THE ROLE OF TREC AND KREC IN ASSESSING THE IMMUNE STATUS OF NEWBORNS

Main Article Content

Authors

N. Sikhayeva

 National center for biotechnology, 010000, Kazakhstan, Astana, Korgalzhyn highway 13/5
National holding «QazBioPharm», 010000, Kazakhstan, Astana, Korgalzhyn highway 13/5

S. Volodchenko

University Medical Center, 010000, Kazakhstan, Astana, Turan avenue 32

E. Kovzel

University Medical Center, 010000, Kazakhstan, Astana, Turan avenue 32

M. Kissykova

National holding «QazBioPharm», 010000, Kazakhstan, Astana, Korgalzhyn highway 13/5

M. Morenko

Medical University Astana, 010000, Kazakhstan, Astana, Beibitshilik street 49a

K. Shnaider

Medical University Astana, 010000, Kazakhstan, Astana, Beibitshilik street 49a

G. Tortayeva

University Medical Center, 010000, Kazakhstan, Astana, Turan avenue 32

Ye. Sagandykova

University Medical Center, 010000, Kazakhstan, Astana, Turan avenue 32

Abstract

Newborn screening, based on the quantitative assessment of T-cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC) in dried blood spots, allows for the early diagnosis of various types of primary immunodeficiencies. TREC and KREC are circular DNA, markers of new lymphocyte production, formed during the maturation of T- and B-cells. These DNAs do not possess replication capability and are diluted as a result of cell division, making them useful markers for evaluating the appearance of new lymphocytes. PCR analysis of TREC and KREC enables the precise quantitative measurement of their levels, which is crucial for the diagnosis and treatment of immune diseases related to T- and B-cells. The implementation of TREC and KREC assays into neonatal screening programs facilitates the early detection of immunodeficiencies and the identification of novel genetic defects, thereby expanding early diagnostic capabilities.

This review provides a detailed examination of the role of TREC and KREC markers in the diagnosis of immunodeficiencies in newborns. Additionally, it analyzes the global experience of implementing TREC and KREC into national newborn screening programs.

Keywords

TREC, KREC, primary immunodeficiencies, severe combined immunodeficiency, screening

Article Details

References

Mishukova O.V., Zimin S. B., Zinov'eva, N. V. i dr. Razrabotka naborov reagentov dlja kolichestvennogo opredelenija molekul DNK TREC i KREC v cel'noj krovi i pjatnah vysushennoj krovi metodom mul'tipleksnoj PCR v real'nom vremeni // Medicinskaja immunologija. – 2015. – T.17(5). – S. 467-478. doi: 10.15789/1563-0625-2015-5-467-478.

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 // Journal of Translational Medicine. – 2013. – Vol. 11:119. doi: 10.1186/1479-5876-11-119.

Doneckova A.D., Jarilin A. A. T-receptornye jekscizionnye kol'ca i znachimost' ih opredelenija v klinike // Immunologija. – 2013. – №4. – S. 220-226.

Chan K. et al. Development of population-based newborn screening for severe combined immunodeficiency // J. Allergy Clin. Immunol. – 2005. – Vol. 115(2). – P. 391-398. doi: 10.1016/j.jaci.2004.10.012.

Nakagawa N. et al. Quantification of κ-deleting recombination excision circles in Guthrie cards for the identification of early B-cell maturation defects // J. Allergy Clin. Immunol. – 2011. – Vol. 128(1). – P. 223-225.e2. doi: 10.1016/j.jaci.2011.01.052.

Wilson J.M.G, Jungner G. Principles and practice of screening for disease. Geneva: World Health Organization // Public health papers. – 1968. – № 34. – URL: URL.

Khalturina E.O., Degtyareva N.D., Bairashevskaia A.V., Mulenkova A.V., Degtyareva A.V. Modern diagnostic capabilities of neonatal screening for primary immunodeficiencies in newborns // Clin Exp Pediatr Clin Exp Pediatr. – 2021. – Vol. 64(10). – P. 504-510. doi: 10.3345/cep.2020.01270.

Tangye S.G., Al-Herz W., Bousfiha A. et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee // J Clin Immunol. – 2022. – Vol. 42(7). – P. 1473-1507. doi: 10.1007/s10875-022-01289-3.

Pai S.Y., Logan B.R., Griffith L.M. et al. Transplantation outcomes for severe combined immunodeficiency, 2000-2009 // N Engl J Med. – 2014. – Vol. 371(5). – P. 434-446. doi: 10.1056/NEJMoa1401177.

Brown L., Xu-Bayford J., Allwood Z., Slatter M., Cant A., Davies E.G., Veys P., Gennery A.R., Gaspar H.B. Neonatal diagnosis of severe combined immunodeficiency leads to significantly improved survival outcome: the case for newborn screening // Blood. – 2011. – Vol. 117(5). – P. 3243-3246. doi: 10.1182/blood-2010-08-300384.

Puck J.M. SCID Newborn Screening Working Group. Population-based newborn screening for severe combined immunodeficiency: steps toward implementation // J Allergy Clin Immunol. – 2007. – 120(4). – P. 760-768. doi: 10.1016/j.jaci.2007.08.043.

