Long-Term Follow-Up of Newborns with 22q11 Deletion Syndrome and Low TRECs

Springer Science and Business Media LLC - 2022
Jenny Lingman Framme1,2, Christina Lundqvist3, Anna-Carin Lundell3, Pauline A. van Schouwenburg4, Andri L. Lemarquis2, Karolina Thörn3, Susanne Lindgren2,3, Judith Gudmundsdottir2,5, Vanja Lundberg2,3, Sofie Degerman6,7, Rolf H. Zetterström8,9, Stephan Borte10, Lennart Hammarström11, Esbjörn Telemo3, Magnus Hultdin6, Mirjam van der Burg4, Anders Fasth2, Sólveig Oskarsdóttir2, Olov Ekwall2,3
1Department of Pediatrics, Halland Hospital Halmstad, Halmstad, Sweden
2Department of Pediatrics, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
3Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
4Department of Pediatrics, Laboratory for Pediatric Immunology, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, The Netherlands
5Children’s Medical Center, National University Hospital of Iceland, Reykjavík, Iceland
6Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
7Department of Clinical Microbiology, Umeå University, Umeå, Sweden
8Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
9Centre for Inherited Metabolic Diseases, Karolinska University Hospital Solna, Stockholm, Sweden
10ImmunoDeficiencyCenter Leipzig (IDCL), Municipal Hospital St. Georg Leipzig, Leipzig, Germany
11Department of Biosciences and Nutrition, Neo, Karolinska Institute, Stockholm, Sweden

Tóm tắt

Population-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). To investigate the long-term prognostic value of low levels of TRECs in newborns with 22q11DS. Subjects 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. At 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. This 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. This 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.

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