Eosinophils in mucosal immune responses

Mucosal Immunology

Volumn 8, Issue 3, 2015, Pages 464-475

  Travers, J ^a   Rothenberg, M E ^a  

^a CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BENRALIZUMAB; BERTILIMUMAB; CCAAT ENHANCER BINDING PROTEIN ALPHA; CHEMOKINE RECEPTOR CCR3; DESMOGLEIN 1; EOSINOPHIL CATIONIC PROTEIN; EOSINOPHIL PEROXIDASE; EOSINOPHIL PROTEIN X; EOTAXIN; EOTAXIN 2; EOTAXIN 3; FC RECEPTOR; IMMUNOGLOBULIN A; INTERLEUKIN 12; INTERLEUKIN 13 RECEPTOR ALPHA1; INTERLEUKIN 25; INTERLEUKIN 33; INTERLEUKIN 4; INTERLEUKIN 5; MACROPHAGE DERIVED CHEMOKINE; MAJOR BASIC PROTEIN; MEPOLIZUMAB; RESLIZUMAB; STAT6 PROTEIN; THYMUS AND ACTIVATION REGULATED CHEMOKINE; TOLL LIKE RECEPTOR; TRANSCRIPTION FACTOR GATA 1; TRANSCRIPTION FACTOR RUNX2; TRANSFORMING GROWTH FACTOR BETA; UNINDEXED DRUG; CYTOKINE; IMMUNOLOGIC FACTOR; MONOCLONAL ANTIBODY;

ADAPTIVE IMMUNITY; ALLERGIC ASTHMA; ASTHMA; BINDING AFFINITY; CELL DIFFERENTIATION; CELL SURVIVAL; CLINICAL FEATURE; CYTOKINE PRODUCTION; DENDRITIC CELL; DIET THERAPY; EOSINOPHIL; EOSINOPHILIC COLITIS; EOSINOPHILIC ENTERITIS; EOSINOPHILIC ESOPHAGITIS; GENE FUNCTION; GENETIC TRANSCRIPTION; GENETIC VARIABILITY; HOMEOSTASIS; HOST RESISTANCE; HUMAN; IMMUNE RESPONSE; IMMUNOMODULATION; INFLAMMATORY BOWEL DISEASE; INNATE IMMUNITY; LEUKOCYTE FUNCTION; MAST CELL; MUCOSAL IMMUNITY; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN SYNTHESIS; REGULATORY MECHANISM; REVIEW; TH1 CELL; TISSUE REPAIR; ANIMAL; DRUG EFFECTS; ENTERITIS; EOSINOPHILIA; GASTRITIS; GENE EXPRESSION; GENETICS; IMMUNOLOGY; INFLAMMATORY BOWEL DISEASES; PATHOLOGY;

ADAPTIVE IMMUNITY; ANIMALS; ANTIBODIES, MONOCLONAL; ASTHMA; CYTOKINES; ENTERITIS; EOSINOPHILIA; EOSINOPHILIC ESOPHAGITIS; EOSINOPHILS; GASTRITIS; GENE EXPRESSION; HOMEOSTASIS; HUMANS; IMMUNITY, INNATE; IMMUNITY, MUCOSAL; IMMUNOLOGIC FACTORS; INFLAMMATORY BOWEL DISEASES;

EID: 84928879692     PISSN: 19330219     EISSN: 19353456     Source Type: Journal    
DOI: 10.1038/mi.2015.2     Document Type: Review

References (156)

1. Rosenberg, H.F., Dyer, K.D. & Foster, P.S. Eosinophils: changing perspectives in health and disease. Nat. Rev. Immunol. 13, 9-22 (2013).
2. de Andres, B. et al. Lack of fc-epsilon receptors on murine eosinophils: implications for the functional significance of elevated IgE and eosinophils in parasitic infections. Blood 89, 3826-3836 (1997).
3. Rothenberg, M.E. & Hogan, S.P. The eosinophil. Annu. Rev. Immunol. 24, 147-174 (2006).
4. Wu, D. et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332, 243-247 (2011).
5. Wang, H.B. & Weller, P.F. Pivotal advance: eosinophils mediate early alum adjuvant-elicited b cell priming and IgM production. J. Leukoc. Biol. 83, 817-821 (2008).
