AD endotypes evaluation with molecular-genetic analysis of local immune response



Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

The basis for the development of atopic dermatitis (AD) is genetic predisposition, hypersensitivity to allergens, Th1/Th2 disbalance, increased degranulation of mast cells and antigen-presenting activity of Langerhans cells, as well as epidermal barrier dysfunction. Recently, genotypes, phenotypes and endotypes of AD, and biomarkers, which can be used to assess the effectiveness of therapy and to develop personalized approaches to the diagnosis, treatment and prognosis of the disease, have been actively studied. The aim of this study was to determine the endotypes of atopic dermatitis on the basis of molecular genetic study of cytokine gene expression in the skin of AD patients. Materials and methods. The study was performed as a «case-control», 90 AD patients and 30 healthy individuals without signs of atopy were included. The material for evaluation of cytokine gene expression was skin biopsy samples taken by punch biopsy. The level of gene expression was determined by real-time PCR with preliminary reverse transcription of mRNA of the corresponding genes («DNA-Technology», Moscow). The transcript levels of ILB, IL2, IL2r, IL4, IL5, IL6, IL7, IL8, IL10, IL12A, IL12B, IL15, IL17A, IL18, IL23, IL28, IL29, IFNy, TNF, TGFß, FOXP3 genes were studied. Results. Based on the molecular genetic study of the local immune response the following endotypes of AD were determined: endotype with predominance of Th1-type immune response (3% of patients); endotype with predominance of Th2-type immune response (3% of patients); mixed endotype with increased expression of IL2 (20% of patients); mixed endotype with reduced expression of IL10 (64% of patients); mixed endotype with increased expression of TGFß (9% of patients). Clinically significant biomarkers of inflammation in atopic dermatitis - decreased mRNA level of IL1ß gene expression and increased mRNA level of IL2R, IL4, IL5, IL6, IL8, IL10, IL12ß, IL23, IL29, IFNy and TGFß genes expression were determined in the skin of AD patients compared to healthy individuals. Conclusion. The use of molecular genetic method for evaluation of local immune response on the basis of cytokines gene expression measurement in the skin allows to identify the most significant biomarkers characterizing different endotypes of AD, and to determine the type of immune response in the individual patient.

Full Text

Restricted Access

About the authors

O G Elisyutina

NRC Institute of Immunology FMBA of Russia

M N Boldyreva

NRC Institute of Immunology FMBA of Russia

O Yu Rebrova

Pirogov Russian National Research Medical University; National Research University Higher School of Economics

