ВРОЖДЕННЫЕ ДЕФЕКТЫ ИММУННОЙ СИСТЕМЫ КАК ПРОЯВЛЕНИЕ ВОСПАЛИТЕЛЬНОГО ЗАБОЛЕВАНИЯ КИШЕЧНИКА - МОНОГЕННОГО ЗАБОЛЕВАНИЯ У ДЕТЕЙ

L. I.  Kastsiukevich; O. N.  Romanova; A. P. Mikhalenko; N. D. Kolomiets; K. Y. Marakhovsky; А. A.  Gusina; O. N. Nazarenko; R. N. Mankevich; Ye. M. Marochkina; Т. A.  Spiridovich; V. I. Babraunichy; T. I. Valoshka; A. V. Kilchevsky

doi:10.25298/2616-5546-2024-8-2-96-104

L. I. Kastsiukevich Belarusian State Medical University, Minsk, Belarus
O. N. Romanova Belarusian State Medical University, Minsk, Belarus https://orcid.org/0000-0001-7383-1727
A. P. Mikhalenko The Institute of Genetics and Cytology of the National Academy of Sciences of Belarus, Minsk, Bealrus https://orcid.org/0000-0003-4543-2862
N. D. Kolomiets Belarusian State Medical University, Minsk, Belarus https://orcid.org/0000-0002-4837-5181
K. Y. Marakhovsky The Children’s Surgery National Applied Research Hospital, Minsk, Bealrus https://orcid.org/0000-0002-4191-6053
А. A. Gusina Republican Scientific and Practical Center "Mother and child", Minsk, Bealrus https://orcid.org/0000-0003-2670-5634
O. N. Nazarenko Belarusian State Medical University, Minsk, Belarus
R. N. Mankevich Belarusian State Medical University, Minsk, Belarus
Ye. M. Marochkina City clinical maternity hospital № 2, Minsk, Bealrus
Т. A. Spiridovich City clinical maternity hospital № 2, Minsk, Bealrus https://orcid.org/0009-0001-9818-915X
V. I. Babraunichy Belarusian State Medical University, Minsk, Belarus
T. I. Valoshka City Children's Infectious Diseases Clinical Hospital, Minsk, Bealrus
A. V. Kilchevsky The Institute of Genetics and Cytology of the National Academy of Sciences of Belarus, Minsk, Bealrus

DOI: https://doi.org/10.25298/2616-5546-2024-8-2-96-104

Keywords: monogenic inflammatory bowel disease-like pathology, congenital defects of the immune system, children

Abstract

Background. Currently, monogenic inflammatory bowel disease-like (IBD) pathologies such as congenital immunity defects, genetic epithelial barrier defects and others are becoming increasingly relevant. Objective. To analyze genetic defects associated with IBD-like immunopathology. Material and methods. The study included 46 patients with IBD manifestations aged 18 years or younger, who underwent whole-exome sequencing using the NGS method. All calculations were performed using the R statistical package, version 4.1. Results. There were identified 11 (23,9%) patients with gene mutations indicating congenital defects of the immune system (CDIS). Of these, 3 (27,3%) children were found to have abnormalities in the genes of immune dysregulation - CTLA-4 (c.151C>T (p.Arg 51*)), (FOXP3 (c.851C>T (p.Ala284Val)) and FOXP3 (c.748_750del (p.Lys250del)); 3 (27.3%) patients had abnormalities in the SLC5A1 gene (c.1666-2delA), SLC5A1 gene (c.1666-2delA and c.1680T>G(p.(Cys560Trp)) responsible for the disruption of the barrier function of the epithelium; 2 (18.2%) patients had abnormalities in the PIK3CD gene (c.3061G>A (p.Glu1021Lys)), manifested as CDIS with a predominant deficiency of antibodies; in 2 (18.2%) patients abnormalities in genes affecting cellular and humoral immunity were detected: JAK3 (c.2518C>T(p.Arg840Cys)), CD40LG (c.430G>A (p.Gly144Arg)); and in one case (9,1%) a congenital defect in the number or function of phagocytes – in CFTR gene (c.43delC (p.Leu15fs) and c.1210-11T>G) was established. According to clinical signs, patients with CDIS had only some differences from IBD patients. Conclusion. It is advisable to conduct molecular genetic analysis of target genes in IBD patients with very early onset of gastrointestinal lesions, which allows timely diagnosis of congenital defects of the immune system for subsequent prescription of adequate therapy.

References

Moran CJ, Klein C, Muise AM, Snapper SB. Very Early-onset Inflammatory Bowel Disease: Gaining Insight Through Focused Discovery. Inflamm Bowel Dis. 2015;21(5):1166-1175. https://doi.org/10.1097/MIB.0000000000000329.

Uhlig HH, Schwerd T, Koletzko S, Shah N, Kammermeier J, Elkadri A, Ouahed J, Wilson DC, Travis SP, Turner D, Klein C, Snapper SB, Muise AM; COLORS in IBD Study Group and NEOPICS. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology. 2014;147(5):990-1007.e3. https://doi.org/10.1053/j.gastro.2014.07.023.

Kastsiukevich LI, Romanova ON, Kolomiets ND, Marakhovsky KY, Krasko OV, Nazarenko ON, Savich OL. Sravnitelnaja harakteristika raznyh tipov vospalitelnyh zabolevanij kishechnika u detej [Comparative characteristics of different types of inflammatory bowel disease in children]. Gepatologija i gastrojenterologija [Hepatology and Gastroenterology]. 2023;7(2):127-134 https://doi.org/10.25298/2616-5546-2023-7-2-127-134. https://elibrary.ru/qoirva. (Russian).

