Immunological Perspectives: Th2 Cells/Mast Cells/Basophils/Eosinophils

  • Takashi HashimotoEmail author
  • Takahiro Satoh


Atopic dermatitis (AD) is a chronic allergic skin disease with severe pruritus. The “three musketeers” of skin barrier dysfunction, allergy/immunology, and pruritus are considered to play important roles. Th2 immunity mediated by the cytokines interleukin (IL)-4, IL-13, IL-5, and IL-31 has been considered as a key immune process in the pathogenesis of AD. Other cytokines (e.g., TSLP) and chemokines (e.g., TARC/CCL17 and MDC/CCL22) also play important roles in Th2 skewing and the development of skin inflammation. Mast cells release several preformed mediators, as well as newly synthesized proteins and cytokines upon stimulation, contributing to the inflammatory processes and pruritus. Eosinophils have been implicated in tissue remodeling. Basophils may contribute to Th2 skewing but may also exert as-yet unidentified but crucial functions that need to be elucidated in future work.


Atopic dermatitis Basophils Eosinophils Mast cells Th2 immunity 


  1. 1.
    Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016;387(10023):1109–22.PubMedCrossRefGoogle Scholar
  2. 2.
    Kabashima K. New concept of the pathogenesis of atopic dermatitis: interplay among the barrier, allergy, and pruritus as a trinity. J Dermatol Sci. 2013;70(1):3–11.PubMedCrossRefGoogle Scholar
  3. 3.
    Bieber T. Atopic dermatitis. Ann Dermatol. 2010;22(2):125–37.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006;38(4):441–6.PubMedCrossRefGoogle Scholar
  5. 5.
    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. 2007;120(1):150–5.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Sonkoly E, Muller A, Lauerma AI, Pivarcsi A, Soto H, Kemeny L, et al. IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol. 2006;117(2):411–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Simon D, Braathen LR, Simon HU. Eosinophils and atopic dermatitis. Allergy. 2004;59(6):561–70.PubMedCrossRefGoogle Scholar
  8. 8.
    Werfel T, Allam JP, Biedermann T, Eyerich K, Gilles S, Guttman-Yassky E, et al. Cellular and molecular immunologic mechanisms in patients with atopic dermatitis. J Allergy Clin Immunol. 2016;138(2):336–49.PubMedCrossRefGoogle Scholar
  9. 9.
    Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335–48.PubMedCrossRefGoogle Scholar
  10. 10.
    Grewe M, Gyufko K, Schöpf E, Krutmann J. Lesional expression of interferon-gamma in atopic eczema. Lancet. 1994;343(8888):25–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Koga C, Kabashima K, Shiraishi N, Kobayashi M, Tokura Y. Possible pathogenic role of Th17 cells for atopic dermatitis. J Invest Dermatol. 2008;128(11):2625–30.PubMedCrossRefGoogle Scholar
  12. 12.
    Noda S, Suárez-Fariñas M, Ungar B, Kim SJ, de Guzman Strong C, Xu H, et al. The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization. J Allergy Clin Immunol. 2015;136(5):1254–64.PubMedCrossRefGoogle Scholar
  13. 13.
    Guttman-Yassky E, Lowes MA, Fuentes-Duculan J, Zaba LC, Cardinale I, Nograles KE, et al. Low expression of the IL-23/Th17 pathway in atopic dermatitis compared to psoriasis. J Immunol. 2008;181(10):7420–7.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol. 2002;3(7):673–80.PubMedCrossRefGoogle Scholar
  15. 15.
    Sano Y, Masuda K, Tamagawa-Mineoka R, Matsunaka H, Murakami Y, Yamashita R, et al. Thymic stromal lymphopoietin expression is increased in the horny layer of patients with atopic dermatitis. Clin Exp Immunol. 2013;171(3):330–7.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Corrigan CJ, Jayaratnam A, Wang Y, Liu Y, de Waal Malefyt R, Meng Q, et al. Early production of thymic stromal lymphopoietin precedes infiltration of dendritic cells expressing its receptor in allergen-induced late phase cutaneous responses in atopic subjects. Allergy. 2009;64(7):1014–22.PubMedCrossRefGoogle Scholar
  17. 17.
