymphocytes, Regulatory, Impaired glucose tolerance, Ikaros Transcription Factor, Interferon-gamma, Downregulation and upregulation, Immunity, Diabetes mellitus, Insulin-Secreting Cells, Glucose Intolerance, medicine, Immunology and Allergy, Humans, Child, Cells, Cultured, Autoantibodies, Type 1 diabetes, business.industry, Interleukin-17, Autoantibody, Interleukin-9, Th1 Cells, medicine.disease, Up-Regulation, medicine.anatomical_structure, Diabetes Mellitus, Type 1, Child, Preschool, Disease Progression, Th17 Cells, Female, business, Biomarkers
Abstract

Upregulation of IL-17 immunity and detrimental effects of IL-17 on human islets have been implicated in human type 1 diabetes. In animal models, the plasticity of Th1/Th17 cells contributes to the development of autoimmune diabetes. In this study, we demonstrate that the upregulation of the IL-17 pathway and Th1/Th17 plasticity in peripheral blood are markers of advanced β cell autoimmunity and impaired β cell function in human type 1 diabetes. Activated Th17 immunity was observed in the late stage of preclinical diabetes in children with β cell autoimmunity and impaired glucose tolerance, but not in children with early β cell autoimmunity. We found an increased ratio of IFN-γ/IL-17 expression in Th17 cells in children with advanced β cell autoimmunity, which correlated with HbA1c and plasma glucose concentrations in an oral glucose tolerance test, and thus impaired β cell function. Low expression of Helios was seen in Th17 cells, suggesting that Th1/Th17 cells are not converted thymus-derived regulatory T cells. Our results suggest that the development of Th1/Th17 plasticity may serve as a biomarker of disease progression from β cell autoantibody positivity to type 1 diabetes. These data in human type 1 diabetes emphasize the role of Th1/Th17 plasticity as a potential contributor to tissue destruction in autoimmune conditions.

