Interaction Between Helminths and Toll-Like Receptors: Possibilities and Potentials for Asthma Therapy

References

• Holgate ST. Innate and adaptive immune responses in asthma. Nature Med 2012;18(5):673–683.
   PubMed Web of Science ®Google Scholar
• Strachan DP. Family size, infection and atopy: the first decade of the’hygiene hypothesis’. Thorax 2000;55(Suppl 1):S2.
   Google Scholar
• Ring J, Krämer U, Schäfer T, Why are allergies increasing? Curr Opin Immunol 2001;13(6):701–708.
   PubMed Web of Science ®Google Scholar
• Riedler J, Braun-Fahrländer C, Eder W, Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. The Lancet 2001;358(9288):1129–1133.
   PubMed Web of Science ®Google Scholar
• Cardoso LS, Costa DM, Almeida MCF, Risk factors for asthma in a helminth endemic area in bahia, Brazil. J Parasit Res 2012;2:796820.
   Google Scholar
• Summers RW, Elliott DE, Urban JF, Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial. Gastroenterology 2005;128(4):825–832.
   Google Scholar
• Shor DB-A, Shoenfeld Y. Autoimmunity: Will worms cure rheumatoid arthritis? Nat Rev Rheum 2013;9(3):138–140.
   PubMed Web of Science ®Google Scholar
• Segura M, Su Z, Piccirillo C, Impairment of dendritic cell function by excretory‐secretory products: A potential mechanism for nematode‐induced immunosuppression. Eur J Immunol 2007;37(7):1887–1904.
   PubMed Web of Science ®Google Scholar
• Bahadori K, Doyle-Waters MM, Marra C, Economic burden of asthma: a systematic review. BMC Pulmonary Med 2009;9(1):24.
   PubMedGoogle Scholar
• Trevor J, Deshane J. Refractory asthma: mechanisms, targets, and therapy. Allergy 2014;69(7):817–827.
   PubMed Web of Science ®Google Scholar
• Pelaia G, Vatrella A, Maselli R. The potential of biologics for the treatment of asthma. Nat Rev Drug Disc 2012;11(12):958–972.
   PubMed Web of Science ®Google Scholar
• Lambrecht BN, Hamida H. The immunology of asthma. Nat Immunol 2015:16.1; 45–56
   PubMed Web of Science ®Google Scholar
• Kim HY, DeKruyff RH, Umetsu DT. The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat Immunol 2010; 11(7):577–584.
   PubMed Web of Science ®Google Scholar
• Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 2012;18(5):716–725.
   PubMed Web of Science ®Google Scholar
• Ober C, Yao TC. The genetics of asthma and allergic disease: a 21st century perspective. Immunol Rev 2011;242(1):10–30.
   PubMed Web of Science ®Google Scholar
• Lambrecht BN, Hammad H. The airway epithelium in asthma. Nat Med 2012;18(5):684–692.
   PubMed Web of Science ®Google Scholar
• Kay AB. The role of eosinophils in the pathogenesis of asthma. Trend Mol Med 2005;11(4):148–152.
   PubMed Web of Science ®Google Scholar
• Bishop B, Lloyd CM. CC chemokine ligand 1 promotes recruitment of eosinophils but not Th2 cells during the development of allergic airways disease. J Immunol 2003;170(9):4810–4817.
   PubMed Web of Science ®Google Scholar
• Trivedi S, Lloyd C. Eosinophils in the pathogenesis of allergic airways disease. Cell Mol Life Sci 2007;64(10):1269–1289.
   PubMed Web of Science ®Google Scholar
• Fahy JV. Type 2 inflammation in asthma — present in most, absent in many. Nat Rev Immunol 2015;15(1):57–65.
   PubMed Web of Science ®Google Scholar
• Chesné J, Braza F, Mahay G, IL-17 in Severe Asthma. Where Do We Stand? Am J Resp Crit Care Med 2014;190(10):1094–1101.
   Google Scholar
• Cosmi L, Liotta F, Maggi E, Th17 cells: new players in asthma pathogenesis. Allergy 2011;66(8):989–998.
   PubMed Web of Science ®Google Scholar
• Irvin C, Zafar I, Good J, Increased frequency of dual-positive Th2/Th17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma. J Allergy Clin Immunol 2014;134(5):1175–86. e7.
   PubMed Web of Science ®Google Scholar
• Al-Ramli W, Préfontaine D, Chouiali F, T H 17-associated cytokines (IL-17A and IL-17F) in severe asthma. J Allergy Clin Immunol 2009;123(5):1185–1187.
   PubMed Web of Science ®Google Scholar
• Doe C, Bafadhel M, Siddiqui S, Expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD. CHEST J 2010;138(5):1140–1147.
   PubMed Web of Science ®Google Scholar
• Bullens D, Truyen E, Coteur L, IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx. Respir Res 2006;7(1):135.
   PubMed Web of Science ®Google Scholar
• Hellings PW, Kasran A, Liu Z, Interleukin-17 orchestrates the granulocyte influx into airways after allergen inhalation in a mouse model of allergic asthma. Am J Resp Cell Mol Biol 2003;28(1):42–50.
   PubMed Web of Science ®Google Scholar
• McKinley L, Alcorn JF, Peterson A, TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J Immunol 2008;181(6):4089–4097.
   PubMed Web of Science ®Google Scholar
• Essilfie A-T, Horvat JC, Kim RY, Macrolide therapy suppresses key features of experimental steroid-sensitive and steroid-insensitive asthma. Thorax 2015, doi:10.1136/thoraxjnl-2014-206067
   Web of Science ®Google Scholar
• Poon A, Eidelman D, Martin J, Pathogenesis of severe asthma. Clin Exp Allergy 2012;42(5):625–637.
