ACTIVITY OF THE NUCLEAR TRANSCRIPTION FACTOR NF-ΚB IN LYMPHOCYTE POPULATIONS IN CHILDREN WITH GAUCHER DISEASE



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Abstract

Abstract

The study is devoted to the role of the transcription factor NF-κB in the pathogenesis of chronic inflammation in Gaucher disease in children. Gaucher disease is an orphan autosomal recessive lysosomal disorder characterized by mutations in the β-glucocerebrosidase gene, leading to a decrease in the activity of this enzyme and, as a consequence, to the accumulation of the substrate - glucoceramide. Macrophages transformed into Gaucher cells, due to the accumulation of glucoceramide, secrete proinflammatory cytokines (IL-1β, IL-6, TNF-α), triggering chronic inflammation in internal organs through the activation of the nuclear transcription factor NF-κB along the canonical pathway.

The aim of the work was to assess the proportion of cells with the activity of the nuclear transcription factor NF-κB in lymphocyte populations in children with Gaucher disease.

The proportion of cells with NF-κB translocation in peripheral blood lymphocyte populations was assessed in 70 patients with Gaucher disease (58 type 1, 12 type 3) receiving enzyme replacement therapy and in 30 conditionally healthy children.

The results of the studies revealed a significant increase in the proportion of cells with NF-κB translocation in T-lymphocytes, T-helpers, cytotoxic T-cells, NK-cells, B-lymphocytes, as well as in T-helpers type 17, activated T-helpers and in regulatory T-cells in patients with Gaucher disease relative to the comparison group (p < 0.001). In children with GD, the highest number of cells with NF-κB translocation was found in B lymphocyte and NK cell populations. In the course of the study of patients with different types of GD, it was found that in children with type 1 GD, a reliable increase in the level of NF-κB translocation was observed in all studied lymphocyte populations; in patients with type 3 GD, a significant increase in NF-κB translocation in T-lymphocytes, T-helpers, cytotoxic T-lymphocytes, NK cells, Th17 cells, activated T-helpers and regulatory T-cells was also noted relative to the comparison group. However, in the populations of B-lymphocytes and double negative T-lymphocytes in patients with type 3 GD relative to the comparison group, statistically significant differences were not found.

The results of the study confirm the key role of NF-κB in maintaining chronic inflammation in Gaucher disease. Modern flow cytometry with visualization allows to determine NF-κB activity in different populations of peripheral blood lymphocytes, including Th17 and Treg, with high accuracy. It is advisable to conduct additional studies on the effect of enzyme replacement therapy initiation on NF-κB activity indices in lymphocyte populations in children with Gaucher disease.

About the authors

Matvey Valeryevich Konyashin

National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Moscow, Russia

Email: matele99@mail.ru
ORCID iD: 0009-0004-3206-8090
SPIN-code: 8749-2973

Doctor of clinical and laboratory diagnostics

Russian Federation, 2/1 Lomonosovsky Ave, Moscow, 119991

Olga V. Kurbatova

National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Moscow, Russia

Email: putintseva@mail.ru
ORCID iD: 0000-0002-9213-5281

Ph.D. (Medicine) Senior Researcher, Laboratory of Experimental Immunology and Virology

Russian Federation, 2/1 Lomonosovsky Ave, Moscow, 119991

Svetlana V. Petrichuk

National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Moscow, Russia

Email: cito@list.ru
ORCID iD: 0000-0003-0896-6996

PhD, MD (Biology), Professor,  Chief Scientist,  Laboratory of  Experimental Immunology and Virology

Russian Federation, 2/1, Lomonosovskiy Pr-t, Moscow, 119991

G. B. Movsisyan

National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Moscow, Russia

Email: movsisyan@nczd.ru
ORCID iD: 0000-0003-2881-4703

PhD (Medicine), Senior Research Associate, Laboratory of Rare Hereditary Diseases, Gastroenterologist of the Gastroenterology Department with the Hepatological Group, National Medical Research Center for Children’s Health

Russian Federation, Moscow

Ekaterina V. Freidlyn

National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Moscow, Russia

Email: frdl-cito@mail.ru
ORCID iD: 0000-0002-5645-5181

Research Laboratory Assistant, Laboratory of Experimental Immunology and Virology

Russian Federation, 2/1, Lomonosovsky prospect., Moscow, 119296

D. G. Kuptsova

National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Moscow, Russia

Email: dg.kuptsova@gmail.com
ORCID iD: 0000-0001-7771-3314

Junior Research Associate, Clinical Laboratory Doctor, Laboratory of Experimental Immunology and Virology, National Medical Research Center for Children’s Health