Chan K, Davis J, Pai S.Y, Bonilla F.A., Puck J.M., Apkon M. A Markov model to analyze cost-effectiveness of screening for severe combined immunodeficiency (SCID) // Mol Genet Metab. – 2011. – Vol. 104(3). – P. 383-389. doi: 10.1016/j.ymgme.2011.07.007.

McGhee S.A., Stiehm E.R., McCabe E.R. Potential costs and benefits of newborn screening for severe combined immunodeficiency // J Pediatr. – 2005. – 147(5). – P. 603-608. doi: 10.1016/j.jpeds.2005.06.001.

Gaspar H.B., Hammarström L., Mahlaoui N., Borte M., Borte S. The case for mandatory newborn screening for severe combined immunodeficiency (SCID) // J Clin Immunol. – 2014. – Vol. 34(4). – P. 393-397. doi: 10.1007/s10875-014-0029-0.

Chen C., Zhang C., Wu D.W. et al. Comprehensive newborn screening for severe combined immunodeficiency, X-linked agammaglobulinemia, and spinal muscular atrophy: the Chinese experience // World J Pediatr. – 2024. – Vol. 20(12). – P. 1270-1282. doi: 10.1007/s12519-024-00846-7.

Douek D., McFarland R., Keiser P. et al. Changes in thymic function with age and during the treatment of HIV infection. Nature. – 1998. – Vol. 396. – P. 690-695. doi: 10.1038/25374.

King J.R., Hammarström L. Newborn screening for primary immunodeficiency diseases: history, current and future practice // J. Clin. Immunol. – 2018. – Vol. 38(1). – P. 56-66. doi: 10.1007/s10875-017-0455-x.

Routes J.M., Grossman W.J., Verbsky J., Laessig R.H., Hoffman G.L., Brokopp C.D. et al. Statewide newborn screening for severe T-cell lymphopenia // JAMA. – 2009. – Vol. 302. – P. 2465-2470. doi: 10.1001/jama.2009.1806.

Baker M.W., Laessig R.H., Katcher M.L., Routes J.M., Grossman W.J., Verbsky J. et al. Implementing routine testing for severe combined immunodeficiency within Wisconsin's newborn screening program // Public Health Rep. – 2010. – Vol. 125 (2 Suppl). – P. 88-95. doi: 10.1177/00333549101250S211.

Jyonouchi S., Jongco A.M., Puck J., Sullivan K.E. Immunodeficiencies associated with abnormal newborn screening for T cell and B cell lymphopenia // J Clin Immunol. – 2017. – Vol. 37(4). – P. 363-374. doi: 10.1007/s10875-017-0388-4.

van Zelm M.C., Szczepanski T., van der Burg M., van Dongen J.J. Replication history of b lymphocytes reveals homeostatic proliferation and extensive antigen-induced b cell expansion // J Exp Med. – 2007. – Vol. 204(3). – P. 645-655. doi: 10.1084/jem.20060964.

Kong F.K., Chen C.L., Six A., Hockett R.D., Cooper M.D. T cell receptor gene deletion circles identify recent thymic emigrants in the peripheral T cell pool // Proc. Natl. Acad. Sci. USA. – 1999. – Vol. 96(4). – P. 1536-1540. doi: 10.1073/pnas.96.4.1536.

Livak F., Schatz D.G. T-cell receptor alpha locus V(D)J recombination by-products are abundant in thymocytes and mature T cells // Mol. Cell. Biol. – 1996. – Vol. 16(2). – P. 609-618. doi: 10.1128/mcb.16.2.609.

Borte S., von Döbeln 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. – Vol. 119(11). – P. 2552–2555. doi: 10.1182/blood-2011-08-371021.

Jung D., Alt F.W. Unraveling V(D)J recombination; insights into gene regulation // Cell. – 2004. – Vol. 116(2). – P. 299-311. doi: 10.1016/s0092-8674(04)00039-x.

Ye P., Kirschner D.E. Measuring emigration of human thymocytes by T-cell receptor excision circles // Crit. Rev. Immunol. – 2002. – Vol. 22(5-6). – P. 483-497.

Nourizadeh M., Borte S., Fazlollahi M.R., Hammarstrom L., Pourpak Z. A New IL-2RG Gene Mutation in an X-linked SCID Identified through TREC/KREC Screening: a Case Report // Iran J. Allergy Asthma Immunol. – 2015. – Vol. 14(4). – P. 457-461.

Ye P., Kirschner D.E. Reevaluation of T cell receptor excision circles as a measure of human recent thymic emigrants // J. Immunol. – 2002. – Vol. 168(10). – P. 4968-4979. doi: 10.4049/jimmunol.168.10.4968.

Hazenberg M.D., Verschuren M.C., Hamann D., Miedema F., van Dongen J.J. T cell receptor excision circles as markers for recent thymic emigrants: basic aspects, technical approach, and guidelines for interpretation // J. Mol. Med. – 2001. – Vol. 79(11). – P. 631-640. doi: 10.1007/s001090100271.