6. Qiu, Y. et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157, 1292-1308 (2014).
7. Moqbel, R. & Lacy, P. Exocytotic events in eosinophils andmast cells. Clin. Exp. Allergy 29, 1017-1022 (1999).
8. Mori, Y. et al. Identification of the human eosinophil lineage-committed progenitor: revision of phenotypic definition of the human common myeloid progenitor. J. Exp. Med. 206, 183-193 (2009).
9. Dent, L.A., Strath, M., Mellor, A.L. & Sanderson., C.J. Eosinophilia in transgenic mice expressing interleukin 5. J. Exp. Med. 172, 1425-1431 (1990).
10. Kopf, M. et al. Il-5-deficient mice have a developmental defect in CD5+ B-1 cells and lack eosinophilia but have normal antibody and cytotoxic T cell responses. Immunity 4, 15-24 (1996).
11. Yoshida, T. et al. Defective B-1 cell development and impaired immunity against angiostrongylus cantonensis in IL-5R alpha-deficient mice. Immunity 4, 483-494 (1996).
12. Yu, C. et al. Targeted deletion of a high-affinity GATA-binding site in the GATA-1 promoter leads to selective loss of the eosinophil lineage in vivo. J. Exp. Med. 195, 1387-1395 (2002).
13. Uhm, T.G., Kim, B.S. & Chung, I.Y. Eosinophil development, regulation of eosinophil-specific genes, and role of eosinophils in the pathogenesis of asthma. Allergy Asthma Immunol. Res. 4, 68-79 (2012).
14. Ben Baruch-Morgenstern, N. et al. Paired immunoglobulin-like receptor A is an intrinsic, self-limiting suppressor of IL-5-induced eosinophil development. Nat. Immunol. 15, 36-44 (2014).
15. Ackerman, S.J. & Bochner, B.S. Mechanisms of eosinophilia in the pathogenesis of hypereosinophilic disorders. Immunol. Allergy Clin. North Am. 27, 357-375 (2007).
16. Wen, T., Besse, J.A., Mingler, M.K., Fulkerson, P.C. & Rothenberg, M.E. Eosinophil adoptive transfer system to directly evaluate pulmonary eosinophil trafficking in vivo. Proc. Natl. Acad. Sci. USA 110, 6067-6072 (2013).
17. Farahi, N. et al. Use of 111-indium-labeled autologous eosinophils to establish the in vivo kinetics of human eosinophils in healthy subjects. Blood 120, 4068-4071 (2012).
18. Jacobsen, E.A. et al. Eosinophil activities modulate the immune/inflammatory character of allergic respiratory responses in mice. Allergy 69, 315-327 (2014).
19. Pope, S.M. et al. Identification of a cooperative mechanism involving interleukin-13 and eotaxin-2 in experimental allergic lung inflammation. J. Biol. Chem. 280, 13952-13961 (2005).
20. Ye, J., Mayer, K.L., Mayer, M.R. & Stone, M.J. NMRsolution structure and backbone dynamics of the CC chemokine eotaxin-3. Biochemistry 40, 7820-7831 (2001).
21. Matthews, A.N. et al. Eotaxin is required for the baseline level of tissue eosinophils. Proc. Natl. Acad. Sci. USA 95, 6273-6278 (1998).
22. Waddell, A. et al. Colonic eosinophilic inflammation in experimental colitis is mediated by Ly6C(high) CCR2(+) inflammatory monocyte/macrophage-derived CCL11. J. Immunol. 186, 5993-6003 (2011).
23. Waddell, A. et al. Intestinal CCL11 and eosinophilic inflammation is regulated by myeloid cell-specific RelA/p65 in mice. J. Immunol. 190, 4773-4785 (2013).
24. Ahrens, R. et al. Intestinal macrophage/epithelial cell-derived CCL11/eotaxin-1 mediates eosinophil recruitment and function in pediatric ulcerative colitis. J. Immunol. 181, 7390-7399 (2008).
25. Humbles, A.A. et al. The murine CCR3 receptor regulates both the role of eosinophils and mast cells in allergen-induced airway inflammation and hyperresponsiveness. Proc. Natl. Acad. Sci. USA 99, 1479-1484 (2002).
