Systemic impact of intestinal helminth infections

Mucosal Immunology

Volumn 7, Issue 4, 2014, Pages 753-762

  Mishra, P K ^a,b   Palma, M ^a,b   Bleich, D ^b   Loke, P ^c   Gause, W C ^a,b  

^a The State University of New Jersey   (United States)

^b RUTGERS NEW JERSEY MEDICAL SCHOOL   (United States)

^c NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GAMMA INTERFERON; INTERLEUKIN 10; INTERLEUKIN 12; INTERLEUKIN 13; INTERLEUKIN 25; INTERLEUKIN 3; INTERLEUKIN 33; INTERLEUKIN 4; INTERLEUKIN 4 RECEPTOR; INTERLEUKIN 5; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA;

ACUTE LUNG INJURY; ADAPTIVE IMMUNITY; ALLERGIC REACTION; ALLERGIC RHINITIS; ANCYLOSTOMA DUODENALE; ASCARIS LUMBRICOIDES; CROHN DISEASE; DENDRITIC CELL; DOWN REGULATION; EOSINOPHILIA; HELIGMOSOMOIDES POLYGYRUS; HELMINTH; HELMINTHIASIS; HOMEOSTASIS; HUMAN; IMMUNE SYSTEM; IMMUNITY; IMMUNOTHERAPY; INFLAMMATION; INFLAMMATORY DISEASE; INNATE IMMUNITY; INSULIN DEPENDENT DIABETES MELLITUS; INSULITIS; INTESTINE FLORA; INTESTINE INFECTION; INTESTINE MUCOSA; LUNG ALVEOLUS MACROPHAGE; METABOLIC SYNDROME X; MICROBIOME; MULTIPLE SCLEROSIS; MYCOBACTERIUM TUBERCULOSIS; NIPPOSTRONGYLUS BRASILIENSIS; NONHUMAN; PLASMODIUM; POPULATION MIGRATION; PRIORITY JOURNAL; REVIEW; SYSTEMIC THERAPY; TRICHINELLA SPIRALIS; TRICHURIS MURIS; TRICHURIS SUIS; TRICHURIS SUIS OVA; TRICHURIS TRICHIURA; ANIMAL; COMPLICATION; DISEASE MODEL; HOST PARASITE INTERACTION; IMMUNOLOGY; INTESTINAL DISEASES, PARASITIC; METABOLISM; MICROBIOLOGY; MICROFLORA; PARASITOLOGY; PATHOLOGY;

ANIMALS; DISEASE MODELS, ANIMAL; HELMINTHIASIS; HOST-PARASITE INTERACTIONS; HUMANS; INFLAMMATION; INTESTINAL DISEASES, PARASITIC; INTESTINAL MUCOSA; METABOLIC SYNDROME X; MICROBIOTA;

EID: 84902586250     PISSN: 19330219     EISSN: 19353456     Source Type: Journal    
DOI: 10.1038/mi.2014.23     Document Type: Review

References (144)

