Пищевая аллергия и особенности нутритивного статуса как проявление дисфункции эпителиального барьера у детей с врожденным ихтиозом

Врожденный ихтиоз – группа редких генетических заболеваний, характеризующихся нарушением кератинизации и дисфункцией кожного барьера. Общим патогенетическим звеном для различных форм ихтиоза является структурное повреждение эпидермиса, приводящее к повышенной трансэпидермальной потере воды и снижению его защитной функции, что создает условия для транскутанной сенсибилизации пищевыми аллергенами. Особенно хорошо описан данный механизм при синдроме Нетертона, связанном с мутацией гена SPINK5, и вульгарном ихтиозе, ассоциированном с мутациями гена филаггрина. Проникновение пищевых аллергенов через нарушенный кожный барьер запускает каскад иммунных реакций, способствующих активации Th2-иммунного ответа и выработке специфического IgE, с высокой частотой, приводя к пищевой сенсибилизации и пищевой аллергии. Развитие пищевой аллергии на фоне врожденного ихтиоза усугубляет течение основного заболевания и способствует формированию нарушения нутритивного статуса и задержки роста вследствие как ограничительных диет без адекватного диетологического сопровождения, так и дефицита нутриентов и микроэлементов. Настоящий обзор фокусируется на роли дисфункции эпидермального барьера как ключевого связующего звена в развитии коморбидной пищевой аллергии у пациентов с врожденным ихтиозом и подчеркивает необходимость междисциплинарного подхода для данной категории пациентов.

1. Murashkin N. N., Avetisyan K. O., Ivanov R. A., Makarova S. G. Congenital Ichthyosis: Clinical and Genetic Characteristics of the Disease. Current Pediatrics. 2022; 21 (5): 362–377. (In Russ.). https://doi.org/10.15690/vsp.v21i5.2459

2. Vahlquist A, Törmä H. Ichthyosis: A Road Model for Skin Research. Acta Derm Venereol. 2020; 100 (7): adv00097. https://doi.org/10.2340/00015555-34333

3. Mazereeuw-Hautier J, Vahlquist A, Traupe H. et al. Management of congenital ichthyoses: European guidelines of care, part one. Br.J. Dermatol. 2019; 180 (2): 272–281. https://doi.org/10.1111/ bjd.17203

4. Oji V, Tadini G, Akiyama M. et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J. Am. Acad Dermatol. 2010; 63 (4): 607–641. https://doi.org/10.1016/j.jaad.2009.11.020

5. Dabas G, Mahajan R, De D. et al. Managing syndromic congenital ichthyosis at a tertiary care institute-Genotype-pheno type correlations, and novel treatments. Dermatol Ther. 2020; 33 (6): e13816. https://doi.org/10.1111/dth.13816

6. Sun Q, Burgren N.M, Cheraghlou S, Paller A.S, Larralde M, Bercovitch L, Levinsohn J. et al. The Genomic and Phenotypic Landscape of Ichthyosis: An Analysis of 1000 Kindreds. JAMA Dermatol. 2022 Jan 1; 158 (1): 16–25. DOI: 10.1001/jamadermatol.2021.4242

7. Richard G. Autosomal Recessive Congenital Ichthyosis. In: GeneReviews [Internet]. Adam MP, Mirzaa GM, Pagon RA. et al, eds. Seattle (WA): University of Washington, Seattle. 1993–2022. Available online: https://www.ncbi.nlm.nih.gov/books/NBK1420. Accessed on October 27, 2022.

8. Mohamad J, Samuelov L, Malchin N. et al. Molecular epidemiology of non-syndromic autosomal recessive congenital ichthyosis in a Middle-Eastern population. Exp Dermatol. 2021; 30 (9): 1290–1297. https://doi.org/10.1111/exd.14345

9. Fischer J, Bourrat E. Genetics of Inherited Ichthyoses and Related Diseases. Acta Derm Venereol. 2020; 100 (7): adv00096. https://doi.org/10.2340/00015555-3432

10. Takeichi T, Akiyama M. Inherited ichthyosis: Non-syndromic forms. J. Dermatol. 2016; 43 (3): 242–251. https://doi.org/10.1111/1346-8138.13243

11. Gutiérrez-Cerrajero C, González-Sarmiento R, Hernández-Martín Á. [Translated article] ICHTHYOSIS: Clinical and Molecular Update. Part 2: Syndromic Ichthyosis. Diagnostic and Therapeutic Approach of Ichthyosis. Actas Dermosifiliogr. 2025 May; 116 (5): T497–T510. English, Spanish. DOI: 10.1016/j.ad.2025.03.013. Epub 2025 Mar 11.