26. Munitz, A., McBride, M.L., Bernstein, J.S. & Rothenberg, M.E. A dual activation and inhibition role for the paired immunoglobulin-like receptorB in eosinophils. Blood 111, 5694-5703 (2008).
27. Mould, A.W., Matthaei, K.I., Young, I.G. & Foster, P.S. Relationship between interleukin-5 and eotaxin in regulating blood and tissue eosinophilia in mice. J. Clin. Invest. 99, 1064-1071 (1997).
28. Nussbaum, J.C. et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502, 245-248 (2013).
29. Ziegler, S.F., Roan, F., Bell, B.D., Stoklasek, T.A., Kitajima, M. & Han, H. The biology of thymic stromal lymphopoietin (TSLP). Adv. Pharmacol. 66, 129-155 (2013).
30. Siracusa, M.C. et al. TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature 477, 229-233 (2011).
31. Schuijs, M.J., Willart, M.A., Hammad, H. & Lambrecht, B.N. Cytokine targets in airway inflammation. Curr. Opin. Pharmacol. 13, 351-361 (2013).
32. Mjosberg, J.M. et al. Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat. Immunol. 12, 1055-1062 (2011).
33. Wong, C.K., Hu, S., Cheung, P.F. & Lam, C.W. Thymic stromal lymphopoietin induces chemotactic and prosurvival effects in eosinophils: implications in allergic inflammation. Am. J. Respir. Cell Mol. Biol. 43, 305-315 (2010).
34. Bouffi, C. et al. IL-33 markedly activates murine eosinophils by an NF-kappaB-dependent mechanism differentially dependent upon an IL-4-driven autoinflammatory loop. J. Immunol. 191, 4317-4325 (2013).
35. Cherry, W.B., Yoon, J., Bartemes, K.R., Iijima, K. & Kita, H. A novel IL-1 family cytokine, IL-33, potently activates human eosinophils. J. Allergy Clin. Immunol. 121, 1484-1490 (2008).
36. Akuthota, P., Wang, H. & Weller, P.F. Eosinophils as antigen-presenting cells in allergic upper airway disease. Curr. Opin. Allergy Clin. Immunol. 10, 14-19 (2010).
37. Wang, H.B., Ghiran, I., Matthaei, K. & Weller, P.F. Airway eosinophils: allergic inflammation recruited professional antigen-presenting cells. J. Immunol. 179, 7585-7592 (2007).
38. Padigel, U.M. et al. Eosinophils act as antigen-presenting cells to induce immunity to strongyloides stercoralis in mice. J. Infect. Dis. 196, 1844-1851 (2007).
39. Lucey, D.R., Nicholson-Weller, A. & Weller, P.F. Mature human eosinophils have the capacity to express HLA-DR. Proc. Natl. Acad. Sci. USA 86, 1348-1351 (1989).
40. Yang, D., Rosenberg, H.F., Chen, Q., Dyer, K.D., Kurosaka, K. & Oppenheim, J.J. Eosinophil-derived neurotoxin (EDN), an antimicrobial protein with chemotactic activities for dendritic cells. Blood 102, 3396-3403 (2003).
41. Chu, D.K. et al. Indigenous enteric eosinophils control DCs to initiate a primary Th2 immune response in vivo. J. Exp. Med. 211, 1657-1672 (2014).
42. Yang, D. et al. Human ribonuclease a superfamily members, eosinophilderived neurotoxin and pancreatic ribonuclease, induce dendritic cell maturation and activation. J. Immunol. 173, 6134-6142 (2004).
43. Yang, D. et al. Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2-MYD88 signal pathway in dendritic cells and enhances Th2 immune responses. J. Exp. Med. 205, 79-90 (2008).
44. Jacobsen, E.A. et al. Allergic pulmonary inflammation in mice is dependent on eosinophil-induced recruitment of effector T cells. J. Exp. Med. 205, 699-710 (2008).
45. Odemuyiwa, S.O. et al. Cutting edge: human eosinophils regulate T cell subset selection through indoleamine 2,3-dioxygenase. J. Immunol. 173, 5909-5913 (2004).
46. Jordan, M.B., Mills, D.M., Kappler, J., Marrack, P. & Cambier, J.C. Promotion of B cell immune responses via an alum-induced myeloid cell population. Science 304, 1808-1810 (2004).
