Microdeletion 22q11.2 syndrome: Does thymus incidental surgical resection affect its immunological profile?
Main Article Content
Keywords
Chromosome 22q11.2 microdeletion syndrome, Thymus gland, Thymectomy
Abstract
Background: The del22q11 syndrome patients present immunological abnormalities associated to thymus alterations. Up to 75% of them present cardiopathies and thymus is frequently removed during surgery. The thymectomy per se has a deleterious effect concerning lymphocyte subpopulations, and T cell function. When compared to healthy controls, these patients have higher infections propensity of variable severity. The factors behind these variations are unknown. We compared immunological profiles of del22q11.2 Syndrome patients with and without thymectomy to establish its effect in the immune profile.
Methods: Forty-six del22q11.2 syndrome patients from 1 to 16 years old, 19 of them with partial or total thymectomy were included. Heart disease type, heart surgery, infections events and thymus resection were identified. Immunoglobulin levels, flow cytometry for lymphocytes subpopulations and TREC levels were determined, and statistical analyses were performed.
Results: The thymectomy group had a lower lymphocyte index, both regarding total cell count and when comparing age-adjusted Z scores. Also, CD3+, CD4+ and CD8+ lower levels were observed in this group, the lowest count in those patients who had undergone thymus resection during the first year of life. Their TREC level median was 23.6/L vs 16.1 L in the non-thymus group (p = 0.22). No differences were identified regarding immunoglobulin levels or infection events frequencies over the previous year.
Conclusion: Patients with del22q11.2 syndrome subjected to thymus resection present lower lymphocyte and TREC indexes when compared to patients without thymectomy. This situation may be influenced by the age at the surgery and the time elapsed since the procedure.
References
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28. Gennery AR, Barge D, O‘Sullivan JJ, Flood TJ, Abinun M, Cant AJ. Antibody deficiency and autoimmunity in 22q11.2 deletion syndrome. Arch Dis Child. 2002;86:422-5.
29. Perez E, Sullivan KE. Chromosome 22q11.2 deletion syndrome (DiGeorge and velocardiofacial syndromes). Curr Opin Pediatr. 2002;14:678-83; Oskarsdottir S, Persson C, Eriksson BO, Fasth A. Presenting phenotype in 100 children with the 22q11 deletion syndrome. Eur J Pediatr. 2005;164:146-53.
30. Douek DC, Vescio RA, Betts MR, Brenchley JM, Hill BJ, Zhang L, et al. Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of Tcell reconstitution. Lancet. 2000;355:1875-81.
31. The Harriet Lane Handbook: The Johns Hopkins Hospital. 19th ed. Editors, Megan M. Tschudy, Kristin M. Arcara. Philadelphia: Elsevier; 2012.
32. Kurobe H, Tominaga T, Sugano M, Hayabuchi Y, Egawa Y, Takahama Y. Kitagawa. Complete but not partial thymectomy in early infancy reduces T-cell-mediated immune response: three-year tracing study after pediatric cardiac surgery. J Thorac Cardiovasc Surg. 2013;145:656-62, 662.e1-2; discussion 662.
33. Fry TJ, Mackall CL. Current concepts of thymic aging. Springer Semin Immunopathol. 2002;24:7-22; Douek DC1, Koup RA. Evidence for thymic function in the elderly. Vaccine. 2000;18:1638-41.
34. Brearley S, Gentle TA, Baynham MI, Roberts KD, Abrams LD, Thompson RA. Immunodeficiency following neonatal thymectomy in man. Clin Exp Immunol. 1987;70:322-7.
35. Eysteinsdottir JH, Freysdottir J, Haraldsson A, et al. The influence of partial or total thymectomy during open-heart surgery in infants on the immune function later in life. Clin Exp Immunol. 2004;136:349-55.
36. Torfadottir H, Freysdottir J, Skaftadottir I, Haraldsson A, Sigfusson G, Ogmundsdottir HM. Evidence for extrathymic T cell maturation after thymectomy in infancy. Clin Exp Immunol. 2006;145:407-12.
37. van Gent R, Schadenberg AW, Otto SA, Nievelstein RA, Sieswerda GT, Haas F, et al. Long-term restoration of the human T-cell compartment after thymectomy during infancy: a role for thymic regeneration? Blood. 2011;118:627-34.
38. Roosen J, Oosterlinck W, Meyns B. Routine thymectomy in congenital cardiac surgery changes adaptive immunity without clinical relevance. Interact Cardiovasc Thorac Surg. 2015;20:101-6.
39. Van der Spek J, Groenwold RH, van der Burg M, can Montfrans JM. TREC-based newborn screening for severe combined immunodeficiency disease: a systematic review. J Clin Immunol. 2015;35:416-30.
40. Gul KA, Overland T, Osnes L, Baumbusch LO, Pettersen RD, Lima L, et al. Neonatal levels of T-cell receptor excision circles (TREC) in patients with 22q11.2 deletion syndrome and later disease features. J Clin Immunol. 2015;35:408-15.
