Investigating the Variation of TREC/KREC in Combined Immunodeficiencies
-
Leila Shakerian
,
Maryam Nourizadeh
,
Mohsen Badalzadeh
,
Mohammad Reza Fazlollahi
,
Raheleh Shokouhi Shoormasti
,
Shiva Saghafi
,
Behnaz Esmaeili
,
Zahra Alizadeh
,
Stephan Borte
,
Massoud Houshmand
,
Lennart Hammarström
,
Zahra Pourpak
Abstract
T-cell receptor excision circles (TREC)/Kappa-deleting recombination excision circles (KREC) assay has been recently recognized for detecting patients with primary (T- and/or B-cell) immunodeficiency (PID). We aimed to investigate the alterations of these biomarkers in some combined immunodeficiency patients compared to the healthy controls in different age groups.
TREC and KREC were assessed in a total of 82 PID patients, most of them with exact genetic diagnosis (3 months to 42 years); using quantitative real-time-polymerase chain reaction (PCR). Patients had a final diagnosis of common variable immunodeficiency (n=23), ataxia-telangiectasia (AT) (n=17), hyper-IgE syndrome (HIES) (7 with DOCK8 deficiency, 4 with signal transducer and activator of transcription 3 (STAT3) deficiency, and 8 children with unknown genetic defects), Wiskott-Aldrich syndrome (WAS) (n=20), purine nucleoside phosphorylase (PNP)deficiency(n=1), dedicator of cytokinesis2 (DOCK2) deficiency (n=1), recombinase activating gene1 (RAG1) deficiency (n=1).
Very low to zero amounts of TREC and/or KREC were detected in 14 out of 23 cases of common variable immunodeficiency (CVID), 14 out of 17 cases of AT, 8 out of 20 cases of WAS, 6 out of 7 cases of DOCK8-deficiency patients, 4 out of 8 cases of HIES with unknown genetic defects and all patients with defects in DOCK2, PNP, and RAG1. STAT3-deficient patients were normal for both biomarkers. All patients showed a significant difference in both markers compared to age-matched healthy controls.
Our findings highlight that apart from severe types of T/B cell defects, this assay can also be used for early diagnosis the patients with late-onset of disease and even PIDs without a positive family history.
1. Serana F, Chiarini M, Zanotti C, Sottini A, Bertoli D, Bosio A, et al. Use of V(D)J recombination excision circles to identify T- and B-cell defects and to monitor the treatment in primary and acquired immunodeficiencies. J Transl Med. 2013;11:119.
2. Borte S, von Dobeln U, Fasth A, Wang N, Janzi M, Winiarski J, et al. Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR. Blood. 2012;119(11):2552-5.
3. Roifman CM, Somech R, Kavadas F, Pires L, Nahum A, Dalal I, et al. Defining combined immunodeficiency. J Allergy Clin Immunol. 2012;130(1):177-83.
4. Bousfiha A, Jeddane L, Picard C, Ailal F, Bobby Gaspar H, Al-Herz W, et al. The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies. J Clin Immunol. 2018;38(1):129-43.
5. Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, et al. Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Allergy Clin Immunol. 2020;40(1):24-64.
6. Boyle JM, Buckley RH. Population prevalence of diagnosed primary immunodeficiency diseases in the United States. J Clin Immunol. 2007;27(5):497-502.
7. Rezaei N, Pourpak Z, Aghamohammadi A, Farhoudi A, Movahedi M, Gharagozlou M, et al. Consanguinity in primary immunodeficiency disorders; the report from Iranian Primary Immunodeficiency Registry. Am J Reprod Immunol. 2006;56(2):145-51.
8. Puck JM. The case for newborn screening for severe combined immunodeficiency and related disorders. Ann N Y Acad Sci. 2011;1246(14):108-17.
9. Puck JM. Laboratory technology for population-based screening for severe combined immunodeficiency in neonates: the winner is T-cell receptor excision circles. J Allergy Clin Immunol 2012;129(3):607-16.