47. Wong, T.W., Doyle, A.D., Lee, J.J. & Jelinek, D.F. Eosinophils regulate peripheral B cell numbers in both mice and humans. J. Immunol. 192, 3548-3558 (2014).
48. McKee, A.S. et al. Alum induces innate immune responses through macrophage and mast cell sensors, but these sensors are not required for alum to act as an adjuvant for specific immunity. J. Immunol. 183, 4403-4414 (2009).
49. Chawla, A., Nguyen, K.D. & Goh, Y.P. Macrophage-mediated inflammation in metabolic disease. Nat. Rev. Immunol. 11, 738-749 (2011).
50. Molofsky, A.B. et al. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J. Exp. Med. 210, 535-549 (2013).
51. Chu, V.T. et al. Eosinophils are required for the maintenance of plasma cells in the bone marrow. Nat. Immunol. 12, 151-159 (2011).
52. Chu, V.T. & Berek, C. Immunization induces activation of bone marrow eosinophils required for plasma cell survival. Eur. J. Immunol. 42, 130-137 (2012).
53. Chu, V.T. et al. Eosinophils promote generation and maintenance of immunoglobulin-A-expressing plasma cells and contribute to gut immune homeostasis. Immunity 40, 582-593 (2014).
54. Jung, Y. et al. Il-1β in eosinophil-mediated small intestinal homeostasis and IgA production. Mucosal Immun; e-pub ahead of print (2015).
55. Stokes, C.R., Soothill, J.F. & Turner, M.W. Immune exclusion is a function of IgA. Nature 255, 745-746 (1975).
56. Weltzin, R., Lucia-Jandris, P., Michetti, P., Fields, B.N., Kraehenbuhl, J.P. & Neutra, M.R. Binding and transepithelial transport of immunoglobulins by intestinal M cells: demonstration using monoclonal IgA antibodies against enteric viral proteins. J. Cell. Biol. 108, 1673-1685 (1989).
57. Taliaferro, W.H. & Sarles, M.P. The cellular reactions in the skin, lungs and intestine of normal and immune rats after infection with nippostrongylus muris. J. Infect. Dis. 64, 157-192 (1939).
58. Tischendorf, F.W., Brattig, N.W., Buttner, D.W., Pieper, A. & Lintzel, M. Serum levels of eosinophil cationic protein, eosinophil-derived neurotoxin and myeloperoxidase in infections with filariae and schistosomes. Acta Trop. 62, 171-182 (1996).
59. Sturrock, R.F. et al. Observations on possible immunity to reinfection among kenyan schoolchildren after treatment for schistosoma mansoni. Trans. R. Soc. Trop. Med. Hyg. 77, 363-371 (1983).
60. Waters, L.S., Taverne, J., Tai, P.C., Spry, C.J., Targett, G.A. & Playfair, J.H. Killing of plasmodium falciparum by eosinophil secretory products. Infect. Immun. 55, 877-881 (1987).
61. Singh, A. & Batra, J.K. Role of unique basic residues in cytotoxic, antibacterial and antiparasitic activities of human eosinophil cationic protein. Biol. Chem. 392, 337-346 (2011).
62. Butterworth, A.E., Wassom, D.L., Gleich, G.J., Loegering, D.A. & David, J.R. Damage to schistosomula of schistosoma mansoni induced directly by eosinophil major basic protein. J. Immunol. 122, 221-229 (1979).
63. Wassom, D.L. & Gleich, G.J. Damageto Trichinella spiralis newbornlarvaeby eosinophilmajor basic protein. Am. J. Trop. Med. Hyg. 28, 860-863 (1979).
64. Butterworth, A.E. et al. Antibody-dependent eosinophil-mediated damage to 51Cr-labeled schistosomula of Schistosoma mansoni: damage by purieid eosinophils. J. Exp. Med. 145, 136-150 (1977).
65. Rotman, H.L. et al. Strongyloides stercoralis: eosinophil-dependent immune-mediated killing of third stage larvae in BALB/cByJ mice. Exp. Parasitol. 82, 267-278 (1996).
66. Lange, A.M., Yutanawiboonchai, W., Scott, P. & Abraham, D. IL-4- and IL-5-dependent protective immunity to Onchocerca volvulus infective larvae in BALB/cBYJ mice. J. Immunol. 153, 205-211 (1994).
