Thymus dysfunction in the 22q11 deletion syndrome
Abstract
Introduction: The 22q11.2 deletion syndrome (22q11DS) is associated with heterogeneous clinical findings, including T-cell immunodeficiency resulting from thymus hypoplasia. Newborn screening programs based on the quantification of T-cell receptor excision circles (TRECs) identify infants with severe combined immunodeficiency, as well as a number of infants with 22q11DS.
Aim: To study the outcome of TRECs at birth in infants with 22q11DS, and to investigate if low numbers of TRECs are predictive of persistent thymus dysfunction in individuals with 22q11DS.
Method: TRECs were retrospectively quantified by PCR using the original newborn screening cards from 48 infants with 22q11DS (Paper I). A follow-up of individuals with low numbers of TRECs (22q11Low, N=10), normal numbers of TRECs (22q11Normal, N=10) and matched healthy controls (N=10), was performed, including quantification of TRECs, flow cytometry for characterization of lymphocyte subsets, deep sequencing of T-cell receptor repertoires, and PCR for assessment of telomere lengths (Paper II). High-density arrays were used for autoantibody profiling (Paper III).
Results: A considerable proportion of infants with 22q11DS had abnormal numbers of TRECs at birth (Paper I). At follow-up (median age 16 years), the 22q11Low group had lower TRECs, lower proportions of naïve T cells, aberrant T-cell receptor repertoires (Paper II) and more autoantibodies (Paper III), as compared to the 22q11Normal group and to healthy controls. Many autoantibody specificities were shared between the two 22q11DS groups.
Conclusion: Newborn screening with TRECs identifies a subpopulation of infants with 22q11DS, in whom low numbers of TRECs at birth are associated with long-term immune aberrations, necessitating follow-up.
Parts of work
I. Lingman Framme J, Borte S, von Döbeln U, Hammarström L, Óskarsdóttir S. Retrospective analysis of TREC based newborn screening results and clinical phenotypes in infants with the 22q11 deletion syndrome. J Clin Immunol. 2014 May; 34(4): 514-9. ::doi::10.1007/s10875-014-0002-y II. Framme JL, Lundqvist C, Lundell AC, van Schouwenburg PA, Lemarquis AL, Thörn K, Lindgren S, Gudmundsdottir J, Lundberg V, Degerman S, Zetterström RH, Borte S, Hammarström L, Telemo E, Hultdin M, van der Burg M, Fasth A, Óskarsdóttir S, Ekwall O. Long-Term Follow-Up of Newborns with 22q11 Deletion Syndrome and Low TRECs. J Clin Immunol. 2022 Apr; 42(3): 618-633.
::doi::10.1007/s10875-021-01201-5 III. Lingman Framme J, Hennings V, Lundell A-C, Thörn K, Lundqvist C, Lindgren S, Lundberg V, Telemo E, Fasth A, Óskarsdóttir S, Ekwall O. Proteome wide autoantibody profiling in the 22q11.2 deletion syndrome. In manuscript.
Degree
Doctor of Philosophy (Medicine)
University
University of Gothenburg. Sahlgrenska Academy
Institution
Institute of Clinical Sciences. Department of Pediatrics
Disputation
Fredagen den 5 maj 2023, kl 9.00, Föreläsningssalen Tallen, Drottning Silvias Barnsjukhus, Göteborg
Date of defence
2023-05-05
jenny.lingman-framme@gu.se
Date
2023-04-12Author
Lingman Framme, Jenny
Keywords
22q11.2 deletion syndrome
TREC
thymus
Publication type
Doctoral thesis
ISBN
978-91-8069-143-7 (print)
978-91-8069-144-4 (PDF)
Language
eng