2. Zemble R, Luning Prak E, McDonald K, McDonald-McGinn D, Zackai E, Sullivan K. Secondary immunologic consequences in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Clin Immunol. 2010;136:409-18.
3. Starr TK, Jameson SC, Hogquist KA. Positive and negative selection of T cells. Annu Rev Immunol. 2003;21:139-76.
4. Spits H. Development of alphabeta T cells in the human thymus. Nat Rev Immunol. 2002;2:760-72.
5. Shprintzen RJ. Velo-Cardio-Facial Syndrome. Management of Genetic Syndromes. New Jersey: John Wiley & Sons, Inc.; 2005. p. 615-31.
6. Sullivan KE. Chromosome 22q11.2 deletion syndrome: DiGeorge syndrome/velocardiofacial syndrome. Immunol Allergy Clin North Am. 2008;28:353-66.
7. Mc Donald McGinn DM, Zackai EH. Genetic counseling for the 22q11.2 deletion. Dev Disabil Res Rev. 2008;14:69-74.
8. Mc Donald-McGinn DM, Tonneen MK, Laufer-Cahana A, et al. Phenotype of the 22q11.2 deletion in individuals identified through an affected relative: cast a wide FISHing net! Genet Med. 2001;3:23-9.
9. Bassett AS, McDonald-McGinn DM, Devriendt K, Digilio MC, Goldenberg P, et al. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr. 2011;159, 332-9.e1.
10. Sullivan KE. The clinical, immunological, and molecular spectrum of chromosome 22q11.2 deletion syndrome and DiGeorge syndrome. Curr Opin Allergy Clin Immunol. 2004;4: 505-12.
11. Guris DL, Fantes J, Tara D, Druker BJ, Imamoto A. Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome. Nat Genet. 2001;27:293-8.
12. Jerome LA, Papaioannou VE. DiGeorge syndrome phenotype in mice mutant for the T-box gene Tbx1. Nat Genet. 2001;27:286-91.
13. Newbern J, Zhong J, Wickramasinghe RS, Li X, Wu Y, Samuels I, et al. Mouse and human phenotypes indicate a critical conserved role for ERK2 signaling in neural crest development. Proc Natl Acad Sci USA. 2008;105:17115-20.
14. Guna A, Butcher NJ, Bassett AS. Comparative mapping of the 22q11.2 deletion region and the potential of simple model organisms. J Neurodev Disord. 2015;7:18.
15. Sullivan K. Secondary immunologic consequences in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Clin Immunol. 2010;136: 409-18.
16. McLean-Tooke A, Barge D, Spickett GP, Gennery AR. Immunologic defects in 22q11.2 deletion syndrome. J Allergy Clin Immunol. 2008;122:362-7, 367.e1-4.
17. Lima K, Abrahamsen TG, Foelling I, Natving S, Ryder LP, Olaussen RW. Low thymic output in the 22q11.2 deletion syndrome measured by CCR9+ CD45RA+ T cell counts and T cell receptor rearrangement excision circles. Clin Exp Immunol. 2010;161:98-107.
18. Sedivá A, Bartúnková J, Zachova r, Poloucková A, Hrusák O, Janda A, et al. Early development of immunity in diGeorge syndrome. Med Sci Monit. 2005;11:CR182-7.
19. Piliero LM, Sandford AN, McDonald-McGinn DM, Zackai EH, Sullivan KE. T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome. Blood. 2004;103:1020-5.
20. Chinen J, Rosenblatt HM, Smith EO, Sheare WT, et al. Long-term assessment of T-cell population in DiGeorge syndrome. J All Clin Immunol. 2003;111:573-9.
21. Taddei I, Morishima M, Huynh T, Lindsay EA. Genetic factors are major determinants of phenotypic variability in a mouse model of the DiGeorge/del22q11.2 syndromes. Proc Nat Acad Sci USA. 2001;98:1428-31.
22. Bassett AS, McDonald-McGinn DM, Devriendt K, Digilio MC, Goldenberg P. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr. 2011;159, 332-9.e1.
23. Sauce D, Larsen M, Fastenackels S, Duperrier A, Keller M, Grubeck-Loebestein B, et al. Evidence of premature immune aging in patients thymectomized during early childhood. J Clin Invest. 2009;119:3070-8.
24. Ferrando-Martínez S, de la Fuente M, Guerrerod JM, Lealb M, Munoz-Fernández ˜ MA. Impacto de la función tímica en el deterioro inmunológico asociado a la edad. Rev Esp Geriatr Gerontol. 2013;48:232-7.
25. Prelog M, Keller M, Geiger R, Brandstätter A, Würzner R, Schweigmann U, et al. Thymectomy in early childhood: significant alterations of the CD4(+)CD45RA(+)CD62L(+) T cell compartment in later life. Clin Immunol. 2009;130: 123-32.
26. Mancebo E, Clemente J, Sanchez J, Ruiz-Contreras J, De Pablos P, Cortezon S, et al. Longitudinal analysis of immune function in the first 3 years of life in thymectomized neonates during cardiac surgery. Clin Exp Immunol. 2008;154: 375-83.