E S Fedenko

NRC Institute of Immunology FMBA of Russia

References

  1. Asher MI, Montefort S., Bjorksten B., Lai CK, Stragan DP, Weiland SK et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 2006;368:733-743.
  2. Намазова-Баранова ЛС, Баранов АА, Кубанова АА, Ильина НИ, Курбачёва ОМ, Вишнёва ЕА и соавт. Атопический дерматит у детей: современные клинические рекомендации по диагностике и терапии. Вопросы современной педиатрии. 20l6;(3):279-294
  3. Mortz CG, Andersen KE, Dellgren C., Barington T., Bindslev-Jensen C. Atopic dermatitis from adolescence to adulthood in the TOACS cohort: prevalence, persistence and comorbidities. Allergy. 20l5;70:836-845. DOI: l0.llll/ all.l26l9.
  4. Arkwright PD, Motala C., Subramanian H., Spergel J., Schneider LC, Wollenberg A. et al. Management of difficult-to treat atopic dermatitis. J. Allergy Clin Immunol in practice. 20l3;l:l42-l5l. DOI: l0.l0l6/j.jaip.20l2.09.002. Epub 20l2 Dec l4.
  5. Schneider L., Hanifin J., Boguniewicz M. et al. Study of the Atopic March: Development of Atopic Comorbidities. Pediatr Dermatol. 20l6;33:388-398. DOI: l0.llll/pde.l2867. Epub 20l6 Jun 7.
  6. Spergel JM. From atopic dermatitis to asthma: the atopic march. Ann Allergy Asthma Immunol. 20l0;l05:99-l06.
  7. Eller E., Kjaer HF, Hest A., Andersen KE, Bindslev-Jensen C. Food allergy and food sensbiitization in early childhood: results from the DARC cohort. Allergy. 2009;64:l023-l027.
  8. Pónyai G., Hidvégi B., Németh I., Sas A., Temesvari E., Karpati S. Contact and aeroallergens in adulthood atopic dermatitis. J. Eur Acad Dermatol Venereol. 2008;22:l346-l355. DOI: l0.llll/j.l468-3083.2008.02886.x. Epub 2008 Aug l.
  9. Grice EA, Segre JA. The skin microbiome. Nat Rev Microbiol. 20ll;9:244-253. DOI: l0.l038/nrmicro2537.
  10. Kobayashi T., Glatz M., Horiuchi K., Kawasaki H., Akiyama H., Kaplan DH et al. Dysbiosis and Staphylococcus aureus colonization drives inflammation in atopic dermatitis. Immunity. 20l5;42:756-766. DOI: l0.l0l6/j.immuni.20l5.03.0l4.
  11. Kabashima K. New concept of the pathogenesis of atopic dermatitis: Interplay among the barrier, allergy, and pruritus as a trinity. J. Dermatol Sci. 20l3;70(l):3-ll. DOI: l0.l0l6/j. jdermsci.20l3.02.00l. Epub 20l3 Feb l5.
  12. Bieber Th. Atopic dermatitis 2.0: from the clinical phenotype to the molecular taxonomy and stratified medicine. Allergy. 20l2;67:l475-l482. DOI: l0.llll/all.l2049. Epub 20l2 Oct 29.
  13. Cabanillas B., Brehler AC, Novak N. Atopic dermatitis phenotypes and the need for personalized medicine. Curr Opin Allergy Clin Immunol. 20l7;l7(4):309-3l5. DOI: l0.l097/ ACI.0000000000000376.
  14. Suarez-Farinas M., Dhingra N., Gittler J., Shemer A., Cardinale I., de Guzman Strong C. et al. Intrinsic atopic dermatitis shows similar TH2 and higher THl7 immune activation compared with extrinsic atopic dermatitis. J. Allergy Clin Immunol. 20l3;l32:36l-370. DOI: l0.l0l6/j.jaci.20l3.04.046. Epub 20l3 Jun l5.
  15. Thijs JL, de Bruin-Weller MS, Hijnen D. Current and Future Biomarkers in Atopic Dermatitis. Immunol Allergy Clin North Am. 20l7;37(l):5l-6l. DOI: l0.l0l6/j.iac.20l6.08.008. Epub 20l6 Oct 28.
  16. Svenningsen S., Nair P. Asthma Endotypes and an Overview of Targeted Therapy for Asthma Front Med (Lausanne). 20l7;26(4):l58. DOI: l0.3389/fmed.20l7.00l58. eCollection 20l7.
  17. Tomassen P., Vandeplas G., Van Zele T., Cardell LO, Arebro J., Olze H. et al. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J. Allergy Clin Immunol. 20l6;l37(5):l449-l456.e4. DOI: l0.l0l6/j. jaci.20l5.l2.l324. Epub 20l6 Mar 4.
  18. Eichenfield LF, Tom WL, Chamlin SL, Feldman SR, Hanifin JM, Simpson EL et al. Guidelines of care for the management of atopic dermatitis: section l. Diagnosis and assessment of atopic dermatitis. J. Am Acad Dermatol. 20l4;70(2):338-35l. DOI: l0.l0l6/j.jaad.20l3.l0.0l0.
  19. Бурменская О.В. Молекулярно-генетические маркеры иммунного ответа при воспалительных заболеваниях органов женской репродуктивной системы. Автореф. дис. д-ра биол. наук: 03.03.03. М., 20l4:48
  20. Филимонова ТВ, Елисютина ОГ, Феденко ЕС, Ниязов ДД, Болдырева МН, Бурменская ОВ, Реброва О.Ю. Локальный и системный иммунный ответ у больных тяжелым атопическим дерматитом. Российский Аллергологический Журнал. 20ll;(5):l0-l5
  21. Nakagawa S., Aiba S., Tagami H. Decreased frequency of interferon-producing CD4+-cells in the peripheral blood of patients with atopic dermatitis. Exp Dermatol. l998;7:ll2-ll8.
  22. Herberth G., Heinrich J., Röder S., Figl A., Weiss M., Diez U. et al. Reduced IFN-gamma and enhanced IL-4-producing CD4+ cord blood T-cells are associated with a higher risk for atopic dermatitis during the first 2 yr of life. Pediatr Allergy Immunol. 20l0;2l:5-l3. DOI: l0.llll/j.l399-3038.2009.00890.x. Epub 2009 Jun 23.
  23. Li AG, Wang D., Feng XH, Wang XJ. Latent TGFbetal overexpression in keratinocytes results in a severe psoriasis-like skin disorder. EMBO J. 2004;23(8):l770-l78l. DOI: l0.l038/ sj.emboj.7600l83.
  24. Chatila TA. Interleukin-4 receptor signaling pathways in asthma pathogenesis. Trends Mol Med. 2004;l0:493-499. DOI: l0.l0l6/j.molmed.2004.08.004.
  25. Howell MD, Kim BE, Gao P., Grant AV, Boguniewicz M., DeBenedetto A. et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J. Allergy Clin Immunol. 2009;l24(3):7-l2. DOI: l0.l0l6/j.jaci.2009.07.0l2.
  26. Beck LA, Thaçi D., Hamilton JD, Graham NM, Bieber T., Rocklin R. et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N. Engl J. Med. 20l4;37l(2):l30-l39. DOI: l0.l056/NEJMoal3l4768.
  27. Thaçi D, Simpson EL, Beck LA, Bieber T, Blauvelt A, Papp K et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet. 2016;387(10013):40-52. DOI: 10.1016/ S0140-6736(15)00388-8.
  28. Lee J, Noh G, Lee S, Youn Y, Rhim J. Atopic dermatitis and cytokines: recent patents in immunoregulatory and therapeutic implications of cytokines in atopic dermatitis - part I: cytokines in atopic dermatitis. Recent Pat Inflamm Allergy Drug Discov. 2012;6(3):222-247.
  29. Antùnez C, Torres MJ, Mayorga C, Corzo JL, Jurado A, Santamaria-Babi LF et al. Cytokine production, activation marker, and skin homing receptor in children with atopic dermatitis and bronchial asthma Pediatr Allergy Immunol. 2006;17(3):166-74. DOI: 0.1111/j.1399-3038.2006.00390.x.
  30. Sohn MH, Song JS, Kim KW, Kim ES, Kim KE, Lee JM. Association of interleukin-10 gene promoter polymorphism in children with atopic dermatitis. J Pediatr. 2007;150(1):106-108. doi: 10.1016/j.jpeds.2006.08.065.
  31. Miyagaki T, Sugaya M, Fujita H, Ohmatsu H, Kakinuma T, Kadono T et al. Eotaxins and CCR3 interaction regulates the Th2 environment of cutaneous T-cell lymphoma. J Invest Dermatol. 2010;130 (9):2304-2311. DOI: 10.1038/ jid.2010.128.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright © Pharmarus Print Media, 2018



This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies