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Early childhood thymectomy - impact on immune function

Doktorsavhandling
Författare Judith Gudmundsdottir
Datum för examination 2017-06-02
Opponent at public defense Martina Prelog
ISBN 978-91-629-0143-1 (print); 978-91-629-0144-8 (PDF)
Förlagsort Göteborg
Publiceringsår 2017
Publicerad vid Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning
Språk en
Länkar hdl.handle.net/2077/51886
Ämnesord Immunologi, Thymus, Pediatric cardiac surgery, Congenital heart defect
Ämneskategorier Immunbiologi, Klinisk immunologi, Immungenetik, Barnkardiologi, Pediatrik, Immunologi

Sammanfattning

Introduction: The thymus is the site of T cell maturation. Children born with a congenital heart defect often endure surgery early in life, and during surgery their thymus is routinely removed, as it blocks the surgeons access to the heart. The overall aim of this study was to investigate the long-term immunologic and clinical effects of early childhood thymectomy. Objectives: Investigation of the immunologic effects of early childhood thymectomy at 18 months and 18 years of age with regards to the subset composition of T cells, thymic output and the T cell receptor repertoire diversity (I, II). Investigation of the association between early childhood thymectomy and risks of autoimmune diseases, cancer, infectious diseases and atopic diseases (III). Methods: Lymphocyte subsets were characterized with flow cytometry in eleven subjects preoperatively, at 18 months and 18-years follow-up. In addition, the T cell receptor repertoire was analyzed with TCR Vß flow cytometry, T cell receptor excision circles were quantified with PCR and telomere lengths of T and B cells were analyzed with PCR at 18-year follow-up (I). Also, the diversity of the T cell receptor and immunoglobulin heavy chain genes was determined using next generation sequencing (II). A nationwide population based cohort study was conducted using Swedish patient registers to identify subjects and controls and to analyze clinical outcome measures (III). Results: Thymectomy was associated with a reduction in the number of T cells, especially the naive subset. The naive regulatory T cells and recent thymic emigrants (CD31+ T cells) were also reduced. TRECs, indicative of thymic output, were below detection level in all but one thymectomized individual. Telomere lengths were shorter in CD8+ T cells of thymectomized individuals (I). Disturbances were found in the TCR Vß repertoire (I), and sequencing of the T cell receptor confirmed reduced diversity (II). Compared with surgery controls, thymectomized individuals were at increased risk for hypothyroidism, type 1 diabetes and both viral and bacterial infections. Compared with the general population they were at increased risk for hypothyroidism, juvenile idiopathic arthritis, rheumatic diseases, celiac disease, cancer, infections and asthma (III). Conclusion: Early childhood thymectomy is associated with immunologic aberrations as well as with increased risks of autoimmune diseases, cancer and infections. These observations stress that avoidance of total thymectomy during early cardiac surgery is advisable. Keywords: Thymus, T lymphocyte, immunology, pediatric cardiac surgery, congenital cardiac defect

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