T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome

Abstract

Patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome) typically exhibit thymic hypoplasia, conotruncal cardiac defects, and hypoparathyroidism. The immunodeficiency that results from the thymic hypoplasia has been extensively described and consists primarily of T-cell lymphopenia. A curious feature of the T-cell lymphopenia is that the age-related rate of decline of T-cell numbers is slower in patients than controls. This leads to T-cell numbers in adulthood that are minimally decreased compared with controls. This suggests that homeostatic mechanisms might be acting to preserve the peripheral blood T-cell numbers in patients. We characterized changes in CD4/ CD45RA and CD4/CD45RO T-cell populations in patients and controls of various ages and determined T-cell recombination excision circles and telomere length within the CD4/CD45RA population. Patients had evidence of accelerated conversion of naive to memory cells and had evidence of more extensive replicative history within the CD4/CD45RA compartment compared with controls. Oligoclonal T-cell receptor (TCR) V␤ families and missing V␤ families were seen more often in patients than controls. These data are consistent with homeostatic proliferation of T cells in patients with limited T-cell production due to thymic hypoplasia. ( IntroductionChromosome 22q11.2 deletion syndrome is a disorder that is classically associated with conotruncal cardiac anomalies, thymic hypoplasia, and hypoparathyriodism. 1 DiGeorge syndrome, velocardiofacial syndrome, Opitz/GBBB syndrome, Coloboma, heart defects, atresa of choanae, retardation of growth and development, genital anomalies, ear anomalies (CHARGE) syndrome, and conotruncal anomaly face syndrome have been associated with the deletion. The thymic hypoplasia is seen in more than 80% of the patients with the deletion regardless of the other clinical manifestations of the syndrome. The immunodeficiency arising as a consequence of the thymic hypoplasia in patients with the deletion syndrome has been studied for nearly 50 years, and it is now known to be extremely variable. [2][3][4][5] The spectrum of immunodeficiency ranges from absent T cells due to thymic aplasia to normal T-cell numbers. 2,6 T-cell function is typically preserved, although standard mitogen proliferation assays are usually diminished when the T-cell count is very low, corresponding to the diminished numbers of cells competent to respond to the stimulus. 4 Immunoglobulin A (IgA) deficiency, hypogammaglobulinemia, and defects in functional antibody production have been occasionally described and are thought to be secondary to the T-cell defect. [7][8][9] The clinical picture for patients with chromosome 22q11.2 deletion syndrome is similarly diverse. Early descriptions of the syndrome emphasized life-threatening infections; however, most of these patients were ascertained due to absent or nearly absent T cells. 3,10 Recent descriptions of populations with the deletion have noted that the very severe immunodeficiency...

CHARGE syndrome: a review of the immunological aspects

“…Furthermore, the median age is quite young in our collected cohort. As the T-cell number may well improve with age, as has been shown in 22q11.2 deletion syndrome, 73 our collected cohort might represent the more severe phenotypes.…”

Transgenic Expression of MicroRNA-185 Causes a Developmental Arrest of T Cells by Targeting Multiple Genes Including Mzb1

“…Such patients can have a thymic hypoplasia, hypoparathyroidism, cardiac anomalies, and/or learning disabilities (11). Some patients have an increased frequency of autoimmune disorders and T helper cell alterations (12,13). One-third of 22q11.2 deletion syndrome patients will develop schizophrenia as adults (14).…”

22q11.2 Deletion Syndrome: Symptoms, Diagnosis, Treatment

“…Иммунные нарушения вследствие недоразвития ти-муса и нарушения образования Т клеток выявляют у 75% больных с синдромом 22q11.2DS [42,43].…”