Kastsiukevich LI, Romanova ON, Kolomiets ND, Mankevich RN, Nazarenko ON, Mikhalenko AP, Mazur OCh, Kilchevsky AV. Geneticheskie narushenija u pacientov s porazheniem kishechnika na fone pervichnogo immunodeficita [Genetic disturbances in patients with intestinal lesion in the background of primary immunodeficiency]. Klinicheskaja patofiziologija [Clinical pathophysiology]. 2021;27(1):49-58. edn: EUPIJK. (Russian).

Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, Klein C, Morio T, Oksenhendler E, Picard C, Puel A, Puck J, Seppänen MRJ, Somech R, Su HC, Sullivan KE, Torgerson TR, Meyts I. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022;42(7):1473-1507. https://doi.org/10.1007/s10875-022-01289-3.

Ouahed J, Spencer E, Kotlarz D, Shouval DS, Kowalik M, Peng K, Field M, Grushkin-Lerner L, Pai SY, Bousvaros A, Cho J, Argmann C, Schadt E, Mcgovern DPB, Mokry M, Nieuwenhuis E, Clevers H, Powrie F, Uhlig H, Klein C, Muise A, Dubinsky M, Snapper SB. Very Early Onset Inflammatory Bowel Disease: A Clinical Approach With a Focus on the Role of Genetics and Underlying Immune Deficiencies. Inflamm Bowel Dis. 202012;26(6):820-842. https://doi.org/10.1093/ibd/izz259.

Kuenzig ME, Fung SG, Marderfeld L, Mak JWY, Kaplan GG, Ng SC, Wilson DC, Cameron F, Henderson P, Kotze PG, Bhatti J, Fang V, Gerber S, Guay E, Kotteduwa Jayawarden S, Kadota L, Maldonado D F, Osei JA, Sandarage R, Stanton A, Wan M; InsightScope Pediatric IBD Epidemiology Group; Benchimol EI. Twenty-first Century Trends in the Global Epidemiology of Pediatric-Onset Inflammatory Bowel Disease: Systematic Review. Gastroenterology. 2022;162(4):1147-1159.e4. https://doi.org/10.1053/j.gastro.2021.12.282.

Moran CJ. Very early onset inflammatory bowel disease. Semin Pediatr Surg. 2017;26(6):356-359. https://doi.org/10.1053/j.sempedsurg.2017.10.004.

Yska HAF, Elsink K, Kuijpers TW, Frederix GWJ, van Gijn ME, van Montfrans JM. Diagnostic Yield of Next Generation Sequencing in Genetically Undiagnosed Patients with Primary Immunodeficiencies: a Systematic Review. J Clin Immunol. 2019;39(6):577-591. https://doi.org/10.1007/s10875-019-00656-x.

Barzaghi F, Passerini L, Gambineri E, Ciullini Mannurita S, Cornu T, Kang ES, Choe YH, Cancrini C, Corrente S, Ciccocioppo R, Cecconi M, Zuin G, Discepolo V, Sartirana C, Schmidtko J, Ikinciogullari A, Ambrosi A, Roncarolo MG, Olek S, Bacchetta R. Demethylation analysis of the FOXP3 locus shows quantitative defects of regulatory T cells in IPEX-like syndrome. J Autoimmun. 2012;38(1):49-58. https://doi.org/10.1016/j.jaut.2011.12.009.

Kim SC. Monozygotic Twin Cases of XIAP Deficiency Syndrome. J Pediatr Gastroenterol Nutr. 2018;67(5):e101. https://doi.org/10.1097/MPG.0000000000001536.

Tam RY, Van Dorst JM, McKay I, Coffey M, Ooi CY. Intestinal Inflammation and Alterations in the Gut Microbiota in Cystic Fibrosis: A Review of the Current Evidence, Pathophysiology and Future Directions. JCM. 2022;11(3):649. https://doi.org/10.3390/jcm11030649.

Adeyemo-Salami O. Cystic Fibrosis in the Intestine and the Influence on Digestion. J Immunol Sci. 2020;4(3):22-32. https://doi.org/10.29245/2578-3009/2020/3.1187.

Chidrawar V, Alsuwayt B. Defining the role of CFTR channel blocker and ClC-2 activator in DNBS induced gastrointestinal inflammation. Saudi Pharm J. 2021;29(4):291-304. https://doi.org/10.1016/j.jsps.2021.02.005.

Trigo Salado C, Leo Carnerero E, De La Cruz Ramírez MD. Crohn’s disease and cystic fibrosis: there is still a lot to learn. Rev Esp Enferm Dig. 2018;110(12):835-836. https://doi.org/10.17235/reed.2018.5725/2018.

Villeda-Ramírez MA, Meza-Guillen D, Barreto-Zúñiga R, Yamamoto-Furusho JK. ABCC7/CFTR Expression Is Associated with the Clinical Course of Ulcerative Colitis Patients. Gastroenterol Res Pract. 2021;2021:5536563. https://doi.org/10.1155/2021/5536563.

Crites KS, Morin G, Orlando V, Patey N, Cantin C, Martel J, Brochiero E, Mailhot G. CFTR Knockdown induces proinflammatory changes in intestinal epithelial cells. J Inflamm (Lond). 2015;12:62. https://doi.org/10.1186/s12950-015-0107-y.

CONGENITAL DEFECTS OF THE IMMUNE SYSTEM AS A MANIFESTATION OF MONOGENIC INFLAMMATORY BOWEL DISEASE IN CHILDREN

Abstract

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