10. King JR, Hammarstrom L. Newborn Screening for Primary Immunodeficiency Diseases: History, Current and Future Practice. J Clin Immunol. 2018;38(1):56-66.
11. Jilkina O, Thompson JR, Kwan L, Van Caeseele P, Rockman-Greenberg C, Schroeder ML. Retrospective TREC testing of newborns with Severe Combined Immunodeficiency and other primary immunodeficiency diseases. Mol Genet Metab Rep. 2014;1(3):324-33.
12. Shakerian L, Pourpak Z, Shamlou S, Domsgen E, Kazemnejad A, Dalili H, et al. Determining Laboratory Reference Values of TREC and KREC in Different Age Groups of Iranian Healthy Individuals. Iran J Allergy Asthma Immunol. 2019;18(2):143-52.
13. Custer JWR, Rachel E. The Harriet Lane handbook : a manual for pediatric house officers. Johns Hopkins Hospital Children's Medical and Surgical Center. Philadelphia, PA : Mosby/Elsevier, c2009.
14. Shokouhi Shoormasti R, Azimdoost A, Saghafi S, Movahhedi M, Haghi Ashtiani MT, Pourpak Z, et al. Normal range determination of lymphocytes subsets in normal adults in Iran. Iran J Allergy Asthma Immunol. 2011;10(4):295-8.
15. Nourizadeh M, Shakerian L, Borte S, Fazlollahi M, Badalzadeh M, Houshmand M, et al. Newborn screening using TREC/KREC assay for severe T and B cell lymphopenia in Iran. Scand J Immunol. 2018:e12699.
16. Alizadeh Z, Mazinani M, Shakerian L, Nabavi M, Fazlollahi MR. DOCK2 Deficiency in a Patient with Hyper IgM Phenotype. J Clin Immunol. 2018;38(1):10-2.
17. Puck JM. Newborn screening for severe combined immunodeficiency and T-cell lymphopenia. Immunol Rev. 2019;287(1):241-52.
18. Atschekzei F, Ahmad F, Witte T, Jacobs R, Schmidt RE. Limitation of Simultaneous Analysis of T-Cell Receptor and kappa-Deleting Recombination Excision Circles Based on Multiplex Real-Time Polymerase Chain Reaction in Common Variable Immunodeficiency Patients. Int Arch Allergy Immunol. 2016;171(2):136-40.
19. la Marca G, Canessa C, Giocaliere E, Romano F, Malvagia S, Funghini S, et al. Diagnosis of immunodeficiency caused by a purine nucleoside phosphorylase defect by using tandem mass spectrometry on dried blood spots. . J Clin Immunol. 2014;134(1):155-9.
20. Mallott J, Kwan A, Church J, Gonzalez-Espinosa D, Lorey F, Tang LF, et al. Newborn screening for SCID identifies patients with ataxia telangiectasia. J Clin Immunol. 2013;33(3):540-9.
21. Biggs CM, Keles S, Chatila TA. DOCK8 deficiency: Insights into pathophysiology, clinical features and management. Clin Immunol. 2017;181(4):75-82.
22. Satoh R, Kakugawa K, Yasuda T, Yoshida H, Sibilia M, Katsura Y, et al. Requirement of Stat3 Signaling in the Postnatal Development of Thymic Medullary Epithelial Cells. PLoS Genet. 2016;12(1):e1005776.
23. Kamae C, Nakagawa N, Sato H, Honma K, Mitsuiki N, Ohara O, et al. Common variable immunodeficiency classification by quantifying T-cell receptor and immunoglobulin kappa-deleting recombination excision circles. . J Clin Immunol. 2013;131(5):1437-40 e5.
24. Guazzi V, Aiuti F, Mezzaroma I, Mazzetta F, Andolfi G, Mortellaro A, et al. Assessment of thymic output in common variable immunodeficiency patients by evaluation of T cell receptor excision circles. Clin Exp Immunol. 2002;129(2):346-53.