   PubMed Web of Science ®Google Scholar
• Trejo Bittar HE, Yousem SA, Wenzel SE. Pathobiology of severe asthma. Ann Rev Pathol: Mech Disease 2014;10:511–545.
   Web of Science ®Google Scholar
• Shannon J, Ernst P, Yamauchi Y, Differences in airway cytokine profile in severe asthma compared to moderate asthma. CHEST J 2008;133(2):420–426.
   PubMed Web of Science ®Google Scholar
• Yu M, Eckart MR, Morgan AA, Identification of an IFN-γ/mast cell axis in a mouse model of chronic asthma. J Clin Invest 2011;121(8):3133.
   PubMed Web of Science ®Google Scholar
• Fahy JV. Eosinophilic and neutrophilic inflammation in asthma: insights from clinical studies. Proc Am Thorac Soc 2009;6(3):256–259.
   PubMedGoogle Scholar
• Flood-Page P, Menzies-Gow A, Phipps S, Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J Clin Invest 2003;112(7):1029.
   PubMed Web of Science ®Google Scholar
• Gupta S, Siddiqui S, Haldar P, Qualitative analysis of high-resolution CT scans in severe asthma. CHEST J 2009;136(6):1521–1528.
   PubMed Web of Science ®Google Scholar
• Hastie AT, Moore WC, Meyers DA, Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes. J Allergy Clin Immunol 2010;125(5):1028–1036. e13.
   PubMed Web of Science ®Google Scholar
• Bingham CO, Austen KF. Mast-cell responses in the development of asthma. J Allergy Clin Immunol 2000;105(2):S527–S34.
   Google Scholar
• Balzar S, Chu HW, Strand M, Relationship of small airway chymase-positive mast cells and lung function in severe asthma. Am J Resp Crit Care Med 2005;171(5):431–439.
   PubMed Web of Science ®Google Scholar
• Balzar S, Fajt ML, Comhair SA, Mast cell phenotype, location, and activation in severe asthma: data from the severe asthma research program. Am J Resp Crit Care Med 2011;183(3):299–309.
   PubMed Web of Science ®Google Scholar
• Deckers J, Madeira FB, Hammad H. Innate immune cells in asthma. Trend Immunol 2013;34(11):540–547.
   PubMed Web of Science ®Google Scholar
• Karimi K, Forsythe P. Natural killer cells in asthma. Front Immunol 2013;4:159.
   PubMed Web of Science ®Google Scholar
• Kvarnhammar AM, Tengroth L, Adner M, Innate immune receptors in human airway smooth muscle cells: activation by TLR1/2, TLR3, TLR4, TLR7 and NOD1 agonists. PloS one 2013;8(7):e68701.
   Google Scholar
• Kato A, Favoreto S, Avila PC, TLR3-and Th2 cytokine-dependent production of thymic stromal lymphopoietin in human airway epithelial cells. J Immunol 2007;179(2):1080–1087.
   PubMed Web of Science ®Google Scholar
• Jacquet A. The role of innate immunity activation in house dust mite allergy. Trend Mol Med 2011;17(10):604–611.
   PubMed Web of Science ®Google Scholar
• Iwamura C, Nakayama T. Toll-like receptors in the respiratory system: their roles in inflammation. Curr Allergy Asthma Rep 2008;8(1):7–13.
   PubMed Web of Science ®Google Scholar
• Voskamp AL, Prickett SR, Mackay F, MHC class II expression in human basophils: induction and lack of functional significance. PloS one 2013;8(12):e81777.
   Google Scholar
• Suurmond J, Stoop JN, Rivellese F, Activation of human basophils by combined toll‐like receptor‐and FcϵRI‐triggering can promote Th2 skewing of naive T helper cells. Eur J Immunol 2014;44(2):386–396.
   PubMed Web of Science ®Google Scholar
• Barboza R, Câmara NOS, Gomes E, Endotoxin exposure during sensitization to Blomia tropicalis allergens shifts TH2 immunity towards a TH17-mediated airway neutrophilic inflammation: role of TLR4 and TLR2. PloS one 2013;8(6):e67115.
   Google Scholar
• Grela F, Aumeunier A, Bardel E, The TLR7 agonist R848 alleviates allergic inflammation by targeting invariant NKT cells to produce IFN-γ. J Immunol 2011;186(1):284–290.
   PubMed Web of Science ®Google Scholar
• Iwamura C, Nakayama T. Role of NKT cells in allergic asthma. Curr Opin Immunol 2010;22(6):807–813.
   PubMed Web of Science ®Google Scholar
• Rzepecka J, Harnett W. Impact of worms and their products on eosinophils and neutrophils in experimental asthma. Curr Mol Med 2013;13(7):1192–1202.
   PubMed Web of Science ®Google Scholar
• Conrad M, Yildirim A, Sonar S, Comparison of adjuvant and adjuvant‐free murine experimental asthma models. Clin Exp Allergy 2009;39(8):1246–1254.
   PubMed Web of Science ®Google Scholar
• Kaplan MH, Hufford MM, Olson MR. The development and in vivo function of T helper 9 cells. Nat Rev Immunol 2015;15(5):295–293, doi:10.1038/nri3824
   PubMed Web of Science ®Google Scholar
• McLane MP, Haczku A, van de Rijn M, Interleukin-9 promotes allergen-induced eosinophilic inflammation and airway hyperresponsiveness in transgenic mice. Am J Resp Cell Mol Biol 1998;19(5):713–720.