67. Meeusen, E.N. & Balic, A. Do eosinophils have a role in the killing of helminth parasites? Parasitol. Today 16, 95-101 (2000).
68. Fabre, V. et al. Eosinophil deficiency compromises parasite survival in chronic nematode infection. J. Immunol. 182, 1577-1583 (2009).
69. Gil, H., Magy, N., Mauny, F. & Dupond, J.L. Value of eosinopenia in inflammatory disorders: an "old" marker revisited. Rev. Med. Interne 24, 431-435 (2003).
70. Bass, D.A. Behavior of eosinophil leukocytes in acute inflammation. II. Eosinophil dynamics during acute inflammation. J. Clin. Invest. 56, 870-879 (1975).
71. Linch, S.N., Kelly, A.M., Danielson, E.T., Pero, R., Lee, J.J. & Gold, J.A. Mouse eosinophils possess potent antibacterial properties in vivo. Infect. Immun. 77, 4976-4982 (2009).
72. Lehrer, R.I., Szklarek, D., Barton, A., Ganz, T., Hamann, K.J. & Gleich, G.J. Antibacterial properties of eosinophil major basic protein and eosinophil cationic protein. J. Immunol. 142, 4428-4434 (1989).
73. Persson, T., Andersson, P., Bodelsson, M., Laurell, M., Malm, J. & Egesten, A. Bactericidal activity of human eosinophilic granulocytes against Escherichia coli. Infect. Immun. 69, 3591-3596 (2001).
74. Yousefi, S. et al. Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense. Nat. Med. 14, 949-953 (2008).
75. Yazdanbakhsh, M., Eckmann, C.M., Bot, A.A. & Roos, D. Bactericidal action of eosinophils from normal human blood. Infect. Immun. 53, 192-198 (1986).
76. Phipps, S. et al. Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus. Blood 110, 1578-1586 (2007).
77. Adamko, D.J., Yost, B.L., Gleich, G.J., Fryer, A.D. & Jacoby, D.B. Ovalbumin sensitization changes the inflammatory response to subsequent parainfluenza infection. Eosinophils mediate airway hyperresponsiveness, M(2) muscarinic receptor dysfunction, and antiviral effects. J. Exp. Med. 190, 1465-1478 (1999).
78. Domachowske, J.B., Dyer, K.D., Bonville, C.A. & Rosenberg, H.F. Recombinant human eosinophil-derived neurotoxin/RNase 2 functions as an effective antiviral agent against respiratory syncytial virus. J. Infect. Dis. 177, 1458-1464 (1998).
79. Castilow, E.M., Legge, K.L. & Varga, S.M. Cutting edge: eosinophils do not contribute to respiratory syncytial virus vaccine-enhanced disease. J. Immunol. 181, 6692-6696 (2008).
80. Ochkur, S.I. et al. Coexpression of IL-5 and eotaxin-2 in mice creates an eosinophil-dependent model of respiratory inflammation with characteristics of severe asthma. J. Immunol. 178, 7879-7889 (2007).
81. Bochner, B.S. & Gleich, G.J. What targeting eosinophils has taught us about their role in diseases. J. Allergy Clin. Immunol. 126, 16-25. quiz 26-17 (2010).
82. Lee, J.J. et al. Defining a link with asthma in mice congenitally deficient in eosinophils. Science 305, 1773-1776 (2004).
83. Song, D.J. et al. Anti-Siglec-F antibody reduces allergen-induced eosinophilic inflammation and airway remodeling. J. Immunol. 183, 5333-5341 (2009).
84. Walsh, E.R. et al. Strain-specific requirement for eosinophils in the recruitment of T cells to the lung during the development of allergic asthma. J. Exp. Med. 205, 1285-1292 (2008).
85. Kotsimbos, T.C., Ernst, P. & Hamid, Q.A. Interleukin-13 and interleukin-4 are coexpressed in atopic asthma. Proc. Assoc. Am. Physicians 108, 368-373 (1996).
86. Naseer, T. et al. Expression of IL-12 and IL-13 mRNA in asthma and their modulation in response to steroid therapy. Am. J. Respir. Crit. Care Med. 155, 845-851 (1997).
87. Prieto, J. et al. Increased interleukin-13 mRNA expression in bronchoalveolar lavage cells of atopic patients with mild asthma after repeated low-dose allergen provocations. Respir. Med. 94, 806-814 (2000).
