Allergic diseases represent some of the most common immunological disorders with high clinical and economic impact. Despite intensive research, there are still few universally accepted and reliable biomarkers capable of predicting their development at an early age. There is therefore a pressing need for identification of potential predictive factors and validation of their prognostic value by correlating them with allergy development. Dysbalance of the branches of immune response, most often excessive Th2 polarization, is the principal cause of allergic diseases. Regulatory T cells (Treg) are a crucial population for the timely establishment of physiological immune polarization and induction and maintenance of tolerance against environmental antigens. This makes them a potentially promising candidate for an early marker predicting allergy development. In our study, we analysed samples of cord blood of children of allergic mothers and children of healthy mothers by flow cytometry and retrospectively correlated the data with clinical allergy status of the children at the age of 6 to 10 years. Studied parameters included cord blood Treg population proportions and functional properties - intracellular presence of IL-10 and TGF-b, MFI of FoxP3. We observed higher percentage of Tregs in cord blood of children who did not develop allergy compared with allergic children. Further, we found higher numbers of IL-10+ Tregs in cord blood of healthy children of healthy mothers than in cord blood of children of allergic mothers and decreased TGF-b+ cord blood Tregs in the group of allergic children of allergic mothers compared to all other groups.

Institute for the Care of Mother and Child Prague Czech Republic

Institute of Immunology and Microbiology 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Zobrazit více v PubMed

Sykes L, MacIntyre DA, Yap XJ, et al. (2012): The Th1:th2 dichotomy of pregnancy and preterm labour. Mediators Inflamm 2012: 967629. PubMed PMC

Mold JE, Michaëlsson J, Burt TD, et al. (2008): Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science 322: 1562-1565. PubMed PMC

Jutel M, Akdis CA (2011): T-cell subset regulation in atopy. Curr Allergy Asthma Rep 11: 139-145. PubMed PMC

Martin R, Nauta AJ, Ben Amor K, et al. (2010): Early life: gut microbiota and immune development in infancy. Benef Microbes 1: 367-382. PubMed

Strachan DP (1989): Hay fever, hygiene, and household size. BMJ 299: 1259-1260. PubMed PMC

Kitagawa Y, Ohkura N, Sakaguchi S (2015): Epigenetic control of thymic Treg-cell development. Eur J Immunol 45: 11-16. PubMed

Iizuka-Koga M, Nakatsukasa H, Ito M, et al. (2017): Induction and maintenance of regulatory T cells by transcription factors and epigenetic modifications. J Autoimmun 83: 113-121. PubMed

Bacchetta R, Passerini L, Gambineri E, et al. (2006): Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J Clin Invest 116: 1713-1722. PubMed PMC

Barzaghi F, Passerini L, Gambineri E, et al. (2012): Deme-thylation analysis of the FOXP3 locus shows quantitative defects of regulatory T cells in IPEX-like syndrome. J Auto-immun 38: 49-58. PubMed PMC

Palomares O, Martín-Fontecha M, Lauener R, et al. (2014): Regulatory T cells and immune regulation of allergic diseases: roles of IL-10 and TGF-b. Genes Immun 15: 511-520. PubMed

Akdis CA, Akdis M (2011): Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol 127: 18–27; quiz 28-29. PubMed

Shevach EM (2009): Mechanisms of Foxp3+ T regulatory cell-mediated suppression. Immunity 30: 636-645. PubMed

Akdis M, Burgler S, Crameri R, et al. (2011): Interleukins, from 1 to 37, and interferon-g: receptors, functions, and roles in diseases. J Allergy Clin Immunol 127: 701-721.e1-70. PubMed

Steinborn A, Engst M, Haensch GM, et al. (2010): Small for gestational age (SGA) neonates show reduced suppressive activity of their regulatory T cells. Clin Immunol 134: 188-197. PubMed

Hrdý J, Zanvit P, Novotná O, et al. (2010): Cytokine expression in cord blood cells of children of healthy and allergic mothers. Folia Microbiol (Praha) 55: 515-519. PubMed

Hrdý J, Vlasáková K, Černý V, et al. (2018): Decreased allergy incidence in children supplemented with E. coli O83: K24:H31 and its possible modes of action. Eur J Immunol 48: 2015-2030. PubMed

Hrdý J, Kocourková I, Prokešová L (2012): Impaired function of regulatory T cells in cord blood of children of allergic mothers. Clin Exp Immunol 170: 10-17. PubMed PMC

Peters JL, Cohen S, Staudenmayer J, et al. (2012): Prenatal negative life events increases cord blood IgE: interactions with dust mite allergen and maternal atopy. Allergy 67: 545-551. PubMed PMC

Belderbos ME, Knol EF, Houben ML, et al. (2012): Low neonatal Toll-like receptor 4-mediated interleukin-10 production is associated with subsequent atopic dermatitis. Clin Exp Allergy 42: 66-75. PubMed

Bullens DMA, Kasran A, Dilissen E, Ceuppens JL (2012): Neonatal IL-10 production and risk of allergy development. Clin Exp Allergy 42: 483-484. PubMed

Rindsjö E, Joerink M, Johansson C, et al. (2010): Maternal allergic disease does not affect the phenotype of T and B cells or the immune response to allergens in neonates: no effect of maternal allergy on neonatal lymphocytes. Allergy 65: 822-830. PubMed

Schaub B, Liu J, Höppler S, et al. (2009): Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. J Allergy Clin Immunol 123: 774-782.e5. PubMed

