Thymic Epithelium Abnormalities in DiGeorge and Down Syndrome Patients Contribute to Dysregulation in T Cell Development

Abstract

The thymus plays a fundamental role in establishing and maintaining central and peripheral tolerance and defects in thymic architecture or AIRE expression result in the development of autoreactive lymphocytes. Patients with partial DiGeorge Syndrome (pDGS) and Down Syndrome (DS) present alterations in size and architecture of the thymus and higher risk to develop autoimmunity. We sought to evaluate thymic architecture and thymocyte development in DGS and DS patients and to determine the extent to which thymic defects result in immune dysregulation and T cell homeostasis perturbation in these patients. Thymi from pediatric patients and age-matched controls were obtained to evaluate cortex and medullary compartments, AIRE expression and thymocyte development. In the same patients we also characterized immunophenotype of peripheral T cells. Phenotypic and functional characterization of thymic and peripheral regulatory T (Treg) cells was finally assessed. Histologic analysis revealed peculiar alterations in thymic medulla size and maturation in DGS and DS patients. Perturbed distribution of thymocytes and altered thymic output was also observed. DGS patients showed lower mature CD4+ and CD8+ T cell frequency, associated with reduced proportion and function of Tregs both in thymus and peripheral blood. DS patients showed increased frequency of single positive (SP) thymocytes and thymic Treg cells. However, Tregs isolated both from thymus and peripheral blood of DS patients showed reduced suppressive ability. Our results provide novel insights on thymic defects associated with DGS and DS and their impact on peripheral immune dysregulation. Indeed, thymic abnormalities and defect in thymocyte development, in particular in Treg cell number and function could contribute in the pathogenesis of the immunodysregulation present in pDGS and in DS patients.

GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility

“…The two independent associations with AIRE point to alterations in central immunological tolerance as an underlying mechanism in AAD development. The importance of a correct expression of AIRE for maintaining immunological tolerance is also exemplified by Down Syndrome in which the extra copy of AIRE , located on chromosome 21, has been coupled to altered expression of AIRE in the thymus, impaired central tolerance and an overrepresentation of autoimmune diseases 40 , 41 . Many of the other risk loci identified in this study harbor genes involved in antigen presentation and recognition, and hence in thymocyte maturation.…”

Autoimmune Thyroid Disease in Specific Genetic Syndromes in Childhood and Adolescence

“…Possible mechanisms may include the following: (1) Absent or hypoplastic thymus may result in impaired maturation and dysregulation of T cells and thus defective central tolerance allowing self-reactive T cells to escape intrathymic negative selection and trigger autoimmune responses ( 124 ). In this regard, abnormal thymic development may lead to decreased AIRE expression and consequently impaired AIRE-mediated intrathymic expression of tissue-restricted antigens (TRAs) ( 140 ). (2) Certain HLA haplotypes, such as HLA-DR14 may increase susceptibility to GD in patients with 22q11.2DS ( 139 , 141 ).…”

T-Cell Immunodeficiencies With Congenital Alterations of Thymic Development: Genes Implicated and Differential Immunological and Clinical Features

“…IgM levels are often low, and some patients may show selective IgA deficiency (78). The study of the thymic architecture and thymocyte development in thymi obtained from pediatric pDGS patients revealed a reduction of mature CD4+ and CD8+ T cell frequency, associated with reduced proportion and function of T regulatory cells (Tregs) (117).…”

“…Autoimmune diseases, mainly presenting as rheumatoid diseases and idiopathic thrombocytopenia purpura, are reported in ~10% of DGS patients ( 113 , 116 , 118 ). Predisposition to autoimmunity in DGS patients is partially explained by the mechanism of lymphopenia induced T-cell homeostatic proliferation together with the reduction of natural Tregs (nTregs) ( 117 , 119 ).…”