12. Yoneda K. Inherited ichthyosis: Syndromic forms. J. Dermatol. 2016 Mar; 43 (3): 252–63. DOI: 10.1111/1346-8138.13284. PMID: 26945533.

13. Gutiérrez-Cerrajero, C., Sprecher, E., Paller, A.S. et al. Ichthyosis. Nat Rev Dis Primers. 2023; 9 (2). https://doi.org/10.1038/s41572-022-00412-3

14. Ishitsuka Y, Roop DR. The Epidermis: Redox Governor of Health and Diseases. Antioxidants (Basel). 2021 Dec 26; 11 (1): 47. DOI: 10.3390/antiox11010047

15. Lima Cunha D, Oram A, Gruber R, Plank R, Lingenhel A, Gupta MK. et al. hiPSC-Derived Epidermal Keratinocytes from Ichthyosis Patients Show Altered Expression of Cornification Markers. Int J. Mol Sci. 2021 Feb 11; 22 (4): 1785. DOI: 10.3390/ijms22041785

16. Paller AS, Renert Yuval Y, Suprun M, Esaki H, Oliva M, Huynh TN. et al. An IL-17 dominant immune profile is shared across the major orphan forms of ichthyosis. J. Allergy Clin Immunol. 2017; 139 (1): 152–65. DOI: 10.1016/j.jaci.2016.07.019

17. Hassani B, Isaian A, Shariat M, Mollanoori H, Sotoudeh S, Babaei V, Ziaali A, Teimourian S. Filaggrin gene polymorphisms in Iranian ichthyosis vulgaris and atopic dermatitis patients. Int J. Dermatol. 2018 Dec; 57 (12): 1485–1491. DOI: 10.1111/ijd.14213. Epub 2018 Sep 23. PMID: 30246302.

18. Stuvel K, Heeringa J.J, Dalm VASH. et al. Comel-Netherton syndrome: A local skin barrier defect in the absence of an underlying systemic immunodeficiency. Allergy. 2020 Jul; 75 (7): 1710–1720. DOI: 10.1111/all.14197

19. Scala E, Condorelli A.G, Scala A, Caprini E, Didona B, Paganelli R. et al. IgE Sensitization Profile in Patients with Netherton Syndrome. Int Arch Allergy Immunol. 2022; 183 (12): 1291–1296. DOI: 10.1159/000526409

20. Barbati F, Giovannini M, Oranges T. et al. Netherton Syndrome in Children: Management and Future Perspective. Front Pediatr. 2021; 9: 645259. https://doi.org/10.3389/fped.2021.645259

21. Mocarska M, Muciek A, Dolinkiewicz J, Maryńczak A.M, Nitschke N, Strakowska K. et al. Netherton Syndrome: A Comprehensive Literature Review of Pathogenesis, Clinical Manifestations, and Therapeutic Strategies. J. Mother Child. 2025 Sep 2; 29 (1): 106–113. DOI: 10.34763/jmotherandchild.20252901.d-25-00014

22. Wei-Li Di, John Harper. Netherton Syndrome. Harper’s Textbook of Pediatric Dermatology, Fourth Edition. 2019. https://doi.org/10.1002/9781119142812.ch132

23. Brough HA, Nadeau KC, Sindher SB, Alkotob SS, Chan S, Bahnson HT, Leung DYM, Lack G. Epicutaneous sensitization in the development of food allergy: What is the evidence and how can this be prevented? Allergy. 2020 Sep; 75 (9): 2185–2205. DOI: 10.1111/all.14304. Epub 2020 May 18. PMID: 32249942; PMCID: PMC7494573.

24. Sampson H.A., O’Mahony L., Burks A.W., Plaut M., Lack G., Akdis C.A. Mechanisms of food allergy. J. Allergy Clin. Immunol. 2018; 141: 11–19.

25. Kawasaki A, Ito N, Murai H, Yasutomi M, Naiki H, Ohshima Y. Skin inflammation exacerbates food allergy symptoms in epicutaneously sensitized mice. Allergy. 2018; 73: 1313–1321.

26. Barni S, Liccioli G, Sarti L, Giovannini M, Novembre E, Mori F. Immunoglobulin E (IgE)-Mediated Food Allergy in Children: Epidemiology, Pathogenesis, Diagnosis, Prevention, and Management. Medicina (Kaunas). 2020 Mar 4; 56 (3): 111. DOI: 10.3390/medicina56030111. PMID: 32143431; PMCID: PMC7142605.