27. Halnon NJ, Jamieson B, Plunkett M, Kitchen CM, Pham T, Krogstad P. Thymic function and impaired maintenance of peripheral T cell populations in children with congenital heart disease and surgical thymectomy. Pediatr Res. 2005;57: 42-8.
28. Gennery AR, Barge D, O‘Sullivan JJ, Flood TJ, Abinun M, Cant AJ. Antibody deficiency and autoimmunity in 22q11.2 deletion syndrome. Arch Dis Child. 2002;86:422-5.
29. Perez E, Sullivan KE. Chromosome 22q11.2 deletion syndrome (DiGeorge and velocardiofacial syndromes). Curr Opin Pediatr. 2002;14:678-83; Oskarsdottir S, Persson C, Eriksson BO, Fasth A. Presenting phenotype in 100 children with the 22q11 deletion syndrome. Eur J Pediatr. 2005;164:146-53.
30. Douek DC, Vescio RA, Betts MR, Brenchley JM, Hill BJ, Zhang L, et al. Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of Tcell reconstitution. Lancet. 2000;355:1875-81.
31. The Harriet Lane Handbook: The Johns Hopkins Hospital. 19th ed. Editors, Megan M. Tschudy, Kristin M. Arcara. Philadelphia: Elsevier; 2012.
32. Kurobe H, Tominaga T, Sugano M, Hayabuchi Y, Egawa Y, Takahama Y. Kitagawa. Complete but not partial thymectomy in early infancy reduces T-cell-mediated immune response: three-year tracing study after pediatric cardiac surgery. J Thorac Cardiovasc Surg. 2013;145:656-62, 662.e1-2; discussion 662.
33. Fry TJ, Mackall CL. Current concepts of thymic aging. Springer Semin Immunopathol. 2002;24:7-22; Douek DC1, Koup RA. Evidence for thymic function in the elderly. Vaccine. 2000;18:1638-41.
34. Brearley S, Gentle TA, Baynham MI, Roberts KD, Abrams LD, Thompson RA. Immunodeficiency following neonatal thymectomy in man. Clin Exp Immunol. 1987;70:322-7.
35. Eysteinsdottir JH, Freysdottir J, Haraldsson A, et al. The influence of partial or total thymectomy during open-heart surgery in infants on the immune function later in life. Clin Exp Immunol. 2004;136:349-55.
36. Torfadottir H, Freysdottir J, Skaftadottir I, Haraldsson A, Sigfusson G, Ogmundsdottir HM. Evidence for extrathymic T cell maturation after thymectomy in infancy. Clin Exp Immunol. 2006;145:407-12.
37. van Gent R, Schadenberg AW, Otto SA, Nievelstein RA, Sieswerda GT, Haas F, et al. Long-term restoration of the human T-cell compartment after thymectomy during infancy: a role for thymic regeneration? Blood. 2011;118:627-34.
38. Roosen J, Oosterlinck W, Meyns B. Routine thymectomy in congenital cardiac surgery changes adaptive immunity without clinical relevance. Interact Cardiovasc Thorac Surg. 2015;20:101-6.
39. Van der Spek J, Groenwold RH, van der Burg M, can Montfrans JM. TREC-based newborn screening for severe combined immunodeficiency disease: a systematic review. J Clin Immunol. 2015;35:416-30.
40. Gul KA, Overland T, Osnes L, Baumbusch LO, Pettersen RD, Lima L, et al. Neonatal levels of T-cell receptor excision circles (TREC) in patients with 22q11.2 deletion syndrome and later disease features. J Clin Immunol. 2015;35:408-15.
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Apr 15, 2019
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Navarrete-Rodríguez, E., Del-Rio-Navarro, B., García-Fajardo, D., Baay-Guzmán, G., Espinosa-Padilla, S., Medina-Torres, E., Moguel-Molina, N., Sánchez-Curiel-Loyo, M., Nájera-Martínez, N., Navarro-Munguía, J., Reyes-Noriega, N., Balderrábano-Saucedo, N., Sánchez-Urbina, R., García Delgado, C., Sienra-Monge, J., & Morán-Barroso, V. (2019). Microdeletion 22q11.2 syndrome: Does thymus incidental surgical resection affect its immunological profile?. Allergologia Et Immunopathologia, 47(2), 141-151. https://www.all-imm.com/index.php/aei/article/view/336
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Navarrete-Rodríguez, E., Del-Rio-Navarro, B., García-Fajardo, D., Baay-Guzmán, G., Espinosa-Padilla, S., Medina-Torres, E., Moguel-Molina, N., Sánchez-Curiel-Loyo, M., Nájera-Martínez, N., Navarro-Munguía, J., Reyes-Noriega, N., Balderrábano-Saucedo, N., Sánchez-Urbina, R., García Delgado, C., Sienra-Monge, J., & Morán-Barroso, V. (2019). Microdeletion 22q11.2 syndrome: Does thymus incidental surgical resection affect its immunological profile?. Allergologia Et Immunopathologia, 47(2), 141-151. https://www.all-imm.com/index.php/aei/article/view/336