Barbaro M., Ohlsson A., Borte S., Jonsson S., Zetterstrom R.H., King J., Winiarski J., von Döbeln U., Hammarström L. Newborn Screening for Severe Primary Immunodeficiency Diseases in Sweden-a 2-Year Pilot TREC and KREC Screening Study // J. Clin. Immunol. – 2017. – Vol. 37(1). – P. 51-60. doi: 10.1007/s10875-016-0347-5.

Siminovitch K.A., Bakhshi A., Goldman P., Korsmeyer S.J. A uniform deleting element mediates the loss of kappa genes in human B cells // Nature. – 1985. – Vol. 316(6025). – P. 260–262. doi: 10.1038/316260a0.

van Zelm M.C., van der Burg M., Langerak A.W., van Dongen J.J. PID comes full circle: applications of V(D)J recombination excision circles in research, diagnostics and newborn screening of primary immunodeficiency disorders // Front. Immunol. – 2011. – Vol. 2:12. doi: 10.3389/fimmu.2011.00012.

Obrazcov I.V., Gordukova M.A., Severina N.A., i dr. Jekscizionnye kol'ca V(D) J-rekombinacii B- i T-kletok kak prognosticheskij marker pri V-kletochnom hronicheskom limfolejkoze // Klinicheskaja onkogematologija. – 2017. – T. 10(2). – C. 131-140. doi: 10.21320/2500-2139-2017-10-2-131-140.

Marinova M., Georgyeva A., Yordanova V., Ivanov N., Atanasova V., Naumova E., Kandilarova S.M. Implementation of TREC/KREC detection protocol for newborn SCID screening in Bulgaria: a pilot study // Cent Eur J Immunol. – 2022. – Vol. 47(4). – P. 339-349. doi: 10.5114/ceji.2022.124396.

Chong-Neto H.J. et al. Newborn screening for inborn errors of immunity: The status worldwide // World Allergy Organization Journal. – 2024. – Vol. 17(6). doi: org/10.1016/j.waojou.2024.100920.

van der Burg M., Mahlaoui N., Gaspar H.B., Pai S.Y. Universal newborn screening for severe combined immunodeficiency (SCID) // Front Pediatr. – 2019. – Vol. 7:373. doi: 10.3389/fped.2019.00373.

Hale J.E., Bonilla F.A., Pai S.Y., Gerstel-Thompson J.L., Notarangelo L.D., Eaton R.B. et al. Identification of an infant with severe combined immunodeficiency by newborn screening // J Allergy Clin Immunol. – 2010. – Vol. 126. – P. 1073-1074. doi: 10.1016/j.jaci.2010.08.043.

Kwan A., Abraham R.S., Currier R., Brower A., Andruszewski K., Abbott J.K. et al. Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States // JAMA. – 2014. – Vol. 312(7). – P. 729-738. doi: 10.1001/jama.2014.9132.

Rechav E., Lev A., Saraf L.T., Etzioni A., Almashanu S., Somech R. Newborn screening for severe combined immunodeficiency in Israel // Int. J. Neonatal Screen. – 2017. – Vol. 3(2):13. doi: 10.3390/ijns3020013.

Chien Y.H., Yu H.H., Lee N.C., Ho H.C., Kao S.M., LU M.Y., Tang-H.J., Wen I.L., Kuei W.C., Chi C.S., Jiann S.C, Shu C.C., Chen C.L., Wuh L.H. Newborn screening for severe combined immunodeficiency in Taiwan // Int. J. Neonatal Screen. – 2017. – Vol. 3(3):16. doi: 10.3390/ijns3030016

Derjabina S.S., Tuzankina I.A., Vlasova E.V., Lavrina S.G., Shershnev V.N. Retrospektivnaja diagnostika pervichnyh immunodeficitnyh sostojanij u detej v Sverdlovskoj oblasti // Medicinskaja immunologija. – 2016. – T. 18(6). – C. 583-588. doi: 10.15789/1563-0625-2016-6-583-588.

Speckman, C., Nennstiel U., Hönig M. et al. Prospective Newborn Screening for SCID in Germany: A First Analysis by the Pediatric Immunology Working Group (API) // J Clin Immunol. – 2023. – Vol. 43. – P. 965-978. doi: 10.1007/s10875-023-01450-6.

Jeffrey Model Foundation [Электронный ресурс]. — URL: URL (дата обращения: 02.12.2024).

King J., Ludvigsson J.F., Hammarström L. Newborn Screening for Primary Immunodeficiency Diseases: The Past, the Present and the Future // International Journal of Neonatal Screening. – 2017. – Vol. 3(3):19. doi: 10.3390/ijns3030019.

Blom M., Soomann M., Soler-Palacín P., Šedivá A., Stray-Pedersen A., Zetterström R., Speckmann C., Gennery A.R., van der Burg M. Newborn screening for SCID and severe T lymphocytopenia in Europe // J Allergy Clin Immunol. – 2024. doi: 10.1016/j.jaci.2024.10.018.