25. Chinen J, Notarangelo LD, Shearer WT. Advances in basic and clinical immunology in 2013. J Clin Immunol. 2014;133(4):967-76.
26. Borte S, Fasth A, von Dobeln U, Winiarski J, Hammarstrom L. Newborn screening for severe T and B cell lymphopenia identifies a fraction of patients with Wiskott-Aldrich syndrome. Clin Immunol. 2014;155(1):74-8.
27. Li W, Sun X, Wang J, Zhao Q, Dai R, Wang Y, et al. Defective thymic output in WAS patients is associated with abnormal actin organization. Sci Rep. 2017;7(1):11978.
28. Wada T, Schurman SH, Garabedian EK, Yachie A, Candotti F. Analysis of T-cell repertoire diversity in Wiskott-Aldrich syndrome. Blood. 2005;106(12):3895-7.
29. Cotta-de-Almeida V, Dupre L, Guipouy D, Vasconcelos Z. Signal Integration during T Lymphocyte Activation and Function: Lessons from the Wiskott-Aldrich Syndrome. Front Immunol. 2015;6(4):47-9.
30. Patel JP, Puck JM, Srinivasan R, Brown C, Sunderam U, Kundu K, et al. Nijmegen breakage syndrome detected by newborn screening for T cell receptor excision circles (TRECs). J Clin Immunol. 2015;35(2):227-33.
31. Vacchio MS, Olaru A, Livak F, Hodes RJ. ATM deficiency impairs thymocyte maturation because of defective resolution of T cell receptor alpha locus coding end breaks. Proc Natl Acad Sci U S A. 2007;104(15):6323-8.
32. Barbaro M, Ohlsson A, Borte S, Jonsson S, Zetterstrom RH, King J, et al. Newborn Screening for Severe Primary Immunodeficiency Diseases in Sweden-a 2-Year Pilot TREC and KREC Screening Study. J Clin Immunol. 2017;37(1):51-60.
33. Kraus M, Lev A, Simon AJ, Levran I, Nissenkorn A, Levi YB, et al. Disturbed B and T cell homeostasis and neogenesis in patients with ataxia telangiectasia. J Clin Immunol. 2014;34(5):561-72.
34. Dobbs K, Dominguez Conde C, Zhang SY, Parolini S, Audry M, Chou J, et al. Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections. N Engl J Med. 2015;372(25):2409-22.
35. Somech R, Lev A, Simon AJ, Hanna S, Etzioni A. T- and B-cell defects in a novel purine nucleoside phosphorylase mutation. The Journal of allergy and clinical immunology. 2012;130(2):539-42.
36. Korsunskiy I, Blyuss O, Gordukova M, Davydova N, Zaikin A, Zinovieva N, et al. Expanding TREC and KREC Utility in Primary Immunodeficiency Diseases Diagnosis. Front Immunol. 2020;11(320):8-15.
2. Borte S, von Dobeln U, Fasth A, Wang N, Janzi M, Winiarski J, et al. Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR. Blood. 2012;119(11):2552-5.
3. Roifman CM, Somech R, Kavadas F, Pires L, Nahum A, Dalal I, et al. Defining combined immunodeficiency. J Allergy Clin Immunol. 2012;130(1):177-83.
4. Bousfiha A, Jeddane L, Picard C, Ailal F, Bobby Gaspar H, Al-Herz W, et al. The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies. J Clin Immunol. 2018;38(1):129-43.
5. Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, et al. Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Allergy Clin Immunol. 2020;40(1):24-64.
6. Boyle JM, Buckley RH. Population prevalence of diagnosed primary immunodeficiency diseases in the United States. J Clin Immunol. 2007;27(5):497-502.
7. Rezaei N, Pourpak Z, Aghamohammadi A, Farhoudi A, Movahedi M, Gharagozlou M, et al. Consanguinity in primary immunodeficiency disorders; the report from Iranian Primary Immunodeficiency Registry. Am J Reprod Immunol. 2006;56(2):145-51.
