Thymic epithelial cell alterations and defective thymopoiesis lead to central and peripheral tolerance perturbation in MHCII deficiency
| Autor: | Francesca Ferrua, Ileana Bortolomai, Elena Fontana, Dario Di Silvestre, Rosita Rigoni, Genni Enza Marcovecchio, Elena Draghici, Francesca Brambilla, Maria Carmina Castiello, Gloria Delfanti, Despina Moshous, Capucine Picard, Tom Taghon, Victoria Bordon, Ansgar S. Schulz, Catharina Schuetz, Silvia Giliani, Annarosa Soresina, Andrew R. Gennery, 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, Marita Bosticardo |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
POSITIVE SELECTION Proteome T-Lymphocytes Major histocompatibility complex Epithelial cells Inbred C57BL T-Lymphocytes Regulatory DISEASE Mice thymus Medicine and Health Sciences Immunology and Allergy Child Immunodeficiency Original Research Mice Knockout central tolerance MHCII primary immunodeficiency thymic epithelial cells Adolescent Animals B-Lymphocytes Case-Control Studies Child Preschool Disease Models Animal Epithelial Cells Europe Female Hematopoietic Stem Cell Transplantation Histocompatibility Antigens Class II Homeodomain Proteins Humans Infant Mice Inbred C57BL North America Severe Combined Immunodeficiency Thymocytes Thymus Gland Transcriptome Young Adult Immune Tolerance BARE LYMPHOCYTE SYNDROME Bare lymphocyte syndrome Peripheral tolerance respiratory system Regulatory Thymus gland medicine.anatomical_structure DIFFERENTIATION Severe combined immunodeficiency B-CELLS Central tolerance CLASS-II DEFICIENCY EXPRESSION Knockout ANTIGEN Immunology chemical and pharmacologic phenomena Biology Immune system Immundefekt medicine REGULATORY T-CELLS ddc:610 Preschool B cell Animal RC581-607 medicine.disease MICE Disease Models biology.protein Primary immunodeficiency Immunologic diseases. Allergy MHC DDC 610 / Medicine & health |
| Zdroj: | Frontiers in Immunology FRONTIERS IN IMMUNOLOGY Frontiers in Immunology, Vol 12 (2021) |
| ISSN: | 1664-3224 |
| Popis: | 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. publishedVersion |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|