27. Muraro A, Werfel T, Hoffmann-Sommergruber K. et al. EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy. Allergy. 2014; 69 (8): 1008–1025. DOI: 10.1111/all.12429

28. Food Allergies in Children and Adolescents: [Monograph] / S.G. Makarova, I.I. Balabolkin, A.P. Fisenko. Moscow: FSAI «National Medical Research Center of Children’s Health» of the Ministry of Health of Russia, 2021. 288 p. (Informational Materials).

29. Jutel M, Agache I, Zemelka-Wiacek M. et al. Nomenclature of allergic diseases and hypersensitivity reactions: Adapted to modern needs: An EAACI position paper. Allergy. 2023; 78: 2851–2874. DOI: 10.1111/all.15889

30. Balan S, Saxena M, Bhardwaj N. Dendritic cell subsets and locations. Int Rev Cell Mol Biol. 2019; 348: 1–68. DOI: 10.1016/bs.ircmb.2019.07.004

31. Gauvreau GM, Bergeron C, Boulet LP. et al. Sounding the alarmins-the role of alarmin cytokines in asthma. Allergy. 2023; 78 (2): 402–417 DOI: 10.1111/all.15609

32. Varricchi G, Bencivenga L, Poto R, Pecoraro A, Shamji MH, Rengo G. The emerging role of T follicular helper (TFH) cells in aging: influence on the immune frailty. Ageing Res Rev. 2020; 61: 101071. DOI: 10.1016/j.arr.2020.101071

33. Morita H, Kubo T, Rückert B. et al. Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid. J. Allergy Clin Immunol. 2019; 143 (6): 2190–2201.e9. DOI: 10.1016/j.jaci.2018.12.1018

34. Stone KD, Prussin C, Metcalfe DD. IgE, mast cells, basophils, and eosinophils. J. Allergy Clin Immunol. 2010; 125(2 Suppl 2): S73–S80. DOI: 10.1016/j.jaci.2009.11.017

35. Valente M, Dölen Y, van Dinther E. et al. Cross-talk between iNKT cells and CD8 T cells in the spleen requires the IL-4/CCL17 axis for the generation of short-lived effector cells. Proc Natl Acad Sci USA. 2019; 116 (51): 25816–25827. DOI: 10.1073/pnas.1913491116

36. Eguiluz-Gracia I, Layhadi JA, Rondon C, Shamji MH. Mucosal IgE immune responses in respiratory diseases. A-Curr Opin Pharmacol. 2019; 46: 100–107. DOI: 10.1016/j.coph.2019.05.009

37. Gigon L, Fettrelet T, Yousefi S, Simon D, Simon HU. Eosinophils from a to Z. Allergy. 2023; 78 (7): 1810–1846. DOI: 10.1111/all.15751

38. Sugita K, Steer CA, Martinez-Gonzalez I. et al. Type 2 innate lymphoid cells disrupt bronchial epithelial barrier integrity by targeting tight junctions through IL-13 in asthmatic patients. J. Allergy Clin Immunol. 2018; 141 (1): 300–310.e11. DOI: 10.1016/j.jaci.2017.02.038

39. Akdis CA. Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions? Nat Rev Immunol. 2021 Nov; 21 (11): 739–751. DOI: 10.1038/s41577-021-00538-7

40. Nakamura M, Kamiya K, Furuhata A, Ikeda K, Niyonsaba F. S100A7 Co-localization and up-regulation of Filaggrin in human Sinonasal epithelial cells. Curr Med Sci. 2021; 41 (5): 863–868. DOI: 10.1007/s11596-021-2431-1

41. Saito K, Orimo K, Kubo T. et al. Laundry detergents and surfactants induced eosinophilic airway inflammation by increasing IL-33 expression and activating ILC2s. Allergy. 2023; 78: 1878–1892.DOI: 10.1111/all.15762

42. Levy M, Kolodziejczyk AA, Thaiss CA, Elinav E. Dysbiosis and the immune system. Nat Rev Immunol. 2017; 17 (4): 219–232. DOI: 10.1038/nri.2017.7

43. Fölster-Holst R, Naß C, Dähnhardt-Pfeiffer S, Freitag-Wolf S. Analysis of the structure and function of the epidermal barrier in patients with ichthyoses-clinical and electron microscopical investigations. J. Eur. Acad Dermatol Venereol. 2022 May; 36 (5): 726–738. DOI: 10.1111/jdv.17914

44. Mazereeuw-Hautier J., Dreyfus I., Barbarot S. et al. Ichthyosis and allergic sensitization. The British Journal of Dermatology, 2017.

