Persistent low thymic activity and non-cardiac mortality in children with chromosome 22q11·2 microdeletion and partial DiGeorge syndrome

• Published in: Clinical and experimental immunology Vol. 155; no. 2; pp. 189 - 198
• Main Authors: Eberle, P, Berger, C, Junge, S, Dougoud, S, Büchel, E. Valsangiacomo, Riegel, M, Schinzel, A, Seger, R, Güngör, T
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.02.2009; Blackwell Publishing Ltd; Blackwell Science Inc
• Subjects: chromosome 22q11·2 microdeletion; DiGeorge syndrome; Immunodeficiency; immunosuppression (physiological); naive CD4‐ T cells; naive CD4⁻ T cells; recent thymic emigrants (TREC)
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/j.1365-2249.2008.03809.x

A subgroup of patients with 22q11·2 microdeletion and partial DiGeorge syndrome (pDGS) appears to be susceptible to non-cardiac mortality (NCM) despite sufficient overall CD4⁺ T cells. To detect these patients, 20 newborns with 22q11·2 microdeletion and congenital heart disease were followed prospectively for 6 years. Besides detailed clinical assessment, longitudinal monitoring of naive CD4⁺ and cytotoxic CD3⁺CD8⁺ T cells (CTL) was performed. To monitor thymic activity, we analysed naive platelet endothelial cell adhesion molecule-1 (CD31⁺) expressing CD45RA⁺RO⁻CD4⁺ cells containing high numbers of T cell receptor excision circle (TREC)-bearing lymphocytes and compared them with normal values of healthy children (n = 75). Comparing two age periods, low overall CD4⁺ and naive CD4⁺ T cell numbers were observed in 65%/75%, respectively, of patients in period A (< 1 year) declining to 22%/50%, respectively, of patients in period B (> 1/< 7 years). The percentage of patients with low CTLs (< P10) remained robust until school age (period A: 60%; period B: 50%). Low numbers of CTLs were associated with abnormally low naive CD45RA⁺RO⁻CD4⁺ T cells. A high-risk (HR) group (n = 11) and a standard-risk (SR) (n = 9) group were identified. HR patients were characterized by low numbers of both naive CD4⁺ and CTLs and were prone to lethal infectious and lymphoproliferative complications (NCM: four of 11; cardiac mortality: one of 11) while SR patients were not (NCM: none of nine; cardiac mortality: two of nine). Naive CD31⁺CD45RA⁺RO⁻CD4⁺, naive CD45RA⁺RO⁻CD4⁺ T cells as well as TRECs/10⁶ mononuclear cells were abnormally low in HR and normal in SR patients. Longitudinal monitoring of naive CD4⁺ and cytotoxic T cells may help to discriminate pDGS patients at increased risk for NCM.