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, VALSANGIACOMO BÜCHEL, E, RIEGEL, M, SCHINZEL, A, SEGER, R, GÜNGOR, T
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell 01.02.2009
• Subjects: Analytical, structural and metabolic biochemistry; Biological and medical sciences; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes - immunology; Cell Proliferation; Chromosome Deletion; Chromosomes, Human, Pair 22 - genetics; DiGeorge Syndrome - genetics; DiGeorge Syndrome - immunology; Female; Follow-Up Studies; Fundamental and applied biological sciences. Psychology; Heart Defects, Congenital - complications; Heart Defects, Congenital - genetics; Heart Defects, Congenital - immunology; Humans; Immunoglobulins - blood; In Situ Hybridization, Fluorescence; Infant, Newborn; Lymphocyte Activation - immunology; Male; Opportunistic Infections - complications; Opportunistic Infections - immunology; Prognosis; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Cytotoxic - immunology; Thymus Gland - abnormalities; Thymus Gland - immunology; Human; Heart; Immunopathology; CD4 T lymphocyte; Thymus gland; DiGeorge syndrome; Mortality; recent thymic emigrants (TREC); Naive cell; Chromosome; Biochemistry; Di George's syndrome; Epidemiology; Biological activity; Partial; T cell receptor excision circle; chromosome 22q11.2 microdeletion; T-Lymphocyte; Deletion; Genetics; naive CD4- T cells; immunodeficiency; Circulatory system; Child
• 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 (T(REC))-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 T(RECs)/10(6) 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.