Abstract
BackgroundPopulation-based neonatal screening using T-cell receptor excision circles (TRECs) identifies infants with profound T lymphopenia, as seen in cases of severe combined immunodeficiency, and in a subgroup of infants with 22q11 deletion syndrome (22q11DS).PurposeTo investigate the long-term prognostic value of low levels of TRECs in newborns with 22q11DS.MethodsSubjects with 22q11DS and low TRECs at birth (22q11Low, N=10), matched subjects with 22q11DS and normal TRECs (22q11Normal, N=10), and matched healthy controls (HC, N=10) were identified. At follow-up (median age 16 years), clinical and immunological characterizations, covering lymphocyte subsets, immunoglobulins, TRECs, T-cell receptor repertoires, and relative telomere length (RTL) measurements were performed.ResultsAt follow-up, the 22q11Low group had lower numbers of naïve T-helper cells, naïve T-regulatory cells, naïve cytotoxic T cells, and persistently lower TRECs compared to healthy controls. Receptor repertoires showed skewed V-gene usage for naïve T-helper cells, whereas for naïve cytotoxic T cells, shorter RTL and a trend towards higher clonality were found. Multivariate discriminant analysis revealed a clear distinction between the three groups and a skewing towards Th17 differentiation of T-helper cells, particularly in the 22q11Low individuals. Perturbations of B-cell subsets were found in both the 22q11Low and 22q11Normal group compared to the HC group, with larger proportions of naïve B cells and lower levels of memory B cells, including switched memory B cells.ConclusionsThis long-term follow-up study shows that 22q11Low individuals have persistent immunologic aberrations and increased risk for immune dysregulation, indicating the necessity of lifelong monitoring.Clinical ImplicationsThis study elucidates the natural history of childhood immune function in newborns with 22q11DS and low TRECs, which may facilitate the development of programs for long-term monitoring and therapeutic choices.
Highlights
Newborn screening for T-cell receptor excision circles (TRECs) enables recognition of infants with severe combined immunodeficiency (SCID) before life-threatening infections occur [1]
Previous reports have indicated that some infants with 22q11DS identified through TREC screening increase their numbers of naïve T lymphocytes over time [2, 17, 18]
We show that low levels of TRECs during the newborn period for infants with 22q11DS are predictive of a long-term impairment of thymic output with defects in the T-cell compartments, bias in TRBV usage and signs of premature ageing of naïve cytotoxic T cells
Summary
Newborn screening for T-cell receptor excision circles (TRECs) enables recognition of infants with severe combined immunodeficiency (SCID) before life-threatening infections occur [1]. Previous reports have indicated that some infants with 22q11DS identified through TREC screening increase their numbers of naïve T lymphocytes over time [2, 17, 18] It is not known if this increase applies to a larger group of patients with 22q11DS or if it entails long-lasting immunological and clinical normalization. We report a controlled follow-up study of newborns with 22q11DS and low TRECs, with detailed immunologic and clinical assessments performed at a median age of 16 years These subjects were compared with individuals with 22q11DS and normal levels of TRECs in the neonatal period, as well as with healthy controls. We performed a multivariate factor analysis to investigate the associations of low TRECs with additional immunologic and clinical data available for these patients
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