    Bogiatzi SI, Fernandez I, Bichet JC, Marloie-Provost MA, Volpe E, Sastre X, et al. Cutting edge: proinflammatory and Th2 cytokines synergize to induce thymic stromal lymphopoietin production by human skin keratinocytes. J Immunol. 2007;178(6):3373–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Kinoshita H, Takai T, Le TA, Kamijo S, Wang XL, Ushio H, et al. Cytokine milieu modulates release of thymic stromal lymphopoietin from human keratinocytes stimulated with double-stranded RNA. J Allergy Clin Immunol. 2009;123(1):179–86.PubMedCrossRefGoogle Scholar
  19. 19.
    Vu AT, Baba T, Chen X, Le TA, Kinoshita H, Xie Y, et al. Staphylococcus aureus membrane and diacylated lipopeptide induce thymic stromal lymphopoietin in keratinocytes through the Toll-like receptor 2-Toll-like receptor 6 pathway. J Allergy Clin Immunol. 2010;126(5):985–93, 993.e1–3.PubMedCrossRefGoogle Scholar
  20. 20.
    Le TA, Takai T, Vu AT, Kinoshita H, Chen X, Ikeda S, et al. Flagellin induces the expression of thymic stromal lymphopoietin in human keratinocytes via toll-like receptor 5. Int Arch Allergy Immunol. 2011;155(1):31–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Kouzaki H, O’Grady SM, Lawrence CB, Kita H. Proteases induce production of thymic stromal lymphopoietin by airway epithelial cells through protease-activated receptor-2. J Immunol. 2009;183(2):1427–34.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Shiraishi H, Masuoka M, Ohta S, Suzuki S, Arima K, Taniguchi K, et al. Periostin contributes to the pathogenesis of atopic dermatitis by inducing TSLP production from keratinocytes. Allergol Int. 2012;61(4):563–72.PubMedCrossRefGoogle Scholar
  23. 23.
    Angelova-Fischer I, Fernandez IM, Donnadieu MH, Bulfone-Paus S, Zillikens D, Fischer TW, et al. Injury to the stratum corneum induces in vivo expression of human thymic stromal lymphopoietin in the epidermis. J Invest Dermatol. 2010;130(10):2505–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Oyoshi MK, Larson RP, Ziegler SF, Geha RS. Mechanical injury polarizes skin dendritic cells to elicit a T(H)2 response by inducing cutaneous thymic stromal lymphopoietin expression. J Allergy Clin Immunol. 2010;126(5):976–84, 984.e1–5.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Kitajima M, Lee HC, Nakayama T, Ziegler SF. TSLP enhances the function of helper type 2 cells. Eur J Immunol. 2011;41(7):1862–71.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Omori M, Ziegler S. Induction of IL-4 expression in CD4(+) T cells by thymic stromal lymphopoietin. J Immunol. 2007;178(3):1396–404.PubMedCrossRefGoogle Scholar
  27. 27.
    Rochman I, Watanabe N, Arima K, Liu YJ, Leonard WJ. Cutting edge: direct action of thymic stromal lymphopoietin on activated human CD4+ T cells. J Immunol. 2007;178(11):6720–4.PubMedCrossRefGoogle Scholar
  28. 28.
    Ito T, Wang YH, Duramad O, Hori T, Delespesse GJ, Watanabe N, et al. TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med. 2005;202(9):1213–23.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Kakinuma T, Nakamura K, Wakugawa M, Mitsui H, Tada Y, Saeki H, et al. Thymus and activation-regulated chemokine in atopic dermatitis: serum thymus and activation-regulated chemokine level is closely related with disease activity. J Allergy Clin Immunol. 2001;107(3):535–41.PubMedCrossRefGoogle Scholar
  30. 30.