Russian Federation, Moscow

T. V. Radygina

National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Moscow, Russia

Email: tvradigina@mail.ru
ORCID iD: 0000-0003-4704-6885

PhD (Medicine), Senior Research Associate, Laboratory of Experimental Immunology and Virology, National Medical Research Center for Children’s Health

Russian Federation, Moscow

Elena L. Semikina

National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Moscow, Russia;
Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg, Russia

Email: semikinaelena@yandex.ru
ORCID iD: 0000-0001-8923-4652

PhD, MD (Medicine), Professor, Chief Research Associate, Laboratory of Research in Pediatric Gastroenterology and Hepatology, Head of Gastroenterology Department with Hepatology Group, Professor, Department of Pediatrics and Pediatric Rheumatology

Russian Federation, 2/1 Lomonosovsky Ave, Moscow, 119991; 8/2, st. Trubetskaya, Moscow, 119991

Alexander S. Potapov

National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Moscow, Russia;
Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg, Russia

Email: potapov@nczd.ru
ORCID iD: 0000-0003-4905-2373

PhD, MD (Medicine), Professor, Chief Research Associate, Laboratory of Scientific Foundations of Pediatric Gastroenterology and Hepatology, Head of the Center for Inflammatory Bowel Diseases in Children, Head of Gastroenterology Department with Hepatology Group, National Medical Research Center for Children’s Health, Professor, Department of Pediatrics and Pediatric Rheumatology

Russian Federation, 1/2, Lomonosovskiy Pr-t, Moscow, 119991; 8/2, st. Trubetskaya, Moscow, 119991

A. P. Fisenko

National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Moscow, Russia

Author for correspondence.
Email: fisenko@nczd.ru
ORCID iD: 0000-0001-8586-7946

PhD, MD (Medicine), Professor, Head, National Medical Research Center for Children’s Health