   PubMed Web of Science ®Google Scholar
• Kara EE, Comerford I, Bastow CR, Distinct chemokine receptor axes regulate Th9 cell trafficking to allergic and autoimmune inflammatory sites. J Immunol 2013;191(3):1110–1117.
   PubMed Web of Science ®Google Scholar
• Erpenbeck VJ, Hohlfeld JM, Volkmann B, Segmental allergen challenge in patients with atopic asthma leads to increased IL-9 expression in bronchoalveolar lavage fluid lymphocytes. J Allergy Clin Immunol 2003;111(6):1319–1327.
   PubMed Web of Science ®Google Scholar
• Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010;11(5):373–384.
   PubMed Web of Science ®Google Scholar
• Drake MG, Scott GD, Proskocil BJ, Toll-like receptor 7 rapidly relaxes human airways. Am J Resp Crit Care Med 2013;188(6):664–672.
   PubMed Web of Science ®Google Scholar
• Fuchs B, Braun A. Modulation of asthma and allergy by addressing toll-like receptor 2. J Occup Med Toxicol 2008;3(Suppl 1):S5.
   Google Scholar
• Revets H, Pynaert G, Grooten J, Lipoprotein I, a TLR2/4 ligand modulates Th2-driven allergic immune responses. J Immunol 2005;174(2):1097–1103.
   PubMed Web of Science ®Google Scholar
• Patel M, Xu D, Kewin P, TLR2 agonist ameliorates established allergic airway inflammation by promoting Th1 response and not via regulatory T cells. J Immunol 2005;174(12):7558–7563.
   PubMed Web of Science ®Google Scholar
• Redecke V, Häcker H, Datta SK, Cutting edge: activation of Toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma. J Immunol 2004;172(5):2739–2743.
   PubMed Web of Science ®Google Scholar
• Buckland K, O’Connor E, Murray L, Toll like receptor-2 modulates both innate and adaptive immune responses during chronic fungal asthma in mice. Inflam Res 2008;57(8):379–387.
   PubMed Web of Science ®Google Scholar
• Nawijn MC1, Motta AC, Gras R, TLR-2 activation induces regulatory T cells and long-term suppression of asthma manifestations in mice. PLoS One 2013;8(2):e55307.
   Google Scholar
• Dillon S, Agrawal A, Van Dyke T, A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells. J Immunol 2004;172(8):4733–4743.
   PubMed Web of Science ®Google Scholar
• Moreira AP, Cavassani KA, Ismailoglu UB, The protective role of TLR6 in a mouse model of asthma is mediated by IL-23 and IL-17A. J Clin Invest 2011;121(11):4420.
   PubMed Web of Science ®Google Scholar
• Chun E, Lee S-H, Lee S-Y, Toll-like receptor expression on peripheral blood mononuclear cells in asthmatics; implications for asthma management. J Clin Immunol 2010;30(3):459–464.
   PubMed Web of Science ®Google Scholar
• Pons J, Sauleda J, Regueiro V, Expression of Toll-like receptor 2 is up-regulated in monocytes from patients with chronic obstructive pulmonary disease. Respir Res 2006;7(1):64–73.
   PubMed Web of Science ®Google Scholar
• Lauener RP, Birchler T, Adamski J, Expression of CD14 and Toll-like receptor 2 in farmers’ and nonfarmers’ children. The Lancet 2002;360(9331):465–466.
   PubMed Web of Science ®Google Scholar
• Re F, Strominger JL. IL-10 released by concomitant TLR2 stimulation blocks the induction of a subset of Th1 cytokines that are specifically induced by TLR4 or TLR3 in human dendritic cells. J Immunol 2004;173(12):7548–7555.
   PubMed Web of Science ®Google Scholar
• Reuter S, Dehzad N, Martin H, TLR3 but not TLR7/8 ligand induces allergic sensitization to inhaled allergen. J Immunol 2012;188(10):5123–5131.
   PubMed Web of Science ®Google Scholar
• Tanaka J, Watanabe N, Kido M, Human TSLP and TLR3 ligands promote differentiation of Th17 cells with a central memory phenotype under Th2‐polarizing conditions. Clin Exp Allergy 2009;39(1):89–100.
   PubMed Web of Science ®Google Scholar
• Hammad H, Lambrecht BN. Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma. Nat Rev Immunol 2008;8(3):193–204.
   PubMed Web of Science ®Google Scholar
• Eisenbarth SC, Piggott DA, Huleatt JW, Lipopolysaccharide-enhanced, toll-like receptor 4–dependent T helper cell type 2 responses to inhaled antigen. J Exp Med 2002;196(12):1645–1651.
   PubMed Web of Science ®Google Scholar
• Piggott DA, Eisenbarth SC, Xu L, MyD88-dependent induction of allergic Th2 responses to intranasal antigen. J Clin Invest 2005;115(2):459.
   PubMed Web of Science ®Google Scholar
• Watanabe J, Miyazaki Y, Zimmerman GA, Endotoxin contamination of ovalbumin suppresses murine immunologic responses and development of airway hyper-reactivity. J Biol Chem 2003;278(43):42361–42368.
   PubMed Web of Science ®Google Scholar
• Simpson A, John SL, Jury F, Endotoxin exposure, CD14, and allergic disease: an interaction between genes and the environment. Am J Resp Crit Care Med 2006;174(4):386–392.
   PubMed Web of Science ®Google Scholar
• Koppelman GH, Reijmerink NE, Colin Stine O, Association of a promoter polymorphism of the CD14 gene and atopy. Am J Resp Crit Care Med 2001;163(4):965–969.