    Kakinuma T, Nakamura K, Wakugawa M, Mitsui H, Tada Y, Saeki H, et al. Serum macrophage-derived chemokine (MDC) levels are closely related with the disease activity of atopic dermatitis. Clin Exp Immunol. 2002;127(2):270–3.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Shimada Y, Takehara K, Sato S. Both Th2 and Th1 chemokines (TARC/CCL17, MDC/CCL22, and Mig/CXCL9) are elevated in sera from patients with atopic dermatitis. J Dermatol Sci. 2004;34(3):201–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Shoda T, Futamura K, Kobayashi F, Saito H, Matsumoto K, Matsuda A. Expression of thymus and activation-regulated chemokine (TARC) by human dermal cells, but not epidermal keratinocytes. J Dermatol Sci. 2014;76(2):90–5.PubMedCrossRefGoogle Scholar
  33. 33.
    Nomura T, Terada N, Kim WJ, Nakano K, Fukuda Y, Wakita A, et al. Interleukin-13 induces thymus and activation-regulated chemokine (CCL17) in human peripheral blood mononuclear cells. Cytokine. 2002;20(2):49–55.PubMedCrossRefGoogle Scholar
  34. 34.
    Vestergaard C, Bang K, Gesser B, Yoneyama H, Matsushima K, Larsen CG. A Th2 chemokine, TARC, produced by keratinocytes may recruit CLA+CCR4+ lymphocytes into lesional atopic dermatitis skin. J Invest Dermatol. 2000;115(4):640–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Vulcano M, Albanesi C, Stoppacciaro A, Bagnati R, D'Amico G, Struyf S, et al. Dendritic cells as a major source of macrophage-derived chemokine/CCL22 in vitro and in vivo. Eur J Immunol. 2001;31(3):812–22.PubMedCrossRefGoogle Scholar
  36. 36.
    Wilson SR, Thé L, Batia LM, Beattie K, Katibah GE, McClain SP, et al. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell. 2013;155(2):285–95.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Raap U, Wichmann K, Bruder M, Ständer S, Wedi B, Kapp A, et al. Correlation of IL-31 serum levels with severity of atopic dermatitis. J Allergy Clin Immunol. 2008;122(2):421–3.PubMedCrossRefGoogle Scholar
  38. 38.
    Ezzat MH, Hasan ZE, Shaheen KY. Serum measurement of interleukin-31 (IL-31) in paediatric atopic dermatitis: elevated levels correlate with severity scoring. J Eur Acad Dermatol Venereol. 2011;25(3):334–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Dillon SR, Sprecher C, Hammond A, Bilsborough J, Rosenfeld-Franklin M, Presnell SR, et al. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol. 2004;5(7):752–60.PubMedCrossRefGoogle Scholar
  40. 40.
    Yoshimoto T, Tsutsui H, Tominaga K, Hoshino K, Okamura H, Akira S, et al. IL-18, although antiallergic when administered with IL-12, stimulates IL-4 and histamine release by basophils. Proc Natl Acad Sci U S A. 1999;96(24):13962–6.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Yoshimoto T, Mizutani H, Tsutsui H, Noben-Trauth N, Yamanaka K, Tanaka M, et al. IL-18 induction of IgE: dependence on CD4+ T cells, IL-4 and STAT6. Nat Immunol. 2000;1(2):132–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Tsutsui H, Yoshimoto T, Hayashi N, Mizutani H, Nakanishi K. Induction of allergic inflammation by interleukin-18 in experimental animal models. Immunol Rev. 2004;202:115–38.PubMedCrossRefGoogle Scholar
  43. 43.
    Yoshizawa Y, Nomaguchi H, Izaki S, Kitamura K. Serum cytokine levels in atopic dermatitis. Clin Exp Dermatol. 2002;27(3):225–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23(5):479–90.PubMedCrossRefGoogle Scholar
  45. 45.
    Iikura M, Suto H, Kajiwara N, Oboki K, Ohno T, Okayama Y, et al. IL-33 can promote survival, adhesion and cytokine production in human mast cells. Lab Investig. 2007;87(10):971–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Allakhverdi Z, Smith DE, Comeau MR, Delespesse G. Cutting edge: the ST2 ligand IL-33 potently activates and drives maturation of human mast cells. J Immunol. 2007;179(4):2051–4.PubMedCrossRefGoogle Scholar
  47. 47.
