Inborn errors of immunity associated with defects of thymic development

Abstract

The main function of the thymus is to support the establishment of a wide repertoire of T lymphocytes capable of eliminating foreign pathogens, yet tolerant to selfantigens. Thymocyte development in the thymus is dependent on the interaction with thymic stromal cells, a complex mixture of cells comprising thymic epithelial cells (TEC), mesenchymal and endothelial cells. The exchange of signals between stromal cells and thymocytes is referred to as "thymic cross-talk". Genetic defects affecting either side of this interaction result in defects in thymic development that ultimately lead to a decreased output of T lymphocytes to the periphery. In the present review, we aim at providing a summary of inborn errors of immunity (IEI) characterized by Tcell lymphopenia due to defects of the thymic stroma, or to hematopoietic-intrinsic defects of T-cell development, with a special focus on recently discovered disorders.Additionally, we review the novel diagnostic tools developed to discover and study new genetic causes of IEI due to defects in thymic development. Finally, we discuss therapeutic approaches to correct thymic defects that are currently available, in addition to potential novel therapies that could be applied in the future.

“Inborn errors of immunity: An expanding horizon through a multitude of biological pathways”

“…In this context, the virtual issue on "Inborn Errors of Immunity" aims at providing the readers of PAI a collection of topical reviews on some of the major immunological pathways that can be affected by pathological genetic variants causing IEIs and a selection of original articles highlighting clinical observations from cohort studies of well-known conditions, as well as original discoveries that extend the genetic and clinical features of less commonly observed IEIs. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] In their review of IEIs caused by defects in the DNA damage response pathways, Fournier and Colleagues 3 Additional reviews of the areas of IEIs characterized by defects of actin cytoskeletal dynamics, the JAK-STAT pathways, and type I interferon disorders have been commissioned and will be available in the near future. These works will complement the current collection and provide the readers of PAI with additional timely updates and perspectives on the scientific and clinical aspects of some of the major disease subgroups in the field of IEIs.…”

“…The topic of appropriate forms of therapy needed for specific IEIs is equally prominent with regard to the group disorders associated with defects of thymic development described in the review by Pala and co‐Authors 4 . The Authors point out the essential difference between IEIs characterized by T‐cell lymphopenia due to defects of the thymic stroma and those due to hematopoietic‐intrinsic defects of T‐cell development.…”

“…The validity of the disease categories derived from this exercise relies heavily on the continuous confirmation and updating of such phenotypic features. In this context, the virtual issue on “Inborn Errors of Immunity” aims at providing the readers of PAI a collection of topical reviews on some of the major immunological pathways that can be affected by pathological genetic variants causing IEIs and a selection of original articles highlighting clinical observations from cohort studies of well‐known conditions, as well as original discoveries that extend the genetic and clinical features of less commonly observed IEIs 1–17 …”

Editorial comment on “Inborn errors of immunity associated with defects of thymic development”

“…The authors describe that thymic stromal cell defects caused by genetic lesions that affect transcriptional regulators or other factors involved in thymus organogenesis (e.g., TBX1 , CHD7 , and FOXN1 ) are generally characterized by thymic hypoplasia or aplasia and are typically associated to T‐cell lymphopenia. However, the reduced T‐cell output is not a constant feature of thymic stromal cell defects as genetic lesions resulting in faulty “thymic cross‐talk” (e.g., mutations in AIRE ) can result in major thymic dysfunction in the presence of normal peripheral T‐cell numbers, as it is seen in patients affected with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy 1 …”

“…In their contribution to the PAI Review series on “Primary immunodeficiencies as windows on the major pathways of immunity”, Pala and Colleagues offer a timely and comprehensive summary of the genetic defects of immunity affecting the crucial role of the thymus in providing the T‐lymphocyte component of the adaptive immune system 1 . A group of 100+ known monogenic diseases affecting the immune system, inborn errors associated with defects of thymic development and/or T‐cell function are among the most profound immunological disorders affecting humans, with a clinical presentation ranging from severe combined immunodeficiency (SCID) to other entities resulting in defective cellular and humoral immunity with or without associated syndromic features 2 .…”