   PubMed Web of Science ®Google Scholar
• Wills-Karp M. Allergen-specific pattern recognition receptor pathways. Curr Opin Immunol 2010;22(6):777–782.
   PubMed Web of Science ®Google Scholar
• Dong L, Li H, Wang S, Different doses of lipopolysaccharides regulate the lung inflammation of asthmatic mice via TLR4 pathway in alveolar macrophages. J Asthma 2009;46(3):229–233.
   PubMed Web of Science ®Google Scholar
• Haapakoski R, Karisola P, Fyhrquist N, Toll-like receptor activation during cutaneous allergen sensitization blocks development of asthma through IFN-gamma-dependent mechanisms. J Invest Dermatol 2013;133(4):964–972.
   PubMed Web of Science ®Google Scholar
• Liu C-F, Drocourt D, Puzo G, Innate immune response of alveolar macrophage to house dust mite allergen is mediated through TLR2/-4 co-activation. PloS one 2013;8(10):e75983.
   Google Scholar
• Wang Y, McCusker C. Neonatal exposure with LPS and/or allergen prevents experimental allergic airways disease: development of tolerance using environmental antigens. J Allergy Clin Immunol 2006;118(1):143–151.
   PubMed Web of Science ®Google Scholar
• Gerhold K, Avagyan A, Seib C, Prenatal initiation of endotoxin airway exposure prevents subsequent allergen-induced sensitization and airway inflammation in mice. J Allergy Clin Immunol 2006;118(3):666–673.
   PubMed Web of Science ®Google Scholar
• Hammad H, Chieppa M, Perros F, House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat Med 2009;15(4):410–416.
   PubMed Web of Science ®Google Scholar
• McSorley HJ, Blair NF, Smith KA, Blockade of IL-33 release and suppression of type 2 innate lymphoid cell responses by helminth secreted products in airway allergy. Mucosal Immunol 2014;7(5):1068–1078.
   PubMed Web of Science ®Google Scholar
• Thorne PS, Kulhánková K, Yin M, Endotoxin exposure is a risk factor for asthma: the national survey of endotoxin in United States housing. Am J Resp Crit Care Med 2005;172(11):1371–1377.
   PubMed Web of Science ®Google Scholar
• Gereda J, Leung D, Thatayatikom A, Relation between house-dust endotoxin exposure, type 1 T-cell development, and allergen sensitisation in infants at high risk of asthma. The Lancet 2000;355(9216):1680–1683.
   PubMed Web of Science ®Google Scholar
• Pace E, Giarratano A, Ferraro M, TLR4 upregulation underpins airway neutrophilia in smokers with chronic obstructive pulmonary disease and acute respiratory failure. Hum Immunol 2011;72(1):54–62.
   PubMed Web of Science ®Google Scholar
• Lun SW, Wong C, Ko FW, Expression and functional analysis of toll-like receptors of peripheral blood cells in asthmatic patients: implication for immunopathological mechanism in asthma. J Clin Immunol 2009;29(3):330–342.
   PubMed Web of Science ®Google Scholar
• Falcón CR, Masih D, Gatti G, Fasciola hepatica Kunitz type molecule decreases dendritic cell activation and their ability to induce inflammatory responses. PloS one 2014;9(12):e114505.
   Google Scholar
• Kane CM, Cervi L, Sun J, Helminth antigens modulate TLR-initiated dendritic cell activation. J Immunol 2004;173(12):7454–7461.
   PubMed Web of Science ®Google Scholar
• Favoretto BC, Silva SR, Jacysyn JF, TLR2-and 4-independent immunomodulatory effect of high molecular weight components from Ascaris suum. Mol Immunol 2014;58(1):17–26.
   PubMed Web of Science ®Google Scholar
• van der Kleij D, Latz E, Brouwers JF, A novel host-parasite lipid cross-talk Schistosomal lyso-phosphatidylserine activates toll-like receptor 2 and affects immune polarization. J Biol Chem 2002;277(50):48122–48129.
   PubMed Web of Science ®Google Scholar
• Thomas PG, Carter MR, Atochina O, Maturation of dendritic cell 2 phenotype by a helminth glycan uses a Toll-like receptor 4-dependent mechanism. J Immunol 2003;171(11):5837–5841.
   PubMed Web of Science ®Google Scholar
• Harn DA, McDonald J, Atochina O, Modulation of host immune responses by helminth glycans. Immunol Rev 2009;230(1):247–257.
   PubMed Web of Science ®Google Scholar
• Zhang M, Gao Y, Du X, Toll‐like receptor (TLR) 2 and TLR4 deficiencies exert differential in vivo effects against Schistosoma japonicum. Parasite Immunol 2011;33(4):199–209.
   PubMed Web of Science ®Google Scholar
• Gao Y, Zhang M, Chen L, Deficiency in TLR2 but not in TLR4 impairs dendritic cells derived IL-10 responses to schistosome antigens. Cell Immunol 2012;272(2):242–250.
   PubMed Web of Science ®Google Scholar
• Burton OT, Gibbs S, Miller N, Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens. Eur J Immunol 2010;40(8):2221–2229.
   PubMed Web of Science ®Google Scholar
• Layland LE, Rad R, Wagner H, Immunopathology in schistosomiasis is controlled by antigen‐specific regulatory T cells primed in the presence of TLR2. Eur J Immunol 2007;37(8):2174–2184.
   PubMed Web of Science ®Google Scholar
• van Riet E, Everts B, Retra K, Combined TLR2 and TLR4 ligation in the context of bacterial or helminth extracts in human monocyte derived dendritic cells: molecular correlates for Th1/Th2 polarization. BMC Immunol 2009;10(1):9.