88. Walsh, E.R., Thakar, J., Stokes, K., Huang, F., Albert, R. & August, A. Computational and experimental analysis reveals a requirement for eosinophil-derived IL-13 for the development of allergic airway responses in C57BL/6 mice. J. Immunol. 186, 2936-2949 (2011).
89. Mattes, J. et al. Intrinsic defect in Tcell production of interleukin (IL)-13 in the absence of both IL-5 and eotaxin precludes the development of eosinophilia and airways hyperreactivity in experimental asthma. J. Exp. Med. 195, 1433-1444 (2002).
90. Solomon, A. et al. Nerve growth factor is preformed in and activates human peripheral blood eosinophils. J. Allergy Clin. Immunol. 102, 454-460 (1998).
91. Piliponsky, A.M., Gleich, G.J., Bar, I. & Levi-Schaffer, F. Effects of eosinophils on mast cells: a new pathway for the perpetuation of allergic inflammation. Mol. Immunol. 38, 1369-1372 (2002).
92. Piliponsky, A.M., Gleich, G.J., Nagler, A., Bar, I. & Levi-Schaffer, F. Non-IgE-dependent activation of human lung-and cord blood-derived mast cells is induced by eosinophil major basic protein and modulated by the membrane form of stem cell factor. Blood 101, 1898-1904 (2003).
93. Furuta, G.T., Ackerman, S.J., Lu, L., Williams, R.E. & Wershil, B.K. Stem cell factor influences mast cell mediator release in response to eosinophilderived granule major basic protein. Blood 92, 1055-1061 (1998).
94. Wilson, S.J., Rigden, H.M., Ward, J.A., Laviolette, M., Jarjour, N.N. & Djukanovic., R. The relationship between eosinophilia and airway remodelling in mild asthma. Clin. Exp. Allergy 43, 1342-1350 (2013).
95. Evans, C.M., Fryer, A.D., Jacoby, D.B., Gleich, G.J. & Costello, R.W. Pretreatment with antibody to eosinophil major basic protein prevents hyperresponsiveness by protecting neuronal M2 muscarinic receptors in antigen-challenged guinea pigs. J. Clin. Invest. 100, 2254-2262 (1997).
96. Fryer, A.D. et al. Neuronal eotaxin and the effects of CCR3 antagonist on airway hyperreactivity and M2 receptor dysfunction. J. Clin. Invest. 116, 228-236 (2006).
97. Cho, J.Y. et al. Inhibition of airway remodeling in IL-5-deficient mice. J. Clin. Invest. 113, 551-560 (2004).
98. Humbles, A.A. et al. A critical role for eosinophils in allergic airways remodeling. Science 305, 1776-1779 (2004).
99. Flood-Page, P. et al. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane ofmild atopic asthmatics. J. Clin. Invest. 112, 1029-1036 (2003).
100. Leckie, M.J. et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356, 2144-2148 (2000).
101. Castro, M. et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am. J. Respir. Crit. Care Med. 184, 1125-1132 (2011).
102. Ortega, H.G. et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N. Engl. J. Med. 371, 1198-1207 (2014).
103. Haldar, P. et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N. Engl. J. Med. 360, 973-984 (2009).
104. Pavord, I.D. et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 380, 651-659 (2012).
105. Bel, E.H. et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N. Engl. J. Med. 371, 1189-1197 (2014).
106. Castro, M. et al. Benralizumab, an anti-interleukin 5 receptor alpha monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir. Med. 2, 879-890 (2014).
107. Gibson, P.G. Inflammatory phenotypes in adult asthma: clinical applications. Clin. Respir. J. 3, 198-206 (2009).
108. Miehlke, S. Clinical features of eosinophilic esophagitis. Dig. Dis. 32, 61-67 (2014).
109. Kagalwalla, A.F. et al. Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis. Clin. Gastroenterol. Hepatol. 4, 1097-1102 (2006).
110. Kagalwalla, A.F. et al. Identificationof specific foodsresponsible for inflammation in children with eosinophilic esophagitis successfully treated with empiric elimination diet. J. Pediatr. Gastroenterol. Nutr. 53, 145-149 (2011).
111. Erwin, E.A., James, H.R., Gutekunst, H.M., Russo, J.M., Kelleher, K.J. & Platts-Mills, T.A. Serum IgE measurement and detection of food allergy in pediatric patients with eosinophilic esophagitis. Ann. Allergy Asthma Immunol. 104, 496-502 (2010).
112. Sugnanam, K.K. et al. Dichotomy of food and inhalant allergen sensitization in eosinophilic esophagitis. Allergy 62, 1257-1260 (2007).
113. Clayton, F. et al. Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE. Gastroenterology 147, 602-609 (2014).
114. Masterson, J.C. et al. Local hypersensitivity reaction in transgenic mice with squamous epithelial IL-5 overexpression provides a novel model of eosinophilic oesophagitis. Gut 63, 43-53 (2014).
115. Mishra, A., Hogan, S.P., Brandt, E.B. & Rothenberg., M.E. An etiological role for aeroallergens and eosinophils in experimental esophagitis. J. Clin. Invest. 107, 83-90 (2001).
116. Mishra, A., Hogan, S.P., Brandt, E.B. & Rothenberg., M.E. IL-5 promotes eosinophil trafficking to the esophagus. J. Immunol. 168, 2464-2469 (2002).
117. Rubinstein, E. et al. Siglec-F inhibition reduces esophageal eosinophilia and angiogenesis in a mouse model of eosinophilic esophagitis. J. Pediatr. Gastroenterol. Nutr. 53, 409-416 (2011).
118. Blanchard, C. et al. IL-13 involvement in eosinophilic esophagitis: transcriptome analysis and reversibility with glucocorticoids. J. Allergy Clin. Immunol. 120, 1292-1300 (2007).
119. Lu, T.X., Munitz, A. & Rothenberg, M.E. Microrna-21 is up-regulated in allergic airway inflammation and regulates iL-12p35 expression. J. Immunol. 182, 4994-5002 (2009).
120. Lexmond, W.S. et al. Involvement of the iNKT cell pathway is associated with early-onset eosinophilic esophagitis and response to allergen avoidance therapy. Am. J. Gastroenterol. 109, 646-657 (2014).
121. Frischmeyer-Guerrerio, P.A. et al. TGFbeta receptor mutations impose a strong predisposition for human allergic disease. Sci. Transl. Med. 5, 195ra194 (2013).
122. Blanchard, C. et al. Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis. J. Clin. Invest. 116, 536-547 (2006).
123. Blanchard, C. et al. Periostin facilitates eosinophil tissue infiltration in allergic lung and esophageal responses. Mucosal. Immunol. 1, 289-296 (2008).
124. Sherrill, J.D. et al. Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis. Mucosal Immunol. 7, 718-729 (2014).
125. Corren, J. et al. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365, 1088-1098 (2011).
126. Mueller, S., Aigner, T., Neureiter, D. & Stolte, M. Eosinophil infiltration and degranulation in oesophageal mucosa from adult patients with eosinophilic oesophagitis: a retrospective and comparative study on pathological biopsy. J. Clin. Pathol. 59, 1175-1180 (2006).
127. Saffari, H. et al. Electron microscopy elucidates eosinophil degranulation patterns in patients with eosinophilic esophagitis. J. Allergy Clin. Immunol. 133, 1728-1734 (2014).
128. Aceves, S.S., Newbury, R.O., Dohil, R., Bastian, J.F. & Broide, D.H. Esophageal remodeling in pediatric eosinophilic esophagitis. J. Allergy Clin. Immunol. 119, 206-212 (2007).
129. Spergel, J. M. et al. Reslizumabinchildren andadolescentswith eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial. J. Allergy Clin. Immunol. 129, 456-463. 463.e451-453 (2012).
130. Straumann, A. et al. Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial. Gut 59, 21-30 (2010).
131. Rothenberg, M.E. et al. Intravenous anti-il-13 mab qax576 for the treatment of eosinophilic esophagitis. J. Allergy Clin. Immunol.; e-pub ahead of print (2014).
132. Blanchard, C. et al. Coordinate interaction between IL-13 and epithelial differentiation cluster genes in eosinophilic esophagitis. J. Immunol. 184, 4033-4041 (2010).
133. Silverman, E.S. et al. Transforming growth factor-beta1 promoter polymorphism C-509T is associated with asthma. Am. J. Respir. Crit. Care Med. 169, 214-219 (2004).