    Liew FY, Pitman NI, McInnes IB. Disease-associated functions of IL-33: the new kid in the IL-1 family. Nat Rev Immunol. 2010;10(2):103–10.PubMedCrossRefGoogle Scholar
  48. 48.
    Pushparaj PN, Tay HK, H’ng SC, Pitman N, Xu D, McKenzie A, et al. The cytokine interleukin-33 mediates anaphylactic shock. Proc Natl Acad Sci U S A. 2009;106(24):9773–8.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Kawakami T, Ando T, Kimura M, Wilson BS, Kawakami Y. Mast cells in atopic dermatitis. Curr Opin Immunol. 2009;21(6):666–78.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Stone KD, Prussin C, Metcalfe DD. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S73–80.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Murota H, Bae S, Hamasaki Y, Maruyama R, Katayama I. Emedastine difumarate inhibits histamine-induced collagen synthesis in dermal fibroblasts. J Investig Allergol Clin Immunol. 2008;18(4):245–52.PubMedGoogle Scholar
  52. 52.
    Otsuka A, Kabashima K. Mast cells and basophils in cutaneous immune responses. Allergy. 2015;70(2):131–40.PubMedCrossRefGoogle Scholar
  53. 53.
    Yamaguchi M, Sayama K, Yano K, Lantz CS, Noben-Trauth N, Ra C, et al. IgE enhances fc epsilon receptor I expression and IgE-dependent release of histamine and lipid mediators from human umbilical cord blood-derived mast cells: synergistic effect of IL-4 and IgE on human mast cell fc epsilon receptor I expression and mediator release. J Immunol. 1999;162(9):5455–65.PubMedGoogle Scholar
  54. 54.
    Ochi H, Hirani WM, Yuan Q, Friend DS, Austen KF, Boyce JA. T helper cell type 2 cytokine-mediated comitogenic responses and CCR3 expression during differentiation of human mast cells in vitro. J Exp Med. 1999;190(2):267–80.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Nakajima T, Matsumoto K, Suto H, Tanaka K, Ebisawa M, Tomita H, et al. Gene expression screening of human mast cells and eosinophils using high-density oligonucleotide probe arrays: abundant expression of major basic protein in mast cells. Blood. 2001;98(4):1127–34.PubMedCrossRefGoogle Scholar
  56. 56.
    Steinhoff M, Neisius U, Ikoma A, Fartasch M, Heyer G, Skov PS, et al. Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin. J Neurosci. 2003;23(15):6176–80.PubMedGoogle Scholar
  57. 57.
    Yang L, Murota H, Serada S, Fujimoto M, Kudo A, Naka T, et al. Histamine contributes to tissue remodeling via periostin expression. J Invest Dermatol. 2014;134(8):2105–13.PubMedCrossRefGoogle Scholar
  58. 58.
    Taniguchi K, Arima K, Masuoka M, Ohta S, Shiraishi H, Ontsuka K, et al. Periostin controls keratinocyte proliferation and differentiation by interacting with the paracrine IL-1α/IL-6 loop. J Invest Dermatol. 2014;134(5):1295–304.PubMedCrossRefGoogle Scholar
  59. 59.
    Niyonsaba F, Ushio H, Hara M, Yokoi H, Tominaga M, Takamori K, et al. Antimicrobial peptides human beta-defensins and cathelicidin LL-37 induce the secretion of a pruritogenic cytokine IL-31 by human mast cells. J Immunol. 2010;184(7):3526–34.PubMedCrossRefGoogle Scholar
  60. 60.
    Hirai H, Tanaka K, Yoshie O, Ogawa K, Kenmotsu K, Takamori Y, et al. Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2. J Exp Med. 2001;193(2):255–61.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Xue L, Salimi M, Panse I, Mjösberg JM, McKenzie AN, Spits H, et al. Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells. J Allergy Clin Immunol. 2014;133(4):1184–94.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Satoh T, Moroi R, Aritake K, Urade Y, Kanai Y, Sumi K, et al. Prostaglandin D2 plays an essential role in chronic allergic inflammation of the skin via CRTH2 receptor. J Immunol. 2006;177(4):2621–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Walsh GM. Eosinophil granule proteins and their role in disease. Curr Opin Hematol. 2001;8(1):28–33.PubMedCrossRefGoogle Scholar
  64. 64.
    Hogan SP, Rosenberg HF, Moqbel R, Phipps S, Foster PS, Lacy P, et al. Eosinophils: biological properties and role in health and disease. Clin Exp Allergy. 2008;38(5):709–50.PubMedCrossRefGoogle Scholar
  65. 65.
    Blanchard C, Rothenberg ME. Biology of the eosinophil. Adv Immunol. 2009;101:81–121.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Kiehl P, Falkenberg K, Vogelbruch M, Kapp A. Tissue eosinophilia in acute and chronic atopic dermatitis: a morphometric approach using quantitative image analysis of immunostaining. Br J Dermatol. 2001;145(5):720–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Jeong CW, Ahn KS, Rho NK, Park YD, Lee DY, Lee JH, et al. Differential in vivo cytokine mRNA expression in lesional skin of intrinsic vs. extrinsic atopic dermatitis patients using semiquantitative RT-PCR. Clin Exp Allergy. 2003;33(12):1717–24.PubMedCrossRefGoogle Scholar
  68. 68.
    Rosenberg HF, Phipps S, Foster PS. Eosinophil trafficking in allergy and asthma. J Allergy Clin Immunol. 2007;119(6):1303–10. quiz 1311-2PubMedCrossRefGoogle Scholar
  69. 69.
    Collins PD, Marleau S, Griffiths-Johnson DA, Jose PJ, Williams TJ. Cooperation between interleukin-5 and the chemokine eotaxin to induce eosinophil accumulation in vivo. J Exp Med. 1995;182(4):1169–74.PubMedCrossRefGoogle Scholar
  70. 70.
    Satoh T, Yokozeki H, Nishioka K. Pathogenic roles of eosinophils in guinea-pig contact sensitivity: regulation of dermal eosinophilia with remotely administered IL-5. Clin Exp Immunol. 2000;122(3):300–7.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Ying S, Meng Q, Barata LT, Robinson DS, Durham SR, Kay AB. Associations between IL-13 and IL-4 (mRNA and protein), vascular cell adhesion molecule-1 expression, and the infiltration of eosinophils, macrophages, and T cells in allergen-induced late-phase cutaneous reactions in atopic subjects. J Immunol. 1997;158(10):5050–7.PubMedGoogle Scholar
  72. 72.
    Miyazaki Y, Satoh T, Nishioka K, Yokozeki H. STAT-6-mediated control of P-selectin by substance P and interleukin-4 in human dermal endothelial cells. Am J Pathol. 2006;169(2):697–707.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Satoh T, Kaneko M, Wu MH, Yokozeki H, Nishioka K. Contribution of selectin ligands to eosinophil recruitment into the skin of patients with atopic dermatitis. Eur J Immunol. 2002;32(5):1274–81.PubMedCrossRefGoogle Scholar
  74. 74.
    Schleimer RP, Sterbinsky SA, Kaiser J, Bickel CA, Klunk DA, Tomioka K, et al. IL-4 induces adherence of human eosinophils and basophils but not neutrophils to endothelium. Association with expression of VCAM-1. J Immunol. 1992;148(4):1086–92.PubMedGoogle Scholar
  75. 75.
    Mochizuki M, Bartels J, Mallet AI, Christophers E, Schröder JM. IL-4 induces eotaxin: a possible mechanism of selective eosinophil recruitment in helminth infection and atopy. J Immunol. 1998;160(1):60–8.PubMedGoogle Scholar
  76. 76.
    Dulkys Y, Schramm G, Kimmig D, Knöss S, Weyergraf A, Kapp A, et al. Detection of mRNA for eotaxin-2 and eotaxin-3 in human dermal fibroblasts and their distinct activation profile on human eosinophils. J Invest Dermatol. 2001;116(4):498–505.PubMedCrossRefGoogle Scholar
  77. 77.