1. de Silva, N.R. et al. Soil-Transmitted helminth infections: Updating the global picture. Trends Parasitol. 19, 547-551 (2003
2. Gulland, F.M. The role of nematode parasites in Soay sheep (Ovis aries L.) mortality during a population crash. Parasitology 105 (Pt 3), 493-503 (1992
3. Gulland, F.M. & Fox, M. Epidemiology of nematode infections of Soay sheep (Ovis aries L.) on St Kilda. Parasitology 105 (Pt 3), 481-492 (1992
4. Li, R.W., Choudhary, R.K., Capuco, A.V. & Urban, J.F. Jr. Exploring the host transcriptome for mechanisms underlying protective immunity and resistance to nematode infections in ruminants. Vet. Parasitol. 190, 1-11 (2012
5. Charlier, J., Hoglund, J., von Samson-Himmelstjerna, G., Dorny, P. & Vercruysse, J. Gastrointestinal nematode infections in adult dairy cattle: Impact on production, diagnosis and control. Vet. Parasitol. 164, 70-79 (2009
6. Valentine, B.A., Cebra, C.K. & Taylor, G.H. Fatal gastrointestinal parasitism in goats: 31 cases (2001-2006). J. Am. Vet. Med. Assoc. 231, 1098-1103 (2007
7. King, C.H. Health metrics for helminthic infections. Adv. Parasitol. 73, 51-69 (2010
8. Jackson, J.A., Friberg, I.M., Little, S. & Bradley, J.E. Review series on helminths, immune modulation and the hygiene hypothesis: Immunity against helminths and immunological phenomena in modern human populations: Coevolutionary legacies?. Immunology 126, 18-27 (2009
9. Gause,W.C., Wynn, T.A. &Allen, J.E. Type 2 immunity andwound healing: Evolutionary refinement of adaptive immunity by helminths. Nat. Rev. Immunol. 13, 607-614 (2013
10. Palm, N.W., Rosenstein, R.K. & Medzhitov, R. Allergic host defences. Nature 484, 465-472 (2012
11. Artis, D., Maizels, R.M. & Finkelman, F.D. Forum: Immunology: Allergy challenged. Nature 484, 458-459 (2012
12. Liang, H.E. et al. Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat. Immunol. 13, 58-66 (2012
13. Moro, K. et al. Innate production of T(H)2 cytokines by adipose tissueassociated c-Kit(+)Sca-1(+) lymphoid cells. Nature 463, 540-544 (2010
14. Saenz, S.A. et al. IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses. Nature 464, 1362-1366 (2010
15. Neill, D.R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367-1370 (2010
16. Wills-Karp, M. & Finkelman, F.D. Innate lymphoid cells wield a doubleedged sword. Nat. Immunol. 12, 1025-1027 (2011
17. Voehringer, D., Reese, T.A., Huang, X., Shinkai, K. & Locksley, R.M. Type 2 immunity is controlled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of the innate immune system. J. Exp Med 203, 1435-1446 (2006
18. van Panhuys, N. et al. Basophils are the major producers of IL-4 during primary helminth infection. J. Immunol. 186, 2719-2728 (2011
19. Rosenberg, H.F., Dyer, K.D. & Foster, P.S. Eosinophils: Changing perspectives in health and disease. Nat. Rev. Immunol. 13, 9-22 (2013
20. Anderson, C.F., Oukka, M., Kuchroo, V.J. & Sacks, D. CD4(+)CD25(-) Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J. Exp. Med. 204, 285-297 (2007
21. Jankovic, D. et al. Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J. Exp. Med. 204, 273-283 (2007
22. Cope, A., Le Friec, G., Cardone, J. & Kemper, C. The Th1 life cycle: Molecular control of IFN-gamma to IL-10 switching. Trends Immunol. 32, 278-286 (2011
23. Hang, L. et al. Heligmosomoides polygyrus bakeri infection activates colonic Foxp3+ T cells enhancing their capacity to prevent colitis. J. Immunol. 191, 1927-1934 (2013
24. Rubtsov, Y.P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546-558 (2008
25. Reynolds, L.A. & Maizels, R.M. Cutting edge: In the absence of TGF-beta signaling in T cells, fewer CD103+ regulatory T cells develop, but exuberant IFN-gamma production renders mice more susceptible to helminth infection. J. Immunol. 189, 1113-1117 (2012
26. Reynolds, L.A., Filbey, K.J. & Maizels, R.M. Immunity to the model intestinal helminth parasite Heligmosomoides polygyrus. Semin. Immunopathol. 34, 829-846 (2012
27. Hubner, M.P. et al. Helminth protection against autoimmune diabetes in nonobese diabetic mice is independent of a type 2 immune shift and requires TGF-beta. J. Immunol. 188, 559-568 (2012
28. Schneider, D.S. & Ayres, J.S. Two ways to survive infection: What resistance and tolerance can teach us about treating infectious diseases. Nat. Rev. Immunol. 8, 889-895 (2008
