Inborn Errors of Adaptive Immunity in Down Syndrome
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CME REVIEW
Inborn Errors of Adaptive Immunity in Down Syndrome Ruud H.J. Verstegen 1,2
&
Maaike A.A. Kusters 3,4
Received: 9 October 2019 / Accepted: 10 June 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Down syndrome fits an immunophenotype of combined immunodeficiency with immunodysregulation, manifesting with increased susceptibility to infections, autoimmunity, autoinflammatory diseases, and hematologic malignancies. Qualitative and quantitative alterations in innate and adaptive immunity are found in most individuals with Down syndrome. However, there is substantial heterogeneity and no correlation between immunophenotype and clinical presentation. Previously, it was thought that the immunological changes in Down syndrome were caused by precocious aging. We emphasize in this review that the immune system in Down syndrome is intrinsically different from the very beginning. The overexpression of specific genes located on chromosome 21 contributes to immunodeficiency and immunodysregulation, but gene expression differs between genes located on chromosome 21 and depends on tissue and cell type. In addition, trisomy 21 results in gene dysregulation of the whole genome, reflecting the complex nature of this syndrome in comparison to well-known inborn errors of immunity that result from monogenic germline mutations. In this review, we provide an updated overview focusing on inborn errors of adaptive immunity in Down syndrome. Keywords Down syndrome . trisomy 21 . immunodeficiency . adaptive immunity . T cells . B cells . immunodysregulation . gene expression dysregulation . immunology
Introduction Down syndrome (trisomy 21; OMIM 190685) is a multisystem condition associated with mental and motor developmental impairment, facial dysmorphia, and congenital malformations—in particular congenital heart disease. Individuals with Down syndrome have an increased susceptibility to develop infections, hematologic malignancies, autoimmunity, and autoinflammatory diseases, which we have reviewed recently [1]. * Ruud H.J. Verstegen [email protected] 1
Division of Clinical Pharmacology and Toxicology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada
2
Division of Rheumatology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada
3
Department of Immunology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
4
University College London Great Ormond Street Institute of Child Health, London, UK
Upper and lower respiratory tract infections are frequently reported by parents of children with Down syndrome, but prospective population-based studies to quantify the burden of disease are currently lacking [2, 3]. What we do know is that both viral and bacterial respiratory infections lead to more health care utilization in Down syndrome [4], as well as higher morbidity and mortality. For example, respiratory syncytial virus (RSV) infections lead to more hospital admissions (odds ratio [OR] 8.
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