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

Abstract

Combined Immunodeficiencies (CID) are rare congenital disorders characterized by defective T-cell development that may be associated with Band 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.

Thymus and autoimmunity

“…Monogenic HAIDs have been crucial to identifying key contributors to tolerance, e.g. the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED, alias autoimmune polyglandular syndrome type 1, APS1) due to autoimmune regulator ( AIRE ) mutations [ 9 , 10 ], the immunodysregulation polyendocrinopathy and enteropathy X-linked (IPEX) syndrome) resulting from FOXP3 mutations [ 11 ] and ‘leaky’ (subtotal) immunodeficiency syndromes due to primary T-cell or stromal cell developmental defects [ 12 , 13 ]. Parallel studies in mouse models helped to elucidate underlying mechanisms and their non-redundancy [ 6 , 14 – 16 ].…”

Case Report: Unmanipulated Matched Sibling Donor Hematopoietic Cell Transplantation In TBX1 Congenital Athymia: A Lifesaving Therapeutic Approach When Facing a Systemic Viral Infection

“…Abnormal newborn screening due to profound T cell lymphopenia can be observed in patients with complete or partial DGS with a T -B + NK + immune phenotype. Hypoplastic thymi and athymia with variable other DGS features have been described in in a small number of patients with TBX1 haploinsufficiency, among other single gene defects (7,17,23,35,36). The International Union of Immunological Societies classifies TBX1 defects in the same category as 22q11.2DS: thymic defects with additional congenital abnormalities, distinguished from hematopoietic defects that cause SCID.…”

Thymus Degeneration and Regeneration

“…It is also documented that abnormalities of other transcription factors such as Pax1 or Pax9, Hoxa3, and Tbx1also lead to impaired thymus organogenesis ( 20 ), implicating the essential role of these factors in thymus development. Further studies are therefore necessary to elucidate tissue specific expression of these genes, their roles in TECs development and how they can be employed to boost thymic function.…”