29. Medzhitov, R., Schneider, D.S. & Soares, M.P. Disease tolerance as a defense strategy. Science 335, 936-941 (2012
30. Chen, F. et al. An essential role for T(H)2-Type responses in limiting acute tissue damage during experimental helminth infection. Nat. Med. 18, 260-266 (2012
31. Pesce, J.T. et al. Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. PLoS Pathog. 5, e1000371 (2009
32. Herbert, D.R. et al. Arginase I suppresses IL-12/IL-23p40-driven intestinal inflammation During acute schistosomiasis. J. Immunol. 184, 6438-6446 (2010
33. Loke, P. & Allison, J.P. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc. Natl. Acad. Sci. USA 100, 5336-5341 (2003
34. deWaal Malefyt, R., Abrams, J., Bennett, B., Figdor, C.G. & de Vries, J.E. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: An autoregulatory role of IL-10 produced by monocytes. J. Exp. Med. 174, 1209-1220 (1991
35. Whyte, C.S. et al. Suppressor of cytokine signaling (SOCS)1 is a key determinant of differential macrophage activation and function. J. Leukoc. Biol. 90, 845-854 (2011
36. Thomas, G.D. et al. The biology of nematode- And IL4Ralpha-dependent murine macrophage polarization in vivo as defined by RNA-Seq and targeted lipidomics. Blood 120, e93-e104 (2012
37. Mosser, D.M. & Edwards, J.P. Exploring the full spectrumofmacrophage activation. Nat. Rev. Immunol. 8, 958-969 (2008
38. Broadhurst, M.J. et al. Upregulation of retinal dehydrogenase 2 in alternatively activated macrophages during retinoid-dependent type-2 immunity to helminth infection inmice. PLoS Pathog. 8, e1002883 (2012
39. Duffield, J.S., Lupher,M., Thannickal, V.J. &Wynn, T.A. Host responses in tissue repair and fibrosis. Annu. Rev. Pathol. 8, 241-276 (2013
40. Borthwick, L.A., Wynn, T.A. & Fisher, A.J. Cytokine mediated tissue fibrosis. Biochim. Biophys. Acta 1832, 1049-1060 (2013
41. Lee, Y.K. &Mazmanian, S.K.Has themicrobiota played a critical role in the evolution of the adaptive immune system?. Science 330, 1768-1773 (2010
42. Matsunaga, T. & Rahman, A. In search of the origin of the thymus: The thymus and GALT may be evolutionarily related. Scand. J. Immunol. 53, 1-6 (2001
43. Saenz, S.A. et al. IL-25 simultaneously elicits distinct populations of innate lymphoid cells andmultipotent progenitor type 2 (MPPtype2) cells. J. Exp. Med. 210, 1823-1837 (2013
44. Siracusa, M.C. et al. TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature 477, 229-233 (2011
45. Schmitz, J. 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 23, 479-490 (2005
46. Chang, Y.J. et al. Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat. Immunol. 12, 631-638 (2011
47. Ikeda, K. et al. Mast cells produce interleukin-25 upon Fc epsilon RImediated activation. Blood 101, 3594-3596 (2003
48. Fock, V. et al. Macrophage-derived IL-33 is a critical factor for placental growth. J. Immunol. 191, 3734-3743 (2013
49. Oboki, K., Nakae, S., Matsumoto, K & Saito, H. IL-33 and Airway Inflammation. Allergy Asthma Immunol. Res. 3, 81-88 (2011
50. Hepworth,M.R. et al. Mast cells orchestrate type 2 immunity to helminths through regulation of tissue-derived cytokines. Proc.Natl. Acad. Sci. USA 109, 6644-6649 (2012
51. Khodoun, M.V., Orekhova, T., Potter, C., Morris, S. & Finkelman, F.D. Basophils initiate IL-4 production During a memory T-dependent response. J. Exp. Med. 200, 857-870 (2004
52. Mitre, E., Taylor, R.T., Kubofcik, J. & Nutman, T.B. Parasite antigen-driven basophils are a major source of IL-4 in human filarial infections. J. Immunol. 172, 2439-2445 (2004
53. Gessner, A.,Mohrs, K. & Mohrs, M. Mast cells, basophils, and eosinophils acquire constitutive IL-4 and IL-13 transcripts during lineage differentiation that are sufficient for rapid cytokine production. J. Immunol. 174, 1063-1072 (2005
54. Voehringer, D., Shinkai, K. & Locksley, R.M. Type 2 immunity reflects orchestrated recruitment of cells committed to IL-4 production. Immunity 20, 267-277 (2004
55. Hung, L.Y. et al. IL-33 drives biphasic IL-13 production for noncanonical Type 2 immunity against hookworms. Proc. Natl. Acad. Sci. USA 110, 282-287 (2013
56. Nussbaum, J.C. et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502, 245-248 (2013
57. Ekkens, M.J. et al. Memory Th2 effector cells can Develop in the absence of B7-1/B7-2, CD28 interactions, and effector Th cells after priming with an intestinal nematