Frontiers in Immunology (Jun 2021)
Thymic Epithelial Cell Alterations and Defective Thymopoiesis Lead to Central and Peripheral Tolerance Perturbation in MHCII Deficiency
- Francesca Ferrua,
- Francesca Ferrua,
- Francesca Ferrua,
- Ileana Bortolomai,
- Elena Fontana,
- Elena Fontana,
- Dario Di Silvestre,
- Rosita Rigoni,
- Rosita Rigoni,
- Genni Enza Marcovecchio,
- Elena Draghici,
- Francesca Brambilla,
- Maria Carmina Castiello,
- Maria Carmina Castiello,
- Gloria Delfanti,
- Despina Moshous,
- Despina Moshous,
- Capucine Picard,
- Capucine Picard,
- Capucine Picard,
- Tom Taghon,
- Victoria Bordon,
- Ansgar S. Schulz,
- Catharina Schuetz,
- Catharina Schuetz,
- Silvia Giliani,
- Annarosa Soresina,
- Andrew R. Gennery,
- Andrew R. Gennery,
- Sara Signa,
- Sara Signa,
- Blachy J. Dávila Saldaña,
- Ottavia M. Delmonte,
- Luigi D. Notarangelo,
- Chaim M. Roifman,
- Pietro Luigi Poliani,
- Paolo Uva,
- Pier Luigi Mauri,
- Anna Villa,
- Anna Villa,
- Marita Bosticardo,
- Marita Bosticardo
Affiliations
- Francesca Ferrua
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
- Francesca Ferrua
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Francesca Ferrua
- Vita-Salute San Raffaele University, Milan, Italy
- Ileana Bortolomai
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
- Elena Fontana
- Human Genome Department, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
- Elena Fontana
- Milan Unit, Institute of Genetic and Biomedical Research, National Research Council (CNR), Milan, Italy
- Dario Di Silvestre
- Department of Biomedical Sciences, Institute for Biomedical Technologies-National Research Council (CNR), Milan, Italy
- Rosita Rigoni
- Human Genome Department, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
- Rosita Rigoni
- Milan Unit, Institute of Genetic and Biomedical Research, National Research Council (CNR), Milan, Italy
- Genni Enza Marcovecchio
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
- Elena Draghici
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
- Francesca Brambilla
- Department of Biomedical Sciences, Institute for Biomedical Technologies-National Research Council (CNR), Milan, Italy
- Maria Carmina Castiello
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
- Maria Carmina Castiello
- Milan Unit, Institute of Genetic and Biomedical Research, National Research Council (CNR), Milan, Italy
- Gloria Delfanti
- Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Despina Moshous
- Department of Pediatric Immunology, Hematology and Rheumatology, Necker Children’s Hospital, AP-HP, Paris, France
- Despina Moshous
- Laboratory “Genome Dynamics in the Immune System”, INSERM UMR1163, Université de Paris, Institut Imagine, Paris, France
- Capucine Picard
- Department of Pediatric Immunology, Hematology and Rheumatology, Necker Children’s Hospital, AP-HP, Paris, France
- Capucine Picard
- 0Centre d’Etude des Déficits Immunitaires, Necker-Enfants Malades Hospital, AP-HP, Paris, France
- Capucine Picard
- 1Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Inserm UMR 1163, University Paris Descartes Sorbonne Paris Cité, Imagine Institute, Paris, France
- Tom Taghon
- 2Department of Diagnostic Sciences, Ghent University Hospital, Ghent University, Ghent, Belgium
- Victoria Bordon
- 3Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
- Ansgar S. Schulz
- 4Department of Pediatrics, University Medical Center Ulm, Ulm, Germany
- Catharina Schuetz
- 4Department of Pediatrics, University Medical Center Ulm, Ulm, Germany
- Catharina Schuetz
- 5Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Silvia Giliani
- 6Cytogenetics and Medical Genetics Unit and “A. Nocivelli” Institute for Molecular Medicine, Spedali Civili Hospital, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
- Annarosa Soresina
- 7Unit of Pediatric Immunology, Pediatrics Clinic, University of Brescia, ASST-Spedali Civili Brescia, Brescia, Italy
- Andrew R. Gennery
- 8Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Andrew R. Gennery
- 9Department of Pediatric Immunology and HSCT, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom
- Sara Signa
- 9Department of Pediatric Immunology and HSCT, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom
- Sara Signa
- 0Autoinflammatory Diseases and Immunodeficiencies Center, IRCCS Istituto G. Gaslini, and Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Children's Sciences, University of Genoa, Genoa, Italy
- Blachy J. Dávila Saldaña
- 1Division of Blood and Marrow Transplantation, Children's National Hospital, Washington, DC, United States
- Ottavia M. Delmonte
- 2Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, United States
- Luigi D. Notarangelo
- 2Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, United States
- Chaim M. Roifman
- 3Division of Immunology & Allergy, Department of Pediatrics, The Hospital for Sick Children, the Canadian Centre for Primary Immunodeficiency and the University of Toronto, Toronto, ON, Canada
- Pietro Luigi Poliani
- 4Department of Molecular and Translational Medicine, Pathology Unit, University of Brescia, Brescia, Italy
- Paolo Uva
- 5CRS4, Science and Technology Park Polaris, Pula, Cagliari, Italy
- Pier Luigi Mauri
- Department of Biomedical Sciences, Institute for Biomedical Technologies-National Research Council (CNR), Milan, Italy
- Anna Villa
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
- Anna Villa
- Milan Unit, Institute of Genetic and Biomedical Research, National Research Council (CNR), Milan, Italy
- Marita Bosticardo
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
- Marita Bosticardo
- 2Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, United States
- DOI
- https://doi.org/10.3389/fimmu.2021.669943
- Journal volume & issue
-
Vol. 12
Abstract
Major Histocompatibility Complex (MHC) class II (MHCII) deficiency (MHCII-D), also known as Bare Lymphocyte Syndrome (BLS), is a rare combined immunodeficiency due to mutations in genes regulating expression of MHCII molecules. MHCII deficiency results in impaired cellular and humoral immune responses, leading to severe infections and autoimmunity. Abnormal cross-talk with developing T cells due to the absence of MHCII expression likely leads to defects in thymic epithelial cells (TEC). However, the contribution of TEC alterations to the pathogenesis of this primary immunodeficiency has not been well characterized to date, in particular in regard to immune dysregulation. To this aim, we have performed an in-depth cellular and molecular characterization of TEC in this disease. We observed an overall perturbation of thymic structure and function in both MHCII−/− mice and patients. Transcriptomic and proteomic profiling of murine TEC revealed several alterations. In particular, we demonstrated that impairment of lymphostromal cross-talk in the thymus of MHCII−/− mice affects mTEC maturation and promiscuous gene expression and causes defects of central tolerance. Furthermore, we observed peripheral tolerance impairment, likely due to defective Treg cell generation and/or function and B cell tolerance breakdown. Overall, our findings reveal disease-specific TEC defects resulting in perturbation of central tolerance and limiting the potential benefits of hematopoietic stem cell transplantation in MHCII deficiency.
Keywords