Published
2014

4. Use of vitamin D supplements during infancy in an international feeding trial

Author

Eveliina Lehtonen, Anne Ormisson, Anita Nucci, David Cuthbertson, Susa Sorkio, Mila Hyytinen, Kirsi Alahuhta, Carol Berseth, Marja Salonen, Shayne Taback, Margaret Franciscus, Teba González-Frutos, Tuuli E Korhonen, Margaret L Lawson, Dorothy J Becker, Jeffrey P Krischer, Mikael Knip, Suvi M Virtanen, Thomas Mandrup-Poulsen, Elias Arjas, Åke Lernmark, Barbara Schmidt, Jeffrey P. Krischer, Hans K. Åkerblom, Katriina Koski, Matti Koski, Eeva Pajakkala, Linda Shanker, Brenda Bradley, Hans-Michael Dosch, John Dupré, William Fraser, Margaret Lawson, Jeffrey L. Mahon, Mathew Sermer, Shayne P. Taback, Dorothy Becker, Jerry Palmer, Minna Pekkala, Suvi M. Virtanen, Jacki Catteau, Neville Howard, Patricia Crock, Maria Craig, Cheril L. Clarson, Lynda Bere, David Thompson, Daniel Metzger, Colleen Marshall, Jennifer Kwan, David K. Stephure, Daniele Pacaud, Wendy Schwarz, Rose Girgis, Marilyn Thompson, Daniel Catte, Margaret L. Lawson, Denis Daneman, Mary-Jean Martin, Valérie Morin, Lyne Frenette, Suzanne Ferland, Susan Sanderson, Kathy Heath, Céline Huot, Monique Gonthier, Maryse Thibeault, Laurent Legault, Diane Laforte, Elizabeth A. Cummings, Karen Scott, Tracey Bridger, Cheryl Crummell, Robyn Houlden, Adriana Breen, George Carson, Sheila Kelly, Koravangattu Sankaran, Marie Penner, Richard A. White, Nancy King, James Popkin, Laurie Robson, Eva Al Taji, Irena Aldhoon, Pavla Mendlova, Jan Vavrinec, Jan Vosahlo, Ludmila Brazdova, Jitrenka Venhacova, Petra Venhacova, Adam Cipra, Zdenka Tomsikova, Petra Krckova, Pavla Gogelova, Ülle Einberg, Mall-Anne Riikjärv, Vallo Tillmann, Päivi Kleemola, Anna Parkkola, Heli Suomalainen, Anna-Liisa Järvenpää, Anu-Maaria Hämälainen, Hannu Haavisto, Sirpa Tenhola, Pentti Lautala, Pia Salonen, Susanna Aspholm, Heli Siljander, Carita Holm, Samuli Ylitalo, Raisa Lounamaa, Anja Nuuja, Timo Talvitie, Kaija Lindström, Hanna Huopio, Jouni Pesola, Riitta Veijola, Päivi Tapanainen, Abram Alar, Paavo Korpela, Marja-Liisa Käär, Taina Mustila, Ritva Virransalo, Päivi Nykänen, Bärbel Aschemeier, Thomas Danne, Olga Kordonouri, Dóra Krikovszky, László Madácsy, Yeganeh Manon Khazrai, Ernesto Maddaloni, Paolo Pozzilli, Carla Mannu, Marco Songini, Carine de Beaufort, Ulrike Schierloh, Jan Bruining, Margriet Bisschoff, Aleksander Basiak, Renata Wasikowa, Marta Ciechanowska, Grazyna Deja, Przemyslawa Jarosz-Chobot, Agnieszka Szadkowska, Katarzyna Cypryk, Malgorzata Zawodniak-Szalapska, Luis Castano, Teba Gonzalez Frutos, Mirentxu Oyarzabal, Manuel Serrano-Ríos, María Teresa Martínez-Larrad, Federico Gustavo Hawkins, Dolores Rodriguez Arnau, Johnny Ludvigsson, Malgorzata Smolinska Konefal, Ragnar Hanas, Bengt Lindblad, Nils-Osten Nilsson, Hans Fors, Maria Nordwall, Agne Lindh, Hans Edenwall, Jan Aman, Calle Johansson, Margrit Gadient, Eugen Schoenle, Ashi Daftary, Carol Gilmour, Rachel Taculad, Marilyn Tanner-Blasiar, Neil White, Uday Devaskar, Heather Horowitz, Lisa Rogers, Roxana Colon, Teresa Frazer, Jose Torres, Robin Goland, Ellen Greenberg, Maudene Nelson, Holly Schachner, Barney Softness, Jorma Ilonen, Massimo Trucco, Lynn Nichol, Erkki Savilahti, Taina Härkönen, Outi Vaarala, and Kristiina Luopajärvi

Subjects
Male, medicine.medical_specialty, Pediatrics, Canada, Medicine (miscellaneous), Rickets, Recommended Dietary Allowances, Article, Internal medicine, medicine, Vitamin D and neurology, Humans, Longitudinal Studies, Vitamin D, Infant feeding, Nutrition and Dietetics, business.industry, Public Health, Environmental and Occupational Health, Infant, medicine.disease, United States, Europe, Endocrinology, Breast Feeding, Logistic Models, Cohort, Dietary Supplements, Female, business, Breast feeding
Abstract

ObjectiveTo examine the use of vitamin D supplements during infancy among the participants in an international infant feeding trial.DesignLongitudinal study.SettingInformation about vitamin D supplementation was collected through a validated FFQ at the age of 2 weeks and monthly between the ages of 1 month and 6 months.SubjectsInfants (n 2159) with a biological family member affected by type 1 diabetes and with increased human leucocyte antigen-conferred susceptibility to type 1 diabetes from twelve European countries, the USA, Canada and Australia.ResultsDaily use of vitamin D supplements was common during the first 6 months of life in Northern and Central Europe (>80 % of the infants), with somewhat lower rates observed in Southern Europe (>60 %). In Canada, vitamin D supplementation was more common among exclusively breast-fed than other infants (e.g. 71 % v. 44 % at 6 months of age). Less than 2 % of infants in the USA and Australia received any vitamin D supplementation. Higher gestational age, older maternal age and longer maternal education were study-wide associated with greater use of vitamin D supplements.ConclusionsMost of the infants received vitamin D supplements during the first 6 months of life in the European countries, whereas in Canada only half and in the USA and Australia very few were given supplementation.

Published
2013

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