   PubMed Web of Science ®Google Scholar
• Wang X, Zhou S, Chi Y, CD4+ CD25+ Treg induction by an HSP60‐derived peptide SJMHE1 from Schistosoma japonicum is TLR2 dependent. Eur J Immunol 2009;39(11):3052–3065.
   PubMed Web of Science ®Google Scholar
• Semnani RT, Venugopal PG, Leifer CA, Inhibition of TLR3 and TLR4 function and expression in human dendritic cells by helminth parasites. Blood 2008;112(4):1290–1298.
   PubMed Web of Science ®Google Scholar
• Babu S, Bhat SQ, Kumar NP, Filarial lymphedema is characterized by antigen-specific Th1 and th17 proinflammatory responses and a lack of regulatory T cells. PLoS Neglected Trop Dis 2009;3(4):e420.
   Google Scholar
• Boyd A, Bennuru S, Wang Y, Quiescent innate response to infective filariae by human Langerhans cells suggests a strategy of immune evasion. Infec Immun 2013;81(5):1420–1429.
   PubMed Web of Science ®Google Scholar
• Cotton RN, McDonald‐Fleming R, Boyd A, Brugia malayi infective larvae fail to activate Langerhans cells and dermal dendritic cells in human skin. Parasite Immunol 2015;37(2):79–91. doi:10.1111/pim.12169
   PubMed Web of Science ®Google Scholar
• Mylonas KJ, Hoeve MA, MacDonald AS, Alternative activation of macrophages by filarial nematodes is MyD88-independent. Immunobiology 2013;218(4):570–578.
   PubMed Web of Science ®Google Scholar
• Verma A, Prasad KN, Cheekatla SS, Immune response in symptomatic and asymptomatic neurocysticercosis. Med Microbiol Immunol 2011;200(4):255–261.
   PubMed Web of Science ®Google Scholar
• Shan JY, JI WZ, Li HT, TLR2 and TLR4 expression in peripheral blood mononuclear cells of patients with chronic cystic echinococcosis and its relationship with IL‐10. Parasite Immunol 2011;33(12):692–696.
   PubMed Web of Science ®Google Scholar
• Kosik-Bogacka D, Wojtkowiak-Giera A, Kolasa A, Hymenolepis diminuta: analysis of the expression of Toll-like receptor genes (TLR2 and TLR4) in the small and large intestines of rats. Exp Parasitol 2012;130(3):261–266.
   PubMed Web of Science ®Google Scholar
• Lee K-D, Guk S-M, Chai J-Y. Toll-like receptor 2 and Muc2 expression on human intestinal epithelial cells by Gymnophalloides seoi adult antigen. J Parasitol 2010;96(1):58–66.
   PubMed Web of Science ®Google Scholar
• Ninlawan K, O’Hara SP, Splinter PL, Opisthorchis viverrini excretory/secretory products induce toll-like receptor 4 upregulation and production of interleukin 6 and 8 in cholangiocyte. Parasitol Int 2010;59(4):616–621.
   PubMed Web of Science ®Google Scholar
• Yongvanit P, Thanan R, Pinlaor S, Increased expression of TLR-2, COX-2, and SOD-2 genes in the peripheral blood leukocytes of opisthorchiasis patients induced by Opisthorchis viverrini antigen. Parasitol Res 2012;110(5):1969–1977.
   PubMed Web of Science ®Google Scholar
• Jin Y, Wi HJ, Choi M-H, Regulation of anti-inflammatory cytokines IL-10 and TGF-[beta] in mouse dendritic cells through treatment with Clonorchis sinensis crude antigen. Exp Mol Med 2014 01/31/online;46:e74.
   Google Scholar
• Yu Y-R, Deng M-J, Lu W-W, Systemic cytokine profiles and splenic toll-like receptor expression during Trichinella spiralis infection. Exp Parasitol 2013;134(1):92–101.
   PubMed Web of Science ®Google Scholar
• Smith KA, Maizels RM. Defeating sepsis by misleading MyD88. Nature 2011;201:1.
   Google Scholar
• Thivierge K, Cotton S, Schaefer DA, Cathelicidin-like helminth defence molecules (HDMs): absence of cytotoxic, anti-microbial and anti-protozoan activities imply a specific adaptation to immune modulation. PLoS Neglected Trop Dis 2013;7(7):e2307.
   Google Scholar
• Vukman K, Adams P, O’Neill S. Fasciola hepatica tegumental coat antigen suppresses MAPK signalling in dendritic cells and up‐regulates the expression of SOCS3. Parasite Immunol 2013;35(7–8):234–238.
   PubMed Web of Science ®Google Scholar
• Vukman KV, Adams PN, Metz M, Fasciola hepatica tegumental coat impairs mast cells’ ability to drive Th1 immune responses. J Immunol 2013;190(6):2873–2879.
   PubMed Web of Science ®Google Scholar
• Bai X, Wu X, Wang X, Regulation of cytokine expression in murine macrophages stimulated by excretory/secretory products from Trichinella spiralis in vitro. Mol Cell Biochem 2012;360(1–2):79–88.
   PubMed Web of Science ®Google Scholar
• Donnelly S, Stack CM, O’Neill SM, Helminth 2-Cys peroxiredoxin drives Th2 responses through a mechanism involving alternatively activated macrophages. FASEB J 2008;22(11):4022–4032.
   PubMed Web of Science ®Google Scholar
• Donnelly S, O’Neill SM, Stack CM, Helminth cysteine proteases inhibit TRIF-dependent activation of macrophages via degradation of TLR3. J Biol Chem 2010;285(5):3383–3392.
