Abstract
Combined Immunodeficiencies (CID) are rare congenital disorders characterized by defective T-cell development that may be associated with B- and NK-cell deficiency. They are usually due to alterations in genes expressed in hematopoietic precursors but in few cases, they are caused by impaired thymic development. Athymia was classically associated with DiGeorge Syndrome due to TBX1 gene haploinsufficiency. Other genes, implicated in thymic organogenesis include FOXN1, associated with Nude SCID syndrome, PAX1, associated with Otofaciocervical Syndrome type 2, and CHD7, one of the genes implicated in CHARGE syndrome. More recently, chromosome 2p11.2 microdeletion, causing FOXI3 haploinsufficiency, has been identified in 5 families with impaired thymus development. In this review, we will summarize the main genetic, clinical, and immunological features related to the abovementioned gene mutations. We will also focus on different therapeutic approaches to treat SCID in these patients.
Highlights
The thymus is a primary lymphoid organ which plays a pivotal role in the development of mature T cells from immature bone marrow CD34+ precursors
Thymic development ranges from athymia in complete DiGeorge syndrome (DGS) to a completely normal thymus development in partial DGS, resulting in a variable spectrum of T-cell deficiency [78, 79, 111]. cDGS is reported in about 1.5% of the patients [111]
With the recent introduction of newborn screening programs a timely identification of patients affected with defects of the T-cell development before the onset of the symptoms is possible, and this prompted the definitive treatment with Hematopoietic stem cell transplantation (HSCT)
Summary
The thymus is a primary lymphoid organ which plays a pivotal role in the development of mature T cells from immature bone marrow CD34+ precursors. Studies suggest that chromodomain helicase DNA-binding 7 (Chd7) might be implicated in the development of both neural crest cell-derived mesenchyme and pharyngeal endoderm-derived thymic epithelial cells (TECs). Foxn induces the expression of chemokine (C-C motif) ligand 25 (CCL25), delta like canonical Notch ligand 4 (Dll4), and Hoxa, allowing thymocyte recruitment and TECs differentiation in cTECs and mTECs. Mesenchymal cells are implicated in the recruitment of hematopoietic thymic seeding progenitors, as well [15, 16]. Double positive thymocytes with a functional TCRαβ receptor capable of binding to self-MHC ligands are positively selected [27,28,29] This process is regulated by Prss and β5t, which are expressed in cTECs [30,31,32,33,34]. Therapeutic options for PIDs with congenital athymia are discussed
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