    Wong CK, Hu S, Cheung PF, Lam CW. Thymic stromal lymphopoietin induces chemotactic and prosurvival effects in eosinophils: implications in allergic inflammation. Am J Respir Cell Mol Biol. 2010;43(3):305–15.PubMedCrossRefGoogle Scholar
  78. 78.
    Fukuoka M, Ogino Y, Sato H, Ohta T, Komoriya K, Nishioka K, et al. RANTES expression in psoriatic skin, and regulation of RANTES and IL-8 production in cultured epidermal keratinocytes by active vitamin D3 (tacalcitol). Br J Dermatol. 1998;138(1):63–70.PubMedCrossRefGoogle Scholar
  79. 79.
    Asakura H, Kashio Y, Nakamura K, Seki M, Dai S, Shirato Y, et al. Selective eosinophil adhesion to fibroblast via IFN-gamma-induced galectin-9. J Immunol. 2002;169(10):5912–8.PubMedCrossRefGoogle Scholar
  80. 80.
    Kameyoshi Y, Dörschner A, Mallet AI, Christophers E, Schröder JM. Cytokine RANTES released by thrombin-stimulated platelets is a potent attractant for human eosinophils. J Exp Med. 1992;176(2):587–92.PubMedCrossRefGoogle Scholar
  81. 81.
    Matsumoto R, Matsumoto H, Seki M, Hata M, Asano Y, Kanegasaki S, et al. Human ecalectin, a variant of human galectin-9, is a novel eosinophil chemoattractant produced by T lymphocytes. J Biol Chem. 1998;273(27):16976–84.PubMedCrossRefGoogle Scholar
  82. 82.
    Jinquan T, Jing C, Jacobi HH, Reimert CM, Millner A, Quan S, et al. CXCR3 expression and activation of eosinophils: role of IFN-gamma-inducible protein-10 and monokine induced by IFN-gamma. J Immunol. 2000;165(3):1548–56.PubMedCrossRefGoogle Scholar
  83. 83.
    Grewe M, Czech W, Morita A, Werfel T, Klammer M, Kapp A, et al. Human eosinophils produce biologically active IL-12: implications for control of T cell responses. J Immunol. 1998;161(1):415–20.PubMedGoogle Scholar
  84. 84.
    Beck LA, Dalke S, Leiferman KM, Bickel CA, Hamilton R, Rosen H, et al. Cutaneous injection of RANTES causes eosinophil recruitment: comparison of nonallergic and allergic human subjects. J Immunol. 1997;159(6):2962–72.PubMedGoogle Scholar
  85. 85.
    Oldhoff JM, Darsow U, Werfel T, Katzer K, Wulf A, Laifaoui J, et al. Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy. 2005;60(5):693–6.PubMedCrossRefGoogle Scholar
  86. 86.
    Levi-Schaffer F, Garbuzenko E, Rubin A, Reich R, Pickholz D, Gillery P, et al. Human eosinophils regulate human lung- and skin-derived fibroblast properties in vitro: a role for transforming growth factor beta (TGF-beta). Proc Natl Acad Sci U S A. 1999;96(17):9660–5.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Horiuchi T, Weller PF. Expression of vascular endothelial growth factor by human eosinophils: upregulation by granulocyte macrophage colony-stimulating factor and interleukin-5. Am J Respir Cell Mol Biol. 1997;17(1):70–7.PubMedCrossRefGoogle Scholar
  88. 88.
    Schwingshackl A, Duszyk M, Brown N, Moqbel R. Human eosinophils release matrix metalloproteinase-9 on stimulation with TNF-alpha. J Allergy Clin Immunol. 1999;104(5):983–9.PubMedCrossRefGoogle Scholar
  89. 89.
    Hoshino M, Takahashi M, Aoike N. Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin immunoreactivity in asthmatic airways and its relationship to angiogenesis. J Allergy Clin Immunol. 2001;107(2):295–301.PubMedCrossRefGoogle Scholar
  90. 90.
    Phipps S, Ying S, Wangoo A, Ong YE, Levi-Schaffer F, Kay AB. The relationship between allergen-induced tissue eosinophilia and markers of repair and remodeling in human atopic skin. J Immunol. 2002;169(8):4604–12.PubMedCrossRefGoogle Scholar
  91. 91.