134. Aceves, S.S. et al. Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids. Allergy 65, 109-116 (2010).
135. Abonia, J.P. et al. High prevalence of eosinophilic esophagitis in patients with inherited connective tissue disorders. J. Allergy Clin. Immunol. 132, 378-386 (2013).
136. Henderson, C.J. et al. Increased prevalence of eosinophilic gastrointestinal disorders in pediatric PTEN hamartoma tumor syndromes. J. Pediatr. Gastroenterol. Nutr. 58, 553-560 (2014).
137. Yu, M. et al. Inactivation of TGF-beta signaling and loss of pten cooperate to induce colon cancer in vivo. Oncogene 33, 1538-1547 (2014).
138. Rothenberg, M.E. et al. Common variants at 5q22 associate with pediatric eosinophilic esophagitis. Nat. Genet. 42, 289-291 (2010).
139. Sherrill, J.D. et al. Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis. J. Allergy Clin. Immunol. 126, 160-165. e163 (2010).
140. Noti, M. et al. Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis. Nat. Med. 19, 1005-1013 (2013).
141. Sleiman, PM et al. GWAS identifies four novel eosinophilic esophagitis loci. Nat. Commun. 5, 5593 (2014).
142. Kottyan, L.C. et al. Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease. Nat. Genet. 46, 895-900 (2014).
143. Gauvreau, G.M. et al. Effects of an anti-TSLP antibody on allergeninduced asthmatic responses. N. Engl. J. Med. 370, 2102-2110 (2014).
144. Zamorano, J., Rivas, M.D., Setien, F. & Perez, G.M. Proteolytic regulation of activated STAT6 by calpains. J. Immunol. 174, 2843-2848 (2005).
145. Hayakawa, M., Hayakawa, H., Matsuyama, Y., Tamemoto, H., Okazaki, H. & Tominaga, S. Mature interleukin-33 is produced by calpain-mediated cleavage in vivo. Biochem. Biophys. Res. Commun. 387, 218-222 (2009).
146. Wen, T. et al. Molecular diagnosis of eosinophilic esophagitis by gene expression profiling. Gastroenterology 145, 1289-1299 (2013).
147. Bischoff, S.C., Mayer, J., Nguyen, Q.T., Stolte, M. & Manns, M.P. Immunnohistological assessment of intestinal eosinophil activation in patients with eosinophilic gastroenteritis and inflammatory bowel disease. Am. J. Gastroenterol. 94, 3521-3529 (1999).
148. Saitoh, O. et al. Fecal eosinophil granule-derived proteins reflect disease activity in inflammatory bowel disease. Am. J. Gastroenterol. 94, 3513-3520 (1999).
149. Furuta, G.T. et al. Eosinophils alter colonic epithelial barrier function: role for major basic protein. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G890-G897 (2005).
150. Vieira, A.T. et al. Treatment with a novel chemokine-binding protein or eosinophil lineage-ablation protects mice from experimental colitis. Am. J. Pathol. 175, 2382-2391 (2009).
151. Masterson, J.C. et al. Eosinophil-mediated signalling attenuates inflammatory responses in experimental colitis. Gut; e-pub ahead of print (2014).
152. Masterson, J.C. et al. CCR3 blockade attenuates eosinophilic ileitis and associated remodeling. Am. J. Pathol. 179, 2302-2314 (2011).
153. Coburn, L.A. et al. High-throughput multi-analyte luminex profiling implicates eotaxin-1 in ulcerative colitis. PLoS One 8, e82300 (2013).
154. Kiwamoto, T., Kawasaki, N., Paulson, J.C. & Bochner., B.S. Siglec-8 as a drugable target to treat eosinophil and mast cell-associated conditions. Pharmacol. Ther. 135, 327-336 (2012).
155. Hamann, J. et al. EMR1, the human homolog of F4/80, is an eosinophilspecific receptor. Eur. J. Immunol. 37, 2797-2802 (2007).
156. Legrand, F. et al. The eosinophil surface receptor epidermal growth factorlike module containing mucin-like hormone receptor 1 (EMR1): a novel therapeutic target for eosinophilic disorders. J. Allergy Clin. Immunol. 133, 1439-1447 (2014).