Prescott SL, King B, Strong TL, Holt PG (2003): The value of perinatal immune responses in predicting allergic disease at 6 years of age. Allergy 58: 1187-1194. PubMed

Meng SS, Gao R, Yan BD, et al. (2016): Maternal allergic disease history affects childhood allergy development through impairment of neonatal regulatory T-cells. Respir Res 17: 114. PubMed PMC

Strömbeck A, Rabe H, Lundell AC, et al. (2014): High proportions of FOXP3 + CD25 high T cells in neonates are positively associated with allergic sensitization later in childhood. Clin Exp Allergy 44: 940-952. PubMed PMC

Hinz D, Bauer M, Röder S, et al. (2012): Cord blood Tregs with stable FOXP3 expression are influenced by prenatal environment and associated with atopic dermatitis at the age of one year. Allergy 67: 380-389. PubMed

Bullens DMA, Seys S, Kasran A, et al. (2015): Low cord blood Foxp3/CD3g mRNA ratios: a marker of increased risk for allergy development. Clin Exp Allergy 45: 232-237. PubMed

Pedros C, Duguet F, Saoudi A, Chabod M (2016): Disrupted regulatory T cell homeostasis in inflammatory bowel diseases. World J Gastroenterol 22: 974-995. PubMed PMC

Jones CA, Holloway JA, Warner JO (2000): Does atopic disease start in foetal life? Allergy 55: 2-10. PubMed

Černý V, Hrdý J, Novotná O, et al. (2018): Distinct characteristics of Tregs of newborns of healthy and allergic mothers. PLoS One 13: e0207998. PubMed PMC

Fu Y, Lou H, Wang Ch, et al. (2013): T cell subsets in cord blood are influenced by maternal allergy and associated with atopic dermatitis. Pediatr Allergy Immunol 24: 178-186. PubMed

Law JP, Hirschkorn DF, Owen RE, et al. (2009): The importance of Foxp3 antibody and fixation/permeabilization buffer combinations in identifying CD4+CD25+Foxp3+ regulatory T cells. Cytometry A 75: 1040-1050. PubMed PMC

Smith M, Tourigny MR, Noakes P, et al. (2008): Children with egg allergy have evidence of reduced neonatal CD4(+)CD25(+)CD127(lo/-) regulatory T cell function. J Allergy Clin Immunol 121: 1460-1466, 1466.e1-7. PubMed

Kmieciak M, Gowda M, Graham L, et al. (2009): Human T cells express CD25 and Foxp3 upon activation and exhibit effector/memory phenotypes without any regulatory/suppressor function. J Transl Med 7: 89. PubMed PMC

Akdis CA, Akdis M (2015): Mechanisms of allergen-specific immunotherapy and immune tolerance to allergens. World Allergy Organ J 8: 17. PubMed PMC

Sakaguchi S, Sakaguchi N, Asano M, et al. (1995): Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155: 1151-1164. PubMed

Roncador G, Brown PJ, Maestre L, et al. (2005): Analysis of FOXP3 protein expression in human CD4+CD25+ regulatory T cells at the single-cell level. Eur J Immunol 35: 1681-1691. PubMed

Sakaguchi S, Vignali DAA, Rudensky AY, et al. (2013): The plasticity and stability of regulatory T cells. Nat Rev Immunol 13: 461-467. PubMed

Barnaba V, Schinzari V (2013): Induction, control, and plasticity of Treg cells: the immune regulatory network revised? Eur J Immunol 43: 318-322. PubMed

Akdis CA, Akdis M (2015): Mechanisms of allergen-specific immunotherapy and immune tolerance to allergens. World Allergy Organ J 8: 1-12. PubMed PMC

Edwards JP, Hand TW, da Fonseca DM, et al. (2016): The GARP/Latent TGF-b1 complex on Treg cells modulates the induction of peripherally derived Treg cells during oral tolerance. Eur J Immunol 46: 1480-1489. PubMed PMC

Josefowicz SZ, Niec RE, Kim HY, et al. (2012): Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482: 395-399. PubMed PMC

Konkel JE, Chen W (2011): Balancing acts: the role of TGF-b in the mucosal immune system. Trends Mol Med 17: 668-676. PubMed PMC

Konkel JE, Zhang D, Zanvit P, et al. (2017): Transforming growth factor-b signaling in regulatory T cells controls T helper-17 cells and tissue-specific immune responses. Immunity 46: 660-674. PubMed

Kumar S, Verma AK, Das M, Dwivedi PD (2013): A molecular insight of CTLA-4 in food allergy. Immunol Lett 149: 101-109. PubMed

Munthe-Kaas MC, Carlsen KH, et al. (2004): CTLA-4 polymorphisms in allergy and asthma and the TH1/ TH2 paradigm. J Allergy Clin Immunol 114: 280-287. PubMed

McAlees JW, Lajoie S, Dienger K, et al. (2015): Differential control of CD4 + T-cell subsets by the PD-1/PD-L1 axis in a mouse model of allergic asthma: cellular immune response. Eur J Immunol 45: 1019-1029. PubMed PMC

McGee HS, Yagita H, Shao Z, Agrawal DK (2010): Programmed death-1 antibody blocks therapeutic effects of T-regulatory cells in cockroach antigen-induced allergic asthma. Am J Respir Cell Mol Biol 43: 432-442. PubMed PMC