   PubMed Web of Science ®Google Scholar
• Dowling DJ, Hamilton CM, Donnelly S, Major secretory antigens of the helminth Fasciola hepatica activate a suppressive dendritic cell phenotype that attenuates Th17 cells but fails to activate Th2 immune responses. Infect Immun 2010;78(2):793–801.
   PubMed Web of Science ®Google Scholar
• Forward NA, Furlong SJ, Yang Y, Signaling through TLR7 enhances the immunosuppressive activity of murine CD4+ CD25+ T regulatory cells. J Leukocyte Biol 2010;87(1):117–125.
   PubMed Web of Science ®Google Scholar
• Falcón C, Carranza F, Martínez FF, Excretory-secretory products (ESP) from Fasciola hepatica induce tolerogenic properties in myeloid dendritic cells. Vet Immunol Immunopathol 2010;137(1):36–46.
   Google Scholar
• Brännström K, Sellin ME, Holmfeldt P, The Schistosoma mansoni protein Sm16/SmSLP/SmSPO-1 assembles into a nine-subunit oligomer with potential To inhibit Toll-like receptor signaling. Infect Immun 2009;77(3):1144–1154.
   Google Scholar
• Correale J, Farez MF. Parasite infections in multiple sclerosis modulate immune responses through a retinoic acid–dependent pathway. J Immunol 2013;191(7):3827–3837.
   PubMed Web of Science ®Google Scholar
• Aksoy E, Zouain CS, Vanhoutte F, Double-stranded RNAs from the helminth parasite Schistosoma activate TLR3 in dendritic cells. J Biol Chem 2005;280(1):277–283.
   PubMed Web of Science ®Google Scholar
• van Stijn CM, Meyer S, van den Broek M, Schistosoma mansoni worm glycolipids induce an inflammatory phenotype in human dendritic cells by cooperation of TLR4 and DC-SIGN. Mol Immunol 2010;47(7):1544–1552.
   PubMed Web of Science ®Google Scholar
• Smith P, Walsh CM, Mangan NE, Schistosoma mansoni worms induce anergy of T cells via selective up-regulation of programmed death ligand 1 on macrophages. J Immunol 2004;173(2):1240–1248.
   PubMed Web of Science ®Google Scholar
• Gao Y, Chen L, Hou M, TLR2 Directing PD-L2 expression inhibit T cells response in Schistosoma japonicum infection. PloS one 2013;8(12):e82480.
   Google Scholar
• Taylor JJ, Krawczyk CM, Mohrs M, Th2 cell hyporesponsiveness during chronic murine schistosomiasis is cell intrinsic and linked to GRAIL expression. J Clin Invest 2009;119(4):1019.
   PubMed Web of Science ®Google Scholar
• Steinfelder S, Andersen JF, Cannons JL, The major component in schistosome eggs responsible for conditioning dendritic cells for Th2 polarization is a T2 ribonuclease (omega-1). J Exp Med 2009;206(8):1681–1690.
   PubMed Web of Science ®Google Scholar
• Klaver EJ, Kuijk LM, Laan LC, Trichuris suis-induced modulation of human dendritic cell function is glycan-mediated. Int J Parasitol 2013;43(3):191–200.
   PubMed Web of Science ®Google Scholar
• Mei G, Dong J, Li Z, Structural basis for the immunomodulatory function of cysteine protease inhibitor from human roundworm ascaris lumbricoides. PloS one 2014;9(4):e96069.
   Google Scholar
• Daniłowicz-Luebert E, Steinfelder S, Kühl AA, A nematode immunomodulator suppresses grass pollen-specific allergic responses by controlling excessive Th2 inflammation. Int J Parasitol 2013;43(3):201–210.
   Google Scholar
• Klotz C, Ziegler T, Figueiredo AS, A helminth immunomodulator exploits host signaling events to regulate cytokine production in macrophages. PLoS Pathogens 2011;7(1):e1001248.
   Google Scholar
• Melendez AJ, Harnett MM, Pushparaj PN, Inhibition of Fcε RI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes. Nat Med 2007;13(11):1375–1381
   PubMed Web of Science ®Google Scholar
• Pineda MA, McGrath MA, Smith PC, The parasitic helminth product ES‐62 suppresses pathogenesis in collagen‐induced arthritis by targeting the interleukin‐17–producing cellular network at multiple sites. Arthrit Rheu 2012;64(10):3168–3178.
   PubMed Web of Science ®Google Scholar
• Al-Riyami L, Pineda MA, Rzepecka J, Designing anti-inflammatory drugs from parasitic worms: a synthetic small molecule analogue of the Acanthocheilonema viteae product ES-62 prevents development of collagen-induced arthritis. J Med Chem 2013;56(24):9982–10002.
   PubMed Web of Science ®Google Scholar
• Pineda MA, Rodgers DT, Al‐Riyami L, ES‐62 protects against collagen‐induced arthritis by resetting interleukin‐22 toward resolution of inflammation in the joints. Arthrit Rheu 2014;66(6):1492–1503.
   PubMed Web of Science ®Google Scholar
• Ottow M, Klaver E, van der Pouw Kraan T, The helminth Trichuris suis suppresses TLR4-induced inflammatory responses in human macrophages. Genes Immun 2014;15(7):477–486.
   PubMed Web of Science ®Google Scholar
• Ebner F, Hepworth M, Rausch S, Therapeutic potential of larval excretory/secretory proteins of the pig whipworm Trichuris suis in allergic disease. Allergy 2014;69(11):1489–1497.
   PubMed Web of Science ®Google Scholar
• Terrazas CA, Alcántara-Hernández M, Bonifaz L, Helminth-excreted/secreted products are recognized by multiple receptors on DCs to block the TLR response and bias Th2 polarization in a cRAF dependent pathway. The FASEB J 2013;27(11):4547–4560.
   PubMed Web of Science ®Google Scholar
• Ince MN, Elliott DE, Setiawan T, Cutting Edge: Heligmosomoides polygyrus induces TLR4 on murine mucosal T cells that produce TGFβ after lipopolysaccharide stimulation. J Immunol 2006;176(2):726–729.
   PubMed Web of Science ®Google Scholar
• Metwali A, Setiawan T, Blum AM, Induction of CD8+ regulatory T cells in the intestine by Heligmosomoides polygyrus infection. Am J Physiol-Gastr Liver Physiol 2006;291(2):G253–G59.
   Google Scholar
• Salgame P, Yap GS, Gause WC. Effect of helminth-induced immunity on infections with microbial pathogens. Nat Immunol 2013;14(11):1118–1126.
   PubMed Web of Science ®Google Scholar
• Strickland, DH, Patrick GH. T regulatory cells in childhood asthma. Trend Immunol 2011;32(9):420–427.
   PubMed Web of Science ®Google Scholar
• Akdis CA, Akdis M. Mechanisms and treatment of allergic disease in the big picture of regulatory T cells. J Allergy Clin Immunol 2009;123(4):735–746.
   PubMed Web of Science ®Google Scholar
• Thorburn AN, Philip MH. Harnessing regulatory T cells to suppress asthma: from potential to therapy. Am J Resp Cell Mol Biol 2010;43(5):511–519.
   PubMed Web of Science ®Google Scholar
• Noh G, Lee JH. Regulatory B cells and allergic diseases. Allergy Asthma Immunol Res 2011;3(3):168–177.
   PubMed Web of Science ®Google Scholar
• Singh A, Carson WF, Secor ER, Regulatory role of B cells in a murine model of allergic airway disease. J Immunol 2008;180(11):7318–7326.
   PubMed Web of Science ®Google Scholar
• van der Vlugt LE, Mlejnek E, Ozir-Fazalalikhan A, CD24(hi)CD27(+) B cells from patients with allergic asthma have impaired regulatory activity in response to lipopolysaccharide. Clin Exp Allergy 2014; 44(4):517–528.
   PubMed Web of Science ®Google Scholar
• Lundy SK, Berlin AA, Martens T, Deficiency of regulatory B cells increases allergic airway inflammation. Inflamm Res 2005; 54(12):514–521.
   PubMed Web of Science ®Google Scholar
• Rodgers DT, Pineda MA, McGrath MA, Protection against collagen‐induced arthritis in mice afforded by the parasitic worm product, ES‐62, is associated with restoration of the levels of interleukin‐10‐producing B cells and reduced plasma cell infiltration of the joints. Immunology 2014;141(3):457–466.
   PubMed Web of Science ®Google Scholar
• Amu S, Saunders SP, Kronenberg M, Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model. J Allergy Clin Immunol 2010;125(5):1114–1124. e8.
   PubMed Web of Science ®Google Scholar
• van der Vlugt LE, Zinsou JF, Ozir-Fazalalikhan A, IL-10-producing CD1dhi regulatory B cells from Schistosoma haematobium-infected individuals induce IL-10-positive T cells and suppress effector T-cell cytokines. J Infect Dis 2014:jiu257.
   Google Scholar
• Rosser EC, Blair PA, Mauri C. Cellular targets of regulatory B cell-mediated suppression. Mol immunol 2014;62(2):296–304.
   PubMed Web of Science ®Google Scholar
• Iwata-Yoshikawa N, Uda A, Suzuki T, Effects of toll-like receptor stimulation on eosinophilic infiltration in lungs of BALB/c mice immunized with UV-inactivated severe acute respiratory syndrome-related coronavirus vaccine. J Virol 2014;88(15):8597–8614.
   PubMed Web of Science ®Google Scholar
• Siebeneicher S, Reuter S, Krause M, Epicutaneous immune modulation with Bet v 1 plus R848 suppresses allergic asthma in a murine model. Allergy 2014;69(3):328–337.
   PubMed Web of Science ®Google Scholar
• Duechs MJ, Tilp C, Tomsic C, Development of a novel severe triple allergen asthma model in mice which is resistant to dexamethasone and partially resistant to TLR7 and TLR9 agonist treatment. PloS one 2014;9(3):e91223.
   Google Scholar
• Sykes A, Edwards MR, Macintyre J, TLR3, TLR4 and TLRs7-9 induced interferons are not impaired in airway and blood cells in well controlled asthma. PloS one 2013;8(6):e65921.
   Google Scholar
• Beeh K-M, Kanniess F, Wagner F, The novel TLR-9 agonist QbG10 shows clinical efficacy in persistent allergic asthma. J Allergy Clin Immunol 2013;131(3):866–874.
   PubMed Web of Science ®Google Scholar
• Hayashi T, Raz E. TLR9-based immunotherapy for allergic disease. Am J Med 2006;119(10):897. e1–97. e6.
   PubMedGoogle Scholar
• Wilson RH, Maruoka S, Whitehead GS, The Toll-like receptor 5 ligand flagellin promotes asthma by priming allergic responses to indoor allergens. Nat Med 2012;18(11):1705–1710.
   PubMed Web of Science ®Google Scholar
• Basith S, Manavalan B, Lee G, Toll-like receptor modulators: a patent review (2006–2010). Expert Opin Ther Pat 2011;21(6):927–944.