45. Kim Y, Lim K.M. Skin barrier dysfunction and filaggrin. Arch Pharm Res. 2021 Jan; 44 (1): 36–48. DOI: 10.1007/s12272-021-01305-x

46. Brown SJ, Asai Y, Cordell HJ. et al. Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy. J. Allergy Clin Immunol. 2011; 127 (3): 661–667. DOI: 10.1016/j.jaci.2011.01.03

47. Gutiérrez-Cerrajero, C., Sprecher, E., Paller, A.S. et al. Ichthyosis. Nat Rev Dis Primers 9, 2 (2023). https://doi.org/10.1038/s41572-022-00412-3

48. Lefevre-Utile A, Braun C, Haftek M, Aubin F. Five functional aspects of the epidermal barrier. Int J. Mol Sci. 2021; 22: 11676.

49. Fluhr JW, Moore DJ, Lane ME, Lachmann N, Rawlings AV. Epidermal barrier function in dry, flaky and sensitive skin: A narrative review. J. Eur. Acad Dermatol Venereol. 2024; 38: 812–820. https://doi.org/10.1111/jdv.19745

50. Suzuki M, Ohno Y, Kihara A. Whole picture of human stratum corneum ceramides, including the chainlength diversity of long-chain bases. J. Lipid Res. 2022; 63: 100235.

51. Ohnemus U, Kohrmeyer K, Houdek P. et al. Regulation of epidermal tight junctions (TJ) during infection with exfoliative toxin-negative Staphylococcus strains. J Invest Dermatol 2007: in press.

52. Egawa G, Kabashima K. Barrier dysfunction in the skin allergy. Allergol Int. 2018; 67 (1): 3–11. DOI: 10.1016/j.alit.2017.10.002

53. Baroni A, Buommino E, De Gregorio V, Ruocco E, Ruocco V, Wolf R. Structure and function of the epidermis related to barrier properties. Clin Dermatol. 2012 May-Jun; 30 (3): 257–62. DOI: 10.1016/j.clindermatol.2011.08.007. PMID: 22507037.

54. Egawa G. Pathomechanism of ‘skin-originated’ allergic diseases. Immunological Medicine. 2018; 41 (4): 170–176. https://doi.org/10.1080/25785826.2018.1540257

55. Tham KC, Lefferdink R, Duan K, Lim SS, Wong XFCC, Ibler E, Wu B, Abu-Zayed H, Rangel SM, Del Duca E, Chowdhury M, Chima M, Kim HJ, Lee B, Guttman-Yassky E, Paller AS, Common JEA. Distinct skin microbiome community structures in congenital ichthyosis. Br.J. Dermatol. 2022 Oct; 187 (4): 557–570. DOI: 10.1111/bjd.21687. Epub 2022 Jul 4. PMID: 35633118; PMCID: PMC10234690.

56. Brough H.A., Lanser B. J., Sindher S. B., Teng J.M.C., Leung D. Y.M., Venter C., Chan S. M., Santos A. F., Bahnson H.T., Guttman-Yassky E. et al. Early intervention and prevention of allergic diseases. Allergy. 2022; 77: 416–441.

57. Dębińska A, Sozańska B. Epicutaneous Sensitization and Food Allergy: Preventive Strategies Targeting Skin Barrier Repair-Facts and Challenges. Nutrients. 2023 Feb 21; 15 (5): 1070. DOI: 10.3390/nu15051070. PMID: 36904070; PMCID: PMC10005101.

58. Leung D.Y.M., Berdyshev E., Goleva E. Cutaneous barrier dysfunction in allergic diseases. J. Allergy Clin. Immunol. 2020; 145: 1485–1497.

59. Zhu TH, Zhu TR, Tran KA, Sivamani RK, Shi VY. Epithelial barrier dysfunctions in atopic dermatitis: a skin-gutlung model linking microbiome alteration and immune dysregulation. Br.J. Dermatol. 2018; 179: 570–581.

60. van Splunter M, Liu L, van Neerven RJJ, Wichers HJ, Hettinga KA, de Jong NW. Mechanisms Underlying the Skin-Gut Cross Talk in the Development of IgE-Mediated Food Allergy. Nutrients. 2020 Dec 15; 12 (12): 3830. DOI: 10.3390/nu12123830

61. Sampson H.A, O’Mahony L, Burks A.W, Plaut M, Lack G, Akdis C.A. Mechanisms of food allergy. J. Allergy Clin Immunol. 2018 Jan; 141 (1): 11–19. DOI: 10.1016/j.jaci.2017.11.005.

62. Strid J, Hourihane J, Kimber I, Callard R, Strobel S. Disruption of the stratum corneum allows potent epicutaneous immunization with protein antigens resulting in a dominant systemic Th2 response. Eur. J. Immunol 2004; 34: 2100–2109.

63. Novik G.A., Zhdanova M.V., Demidova A.S. Epicutaneous sensitization. what do we know? Bulletin of Siberian Medicine. 2021; 20 (4): 180–192. https://doi.org/10.20538/1682-0363-2021-4-180-192

64. Leyva-Castillo J.M., McGurk A., Geha M.D.R. Allergic skin inflammation and S. aureus skin colonization are mutually re inforcing. Clin. Immunol. 2020; 218: 108511. DOI: 10.1016/j.clim.2020.108511

65. Diaz LZ, Browning JC, Smidt AC, Rizzo WB, Levy ML. Complications of ichthyosis beyond the skin. Dermatol Ther. 2013 Jan-Feb; 26 (1): 39–45. DOI: 10.1111/j.1529-8019.2012.01517.x. PMID: 23384019.

66. Yang L, Xia JN. Beyond the Skin: Exploring the Gut-Skin Axis and Metabolic Pathways in Atopic Dermatitis Pathogenesis. Int J. Gen Med. 2025 Oct 8; 18: 6123–6136. DOI: 10.2147/IJGM.S550152. PMID: 41084738; PMCID: PMC12515402.

67. Tetarbe S, Jain S, Shah I. Hereditary Ichthyosis With Gastrointestinal Manifestations: A Case Report. JPGN Rep. 2023 Oct 9; 4 (4): e370. DOI: 10.1097/PG9.0000000000000370. PMID: 38034450; PMCID: PMC10684232.

68. Paluel-Marmont C, Bellon N, Barbet P. et al. Eosinophilic esophagitis and colonic mucosal eosinophilia in Netherton syndrome. J. Allergy Clin Immunol. 2017; 139 (6): 2003–2005.e1.

69. Fry L, McMinn RMH, Shuster S. The small intestine in skin diseases. Archives of Dermatology. 1966; 93: 647–653.

70. Ali IA, Foolad N, Sivamani RK. Considering the gut-skin axis for dermatological diseases. Austin J. Dermatolog. 2014;1:1024.

71. Fowler AJ, Moskowitz DG, Wong A, Cohen SP, Williams ML, Heyman MB. Nutritional status and gastrointestinal structure and function in children with ichthyosis and growth failure. J Pediatr Gastroenterol Nutr. 2004; 38: 164–169.

72. Moskowitz DG, Fowler AJ, Heyman MB, Cohen SP, Crumrine D, Elias PM, Williams ML. Pathophysiologic basis for growth failure in children with ichthyosis: an evaluation of cutaneous ultrastructure, epidermal permeability barrier function, and energy expenditure. J. Pediatr. 2004 Jul;145(1):82–92. DOI: 10.1016/j.jpeds.2004.03.052. PMID: 15238912.

73. Rodríguez-Manchón S, Pedrón-Giner C, Cañedo-Villarroya E, Muñoz-Codoceo RA, Hernández-Martín Á. Malnutrition in children with ichthyosis: Recommendations for monitoring from a multidisciplinary clinic experience. J Am Acad Dermatol. 2021 Jul; 85 (1): 144–151. DOI: 10.1016/j.jaad.2020.06.064. Epub 2020 Jun 22. PMID: 32585277.

74. Prodinger C, Yerlett N, MacDonald C, Chottianchaiwat S, Goh L, Du Toit G, Mellerio JE, Petrof G, Martinez AE. Prevalence of and risk factors for nutritional deficiency and food allergy in a cohort of 21 patients with Netherton syndrome. Pediatr Allergy Immunol. 2023 Jan; 34 (1): e13914. DOI: 10.1111/pai.13914. PMID: 36705039.

75. Kaushik H, Mahajan R, Dabas G, Shrivastava N, Ashraf R, De D, Pal A, Kumar R, Handa S. A cross-sectional study to find association of VDR gene polymorphism with non-syndromic congenital ichthyosis and with vitamin D deficiency. Arch Dermatol Res. 2023 Apr; 315 (3): 551–557. DOI: 10.1007/s00403-022-02399-z. Epub 2022 Oct 3. PMID: 36192561.