    Phipps S, Flood-Page P, Menzies-Gow A, Ong YE, Kay AB. Intravenous anti-IL-5 monoclonal antibody reduces eosinophils and tenascin deposition in allergen-challenged human atopic skin. J Invest Dermatol. 2004;122(6):1406–12.PubMedCrossRefGoogle Scholar
  92. 92.
    Hashimoto T, Satoh T, Yokozeki H. Protective role of STAT6 in basophil-dependent Prurigo-like allergic skin inflammation. J Immunol. 2015;194(10):4631–40.PubMedCrossRefGoogle Scholar
  93. 93.
    Lee JJ, Protheroe CA, Luo H, Ochkur SI, Scott GD, Zellner KR, et al. Eosinophil-dependent skin innervation and itching following contact toxicant exposure in mice. J Allergy Clin Immunol. 2015;135(2):477–87.PubMedCrossRefGoogle Scholar
  94. 94.
    Foster EL, Simpson EL, Fredrikson LJ, Lee JJ, Lee NA, Fryer AD, et al. Eosinophils increase neuron branching in human and murine skin and in vitro. PLoS One. 2011;6(7):e22029.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Fujisawa D, Kashiwakura J, Kita H, Kikukawa Y, Fujitani Y, Sasaki-Sakamoto T, et al. Expression of Mas-related gene X2 on mast cells is upregulated in the skin of patients with severe chronic urticaria. J Allergy Clin Immunol. 2014;134(3):622–633.e9.PubMedCrossRefGoogle Scholar
  96. 96.
    Karasuyama H, Yamanishi Y. Basophils have emerged as a key player in immunity. Curr Opin Immunol. 2014;31:1–7.PubMedCrossRefGoogle Scholar
  97. 97.
    Ito Y, Satoh T, Takayama K, Miyagishi C, Walls AF, Yokozeki H. Basophil recruitment and activation in inflammatory skin diseases. Allergy. 2011;66(8):1107–13.PubMedCrossRefGoogle Scholar
  98. 98.
    Grundström J, Reimer JM, Magnusson SE, Nilsson G, Wernersson S, Hellman L. Human cord blood derived immature basophils show dual characteristics, expressing both basophil and eosinophil associated proteins. PLoS One. 2012;7(10):e48308.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Siracusa MC, Saenz SA, Hill DA, Kim BS, Headley MB, Doering TA, et al. TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature. 2011;477(7363):229–33.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Kepley CL, Andrews RP, Brown DC, Chigaev A, Sklar LA, Oliver JM, et al. Regulation of human basophil adhesion to endothelium under flow conditions: different very late antigen 4 regulation on umbilical cord blood-derived and peripheral blood basophils. J Allergy Clin Immunol. 2002;110(3):469–75.PubMedCrossRefGoogle Scholar
  101. 101.
    Saeki K, Satoh T, Yokozeki H. α(1,3) Fucosyltransferases IV and VII are essential for the initial recruitment of basophils in chronic allergic inflammation. J Invest Dermatol. 2013;133(9):2161–9.PubMedCrossRefGoogle Scholar
  102. 102.
    Garcia-Zepeda EA, Combadiere C, Rothenberg ME, Sarafi MN, Lavigne F, Hamid Q, et al. Human monocyte chemoattractant protein (MCP)-4 is a novel CC chemokine with activities on monocytes, eosinophils, and basophils induced in allergic and nonallergic inflammation that signals through the CC chemokine receptors (CCR)-2 and -3. J Immunol. 1996;157(12):5613–26.PubMedGoogle Scholar
  103. 103.
    Iikura M, Ebisawa M, Yamaguchi M, Tachimoto H, Ohta K, Yamamoto K, et al. Transendothelial migration of human basophils. J Immunol. 2004;173(8):5189–95.PubMedCrossRefGoogle Scholar
  104. 104.