8. Puck JM. The case for newborn screening for severe combined immunodeficiency and related disorders. Ann N Y Acad Sci. 2011;1246(14):108-17.
9. Puck JM. Laboratory technology for population-based screening for severe combined immunodeficiency in neonates: the winner is T-cell receptor excision circles. J Allergy Clin Immunol 2012;129(3):607-16.
10. King JR, Hammarstrom L. Newborn Screening for Primary Immunodeficiency Diseases: History, Current and Future Practice. J Clin Immunol. 2018;38(1):56-66.
11. Jilkina O, Thompson JR, Kwan L, Van Caeseele P, Rockman-Greenberg C, Schroeder ML. Retrospective TREC testing of newborns with Severe Combined Immunodeficiency and other primary immunodeficiency diseases. Mol Genet Metab Rep. 2014;1(3):324-33.
12. Shakerian L, Pourpak Z, Shamlou S, Domsgen E, Kazemnejad A, Dalili H, et al. Determining Laboratory Reference Values of TREC and KREC in Different Age Groups of Iranian Healthy Individuals. Iran J Allergy Asthma Immunol. 2019;18(2):143-52.
13. Custer JWR, Rachel E. The Harriet Lane handbook : a manual for pediatric house officers. Johns Hopkins Hospital Children's Medical and Surgical Center. Philadelphia, PA : Mosby/Elsevier, c2009.
14. Shokouhi Shoormasti R, Azimdoost A, Saghafi S, Movahhedi M, Haghi Ashtiani MT, Pourpak Z, et al. Normal range determination of lymphocytes subsets in normal adults in Iran. Iran J Allergy Asthma Immunol. 2011;10(4):295-8.
15. Nourizadeh M, Shakerian L, Borte S, Fazlollahi M, Badalzadeh M, Houshmand M, et al. Newborn screening using TREC/KREC assay for severe T and B cell lymphopenia in Iran. Scand J Immunol. 2018:e12699.
16. Alizadeh Z, Mazinani M, Shakerian L, Nabavi M, Fazlollahi MR. DOCK2 Deficiency in a Patient with Hyper IgM Phenotype. J Clin Immunol. 2018;38(1):10-2.
17. Puck JM. Newborn screening for severe combined immunodeficiency and T-cell lymphopenia. Immunol Rev. 2019;287(1):241-52.
18. Atschekzei F, Ahmad F, Witte T, Jacobs R, Schmidt RE. Limitation of Simultaneous Analysis of T-Cell Receptor and kappa-Deleting Recombination Excision Circles Based on Multiplex Real-Time Polymerase Chain Reaction in Common Variable Immunodeficiency Patients. Int Arch Allergy Immunol. 2016;171(2):136-40.
19. la Marca G, Canessa C, Giocaliere E, Romano F, Malvagia S, Funghini S, et al. Diagnosis of immunodeficiency caused by a purine nucleoside phosphorylase defect by using tandem mass spectrometry on dried blood spots. . J Clin Immunol. 2014;134(1):155-9.
20. Mallott J, Kwan A, Church J, Gonzalez-Espinosa D, Lorey F, Tang LF, et al. Newborn screening for SCID identifies patients with ataxia telangiectasia. J Clin Immunol. 2013;33(3):540-9.
21. Biggs CM, Keles S, Chatila TA. DOCK8 deficiency: Insights into pathophysiology, clinical features and management. Clin Immunol. 2017;181(4):75-82.
22. Satoh R, Kakugawa K, Yasuda T, Yoshida H, Sibilia M, Katsura Y, et al. Requirement of Stat3 Signaling in the Postnatal Development of Thymic Medullary Epithelial Cells. PLoS Genet. 2016;12(1):e1005776.