   PubMed Web of Science ®Google Scholar
• Steinhagen F, Kinjo T, Bode C, TLR-based immune adjuvants. Vaccine 2011;29(17):3341–3355.
   PubMed Web of Science ®Google Scholar
• Tabatabaeizadeh S-E, Haghparast A. Improving the effectiveness of adjuvants: Targeting innate immune receptors with a special focus on toll-like receptor agonists. J Isfahan Med Sch 2013;30(214):1986–2009.
   Google Scholar
• Robinson MW, Donnelly S, Hutchinson AT, A family of helminth molecules that modulate innate cell responses via molecular mimicry of host antimicrobial peptides. PLoS Pathogens 2011;7(5):e1002042.
   Google Scholar
• Panda SK, Kumar S, Tupperwar NC, Chitohexaose activates macrophages by alternate pathway through TLR4 and blocks endotoxemia. PLoS Pathogens 2012;8(5):e1002717.
   Google Scholar
• Aparnaa R, Kaliraj P. Immunomodulation of ALT-2 and TLR may collude in antigen specific T cell hyporesponsiveness: Proposed mechanism for elevated IL-10 levels in Balb/C mice. Acta Parasitol 2014;59(1):25–30.
   PubMed Web of Science ®Google Scholar
• Halim TY, Steer CA, Mathä L, Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation. Immunity 2014;40(3):425–435.
   PubMed Web of Science ®Google Scholar
• Jeong Y-I, Kim Y-J, Ju J-W, Identification of anti-allergic effect of Clonorchis sinensis-derived protein venom allergen-like proteins (CsVAL). Biochem Biophys Res Vommun 2014;445(3):549–555.
   PubMed Web of Science ®Google Scholar
• Rzepecka J, Coates ML, Saggar M, Small molecule analogues of the immunomodulatory parasitic helminth product ES-62 have anti-allergy properties. Int J Parasitol 2014;44(9):669–674.
   PubMed Web of Science ®Google Scholar
• Hartgers FC, Obeng BB, Kruize YC, Lower expression of TLR2 and SOCS-3 is associated with Schistosoma haematobium infection and with lower risk for allergic reactivity in children living in a rural area in Ghana. PLoS Neglected Trop Dis 2008;2(4):e227.
   Google Scholar
• Zafra MP, Mazzeo C, Gámez C, Gene Silencing of SOCS3 by siRNA Intranasal Delivery Inhibits Asthma Phenotype in Mice. PloS one 2014;9(3):e91996.
   Google Scholar
• Nono JK, Pletinckx K, Lutz MB, Excretory/secretory-products of Echinococcus multilocularis larvae induce apoptosis and tolerogenic properties in dendritic cells in vitro. PLoS Neglected Trop Dis 2012;6(2):e1516.
   Google Scholar
• Babu S, Blauvelt CP, Nutman TB. Filarial parasites induce NK cell activation, type 1 and type 2 cytokine secretion, and subsequent apoptotic cell death. J Immunol 2007;179(4):2445–2456.
   PubMed Web of Science ®Google Scholar
• Serradell MC, Guasconi L, Masih DT. Involvement of a mitochondrial pathway and key role of hydrogen peroxide during eosinophil apoptosis induced by excretory–secretory products from Fasciola hepatica. Mol Biochem Parasitol 2009;163(2):95–106.
   PubMed Web of Science ®Google Scholar
• Mohapatra AD, Panda SK, Pradhan AK, Filarial antigens mediate apoptosis of human monocytes through toll-like receptor 4. J Inf Dis 2014:jiu208.
   Google Scholar
• Evans 1, Mitre E. Worms as therapeutic agents for allergy and asthma: Understanding why benefits in animal studies have not translated into clinical success. J Allergy Clin Immunol 2015 135(2):343–353.
   PubMed Web of Science ®Google Scholar
• Zakeri A, Haghparast A. What should be taken into account during study on immunoregulatory effects of helminths: a critical analyzing on “Downregulation of immune responses in asthmatic patients by ES products of Marshallagia marshalli”. Clin Resp J 2015 doi:10.1111/crj.12350
   Google Scholar
• Chehayeb JF, Robertson AP, Martin RJ, Proteomic analysis of adult Ascaris suum fluid compartments and secretory products. PLoS Neglected Trop Dis 2014;8(6):e2939.
   Google Scholar
• Sotillo J, Sanchez-Flores A, Cantacessi C, Secreted proteomes of different developmental stages of the gastrointestinal nematode Nippostrongylus brasiliensis. Mol Cell Proteomics 2014;13(10):2736–2751.
   PubMed Web of Science ®Google Scholar
• Cho MK, Park MK, Kang S, TLR2-dependent amelioration of allergic airway inflammation by parasitic nematode type II MIF in mice. Parasite Immunol 2015;37:180–191. doi:10.1111/pim.12172
   PubMed Web of Science ®Google Scholar
• McConchie BW, Norris HH, Bundoc VG, Ascaris suum-derived products suppress mucosal allergic inflammation in an interleukin-10-independent manner via interference with dendritic cell function. Infection Immun 2006;74(12):6632–6641.
   PubMed Web of Science ®Google Scholar
• Hayashi T, Crain B, Yao S, Novel synthetic toll-like receptor 4/MD2 ligands attenuate sterile inflammation. J Pharm Exp Ther 2014;350(2):330–340.
   PubMed Web of Science ®Google Scholar
• Ashour DS. Toll-like receptor signaling in parasitic infections. Expert Rev. Clin Immunol 2015; 1(10), doi:10.1586/1744666X.2015.1037286
   Web of Science ®Google Scholar