Russian Federation, Moscow

References

  1. Курбатова О.В., Мовсесян Г.Б., Коняшин М.В., Петричук С.В., Купцова Д.Г., Радыгина Т.В., Семикина Е.Л., Потапов А.С., Фисенко А.П. Возрастная динамика показателей клеточного иммунитета, активность внутриклеточных дегидрогеназ лимфоцитов и функциональная активность нейтрофилов у детей с болезнью Гоше. Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2024;23(1):128-138. https://doi.org/10.24287/1726-1708-2024-23-1-128-138. EDN: NFSNIM
  2. Kurbatova O.V., Movsisyan G.B., Konyashin M.V., Petrichuk S.V., Kuptsova D.G., Radygina T.V., Semikina E.L., Potapov A.S., Fisenko A.P. Age-related changes in the parameters of cellular immunity, the activity of intracellular lymphocyte dehydrogenases and functional activity of neutrophils in children with Gaucher disease. Pediatric Hematology/Oncology and Immunopathology. 2024;23(1):128-138. (In Russ.) https://doi.org/10.24287/1726-1708-2024-23-1-128-138. EDN: NFSNIM
  3. https://doi.org/10.24287/1726-1708-2024-23-1-128-138.
  4. Курбатова О.В., Петричук С.В., Купцова Д.Г., Мовсисян Г.Б., Радыгина Т.В., Комарова А.Д., Анушенко А.О., Фрейдлин Е.В., Семикина Е.Л., Потапов А.С., Фисенко А.П. Активность ядерного фактора транскрипции kB (NF-kB) в популяциях лимфоцитов у детей с болезнью Вильсона-Коновалова. Медицинская иммунология. 2023;25(5):1205-1212. https://doi.org/10.15789/1563-0625-NTF-2799
  5. Kurbatova O.V., Petrichuk S.V., Kuptsova D.G., Movsisyan G.B., Radygina T.V., Komarova A.D., Anushenko A.O., Freidlin E.V., Semikina E.L., Potapov A.S., Fisenko A.P. Nuclear transcription factor kB (NF-kB) activity in lymphocyte populations in children with Wilson-Konovalov disease. Medical Immunology (Russia). 2023;25(5):1205-1212. https://doi.org/10.15789/1563-0625-NTF-2799
  6. https://www.mimmun.ru/mimmun/article/view/2799
  7. Петричук С.В., Радыгина Т.В., Купцова Д.Г., Курбатова О.В., Семикина Е.Л., Мурашкин Н.Н., Потапов А.С., Фисенко А.П. Оценка эффективности анти-tnf терапии у детей с иммунозависимыми заболеваниями по активности NF-κB в популяциях лимфоцитов // Российский иммунологический журнал. - 2022. - Т. 25. - №4. - C. 491-498. doi: 10.46235/1028-7221-1191-EOA
  8. Petrichuk S.V., Radygina T.V., Kuptsova D.G., Kurbatova O.V., Semikina E.L., Murashkin N.N., Potapov A.S., Fisenko A.P. Evaluation of anti-TNF treatment efficiency in children with immune-dependent diseases by means of testing the NF-κB activity in lymphocyte populations // Russian Journal of Immunology. - 2022. - Vol. 25. - N. 4. - P. 491-498. doi: 10.46235/1028-7221-1191-EOA
  9. doi: 10.46235/1028-7221-1191-EOA
  10. Aflaki E, Moaven N, Borger DK, Lopez G, Westbroek W, Chae JJ, Marugan J, Patnaik S, Maniwang E, Gonzalez AN, Sidransky E. Lysosomal storage and impaired autophagy lead to inflammasome activation in Gaucher macrophages. Aging Cell. 2016;15(1):77-88. doi: 10.1111/acel.12409.
  11. doi: 10.1111/acel.12409.
  12. Cox TM, Drelichman G, Cravo R, Balwani M, Burrow TA, Martins AM, Lukina E, Rosenbloom B, Ross L, Angell J, Puga AC. Eliglustat compared with imiglucerase in patients with Gaucher's disease type 1 stabilised on enzyme replacement therapy: a phase 3, randomised, open-label, non-inferiority trial. Lancet. 2015;385(9985):2355-2362. doi: 10.1016/S0140-6736(14)61841-9.
  13. doi: 10.1016/S0140-6736(14)61841-9.
  14. Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher's disease. Lancet. 2008;372(9645):1263-1271. doi: 10.1016/S0140-6736(08)61522-6.
  15. doi: 10.1016/S0140-6736(08)61522-6.
  16. Lawrence T. The nuclear factor NF-κB pathway in inflammation. Cold Spring Harb Perspect Biol. 2009;1(6):a001651. doi: 10.1101/cshperspect.a001651.
  17. doi: 10.1101/cshperspect.a001651.
  18. Liu T, T Liu, L Zhang, D Joo, SC Sun. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017;2:17023. doi: 10.1038/sigtrans.2017.23.
  19. doi: 10.1038/sigtrans.2017.23.
  20. Mignot C, Gelot A, Bessières B, Daffos F, Voyer M, Menez F, Fallet Bianco C, Odent S, Le Duff D, Loget P, Fargier P, Costil J, Josset P, Roume J, Vanier MT, Maire I, Billette de Villemeur T. Perinatal-lethal Gaucher disease. Am J Med Genet A. 2003;120A(3):338-344. doi: 10.1002/ajmg.a.20117.
  21. doi: 10.1002/ajmg.a.20117
  22. Pandey MK, Grabowski GA. Immunological cells and mediators in Gaucher disease. Blood Cells Mol Dis. 2018;68:200-205. doi: 10.1016/j.bcmd.2016.10.011.
  23. doi: 10.1016/j.bcmd.2016.10.011.
  24. Sen R, Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell. 1986;47(6):921-928. doi: 10.1016/0092-8674(86)90807-X.
  25. doi: 10.1016/0092-8674(86)90807-X.
  26. Sidransky E. Gaucher disease: insights from a rare Mendelian disorder. Discov Med. 2012;14(77):273-281. PMID: 23200059; PMCID: PMC3778625.
  27. https://pmc.ncbi.nlm.nih.gov/articles/PMC4141347/
  28. Şoroğlu CV, Berkay EG. Old disease-New reflections: Gaucher, immunity, and inflammation. Journal of Cellular and Molecular Medicine. 2024 Oct;28(20):e70087. doi: 10.1111/jcmm.70087. PMID: 39463025; PMCID: PMC11513444. https://pmc.ncbi.nlm.nih.gov/articles/PMC11513444/
  29. Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C, Levade T, Astudillo L, Serratrice J, Brassier A, Rose C, Billette de Villemeur T, Berger MG. A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. Int J Mol Sci. 2017;18(2):441. doi: 10.3390/ijms18020441.
  30. doi: 10.3390/ijms18020441.
  31. Zahran AM, Saad K, Elsayh KI, Abdou MAA, Abo-Elgheet AM, Eloseily EM, Khalaf SM, Sror S, Ahmad FA, Elhoufey A, Ghandour A, Osman NS. Upregulation of Cytotoxic T-cells in pediatric patients with Gaucher disease. Sci Rep. 2022;12(1):4977. doi: 10.1038/s41598-022-08843-4.
  32. doi: 10.1038/s41598-022-08843-4.

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Copyright (c) Konyashin M.V., Kurbatova O.V., Petrichuk S.V., Movsisyan G.B., Freidlyn E.V., Kuptsova D.G., Radygina T.V., Semikina E.L., Potapov A.S., Fisenko A.P.

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