    Mommert S, Kleiner S, Gehring M, Eiz-Vesper B, Stark H, Gutzmer R, et al. Human basophil chemotaxis and activation are regulated via the histamine H4 receptor. Allergy. 2016;71(9):1264–73.PubMedCrossRefGoogle Scholar
  105. 105.
    Hida S, Yamasaki S, Sakamoto Y, Takamoto M, Obata K, Takai T, et al. Fc receptor gamma-chain, a constitutive component of the IL-3 receptor, is required for IL-3-induced IL-4 production in basophils. Nat Immunol. 2009;10(2):214–22.PubMedCrossRefGoogle Scholar
  106. 106.
    MacGlashan D Jr, White JM, Huang SK, Ono SJ, Schroeder JT, Lichtenstein LM. Secretion of IL-4 from human basophils. The relationship between IL-4 mRNA and protein in resting and stimulated basophils. J Immunol. 1994;152(6):3006–16.PubMedGoogle Scholar
  107. 107.
    Gibbs BF, Haas H, Falcone FH, Albrecht C, Vollrath IB, Noll T, et al. Purified human peripheral blood basophils release interleukin-13 and preformed interleukin-4 following immunological activation. Eur J Immunol. 1996;26(10):2493–8.PubMedCrossRefGoogle Scholar
  108. 108.
    Ugajin T, Satoh T, Kanamori T, Aritake K, Urade Y, Yokozeki H. FcεRI, but not FcγR, signals induce prostaglandin D2 and E2 production from basophils. Am J Pathol. 2011;179(2):775–82.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Otsuka A, Nakajima S, Kubo M, Egawa G, Honda T, Kitoh A, et al. Basophils are required for the induction of Th2 immunity to haptens and peptide antigens. Nat Commun. 2013;4:1739.PubMedCrossRefGoogle Scholar
  110. 110.
    Kitzmüller C, Nagl B, Deifl S, Walterskirchen C, Jahn-Schmid B, Zlabinger GJ, et al. Human blood basophils do not act as antigen-presenting cells for the major birch pollen allergen Bet v 1. Allergy. 2012;67(5):593–600.PubMedCrossRefGoogle Scholar
  111. 111.
    Eckl-Dorna J, Ellinger A, Blatt K, Ghanim V, Steiner I, Pavelka M, et al. Basophils are not the key antigen-presenting cells in allergic patients. Allergy. 2012;67(5):601–8.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Sharma M, Hegde P, Aimanianda V, Beau R, Maddur MS, Sénéchal H, et al. Circulating human basophils lack the features of professional antigen presenting cells. Sci Rep. 2013;3:1188.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Macfarlane AJ, Kon OM, Smith SJ, Zeibecoglou K, Khan LN, Barata LT, et al. Basophils, eosinophils, and mast cells in atopic and nonatopic asthma and in late-phase allergic reactions in the lung and skin. J Allergy Clin Immunol. 2000;105(1 Pt 1):99–107.PubMedCrossRefGoogle Scholar
  114. 114.
    Ying S, Robinson DS, Meng Q, Barata LT, McEuen AR, Buckley MG, et al. C-C chemokines in allergen-induced late-phase cutaneous responses in atopic subjects: association of eotaxin with early 6-hour eosinophils, and of eotaxin-2 and monocyte chemoattractant protein-4 with the later 24-hour tissue eosinophilia, and relationship to basophils and other C-C chemokines (monocyte chemoattractant protein-3 and RANTES). J Immunol. 1999;163(7):3976–84.PubMedGoogle Scholar
  115. 115.
    Cheng LE, Sullivan BM, Retana LE, Allen CD, Liang HE, Locksley RM. IgE-activated basophils regulate eosinophil tissue entry by modulating endothelial function. J Exp Med. 2015;212(4):513–24.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Obata K, Mukai K, Tsujimura Y, Ishiwata K, Kawano Y, Minegishi Y, et al. Basophils are essential initiators of a novel type of chronic allergic inflammation. Blood. 2007;110(3):913–20.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of Dermatology, Graduate SchoolTokyo Medical and Dental UniversityTokyoJapan
  2. 2.Department of DermatologyNational Defense Medical CollegeSaitamaJapan

Personalised recommendations