23. Kamae C, Nakagawa N, Sato H, Honma K, Mitsuiki N, Ohara O, et al. Common variable immunodeficiency classification by quantifying T-cell receptor and immunoglobulin kappa-deleting recombination excision circles. . J Clin Immunol. 2013;131(5):1437-40 e5.
24. Guazzi V, Aiuti F, Mezzaroma I, Mazzetta F, Andolfi G, Mortellaro A, et al. Assessment of thymic output in common variable immunodeficiency patients by evaluation of T cell receptor excision circles. Clin Exp Immunol. 2002;129(2):346-53.
25. Chinen J, Notarangelo LD, Shearer WT. Advances in basic and clinical immunology in 2013. J Clin Immunol. 2014;133(4):967-76.
26. Borte S, Fasth A, von Dobeln U, Winiarski J, Hammarstrom L. Newborn screening for severe T and B cell lymphopenia identifies a fraction of patients with Wiskott-Aldrich syndrome. Clin Immunol. 2014;155(1):74-8.
27. Li W, Sun X, Wang J, Zhao Q, Dai R, Wang Y, et al. Defective thymic output in WAS patients is associated with abnormal actin organization. Sci Rep. 2017;7(1):11978.
28. Wada T, Schurman SH, Garabedian EK, Yachie A, Candotti F. Analysis of T-cell repertoire diversity in Wiskott-Aldrich syndrome. Blood. 2005;106(12):3895-7.
29. Cotta-de-Almeida V, Dupre L, Guipouy D, Vasconcelos Z. Signal Integration during T Lymphocyte Activation and Function: Lessons from the Wiskott-Aldrich Syndrome. Front Immunol. 2015;6(4):47-9.
30. Patel JP, Puck JM, Srinivasan R, Brown C, Sunderam U, Kundu K, et al. Nijmegen breakage syndrome detected by newborn screening for T cell receptor excision circles (TRECs). J Clin Immunol. 2015;35(2):227-33.
31. Vacchio MS, Olaru A, Livak F, Hodes RJ. ATM deficiency impairs thymocyte maturation because of defective resolution of T cell receptor alpha locus coding end breaks. Proc Natl Acad Sci U S A. 2007;104(15):6323-8.
32. Barbaro M, Ohlsson A, Borte S, Jonsson S, Zetterstrom RH, King J, et al. Newborn Screening for Severe Primary Immunodeficiency Diseases in Sweden-a 2-Year Pilot TREC and KREC Screening Study. J Clin Immunol. 2017;37(1):51-60.
33. Kraus M, Lev A, Simon AJ, Levran I, Nissenkorn A, Levi YB, et al. Disturbed B and T cell homeostasis and neogenesis in patients with ataxia telangiectasia. J Clin Immunol. 2014;34(5):561-72.
34. Dobbs K, Dominguez Conde C, Zhang SY, Parolini S, Audry M, Chou J, et al. Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections. N Engl J Med. 2015;372(25):2409-22.
35. Somech R, Lev A, Simon AJ, Hanna S, Etzioni A. T- and B-cell defects in a novel purine nucleoside phosphorylase mutation. The Journal of allergy and clinical immunology. 2012;130(2):539-42.
36. Korsunskiy I, Blyuss O, Gordukova M, Davydova N, Zaikin A, Zinovieva N, et al. Expanding TREC and KREC Utility in Primary Immunodeficiency Diseases Diagnosis. Front Immunol. 2020;11(320):8-15.
| Files | ||
| Issue | Vol 20 No 4 (2021) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v20i4.6950 | |
| Keywords | ||
| Neonatal screening Primary immunodeficiency disorders Real-time polymerase chain reaction | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Shakerian L, Nourizadeh M, Badalzadeh M, Fazlollahi MR, Shokouhi Shoormasti R, Saghafi S, Esmaeili B, Alizadeh Z, Borte S, Houshmand M, Hammarström L, Pourpak Z. Investigating the Variation of TREC/KREC in Combined Immunodeficiencies. Iran J Allergy Asthma Immunol. 2021;20(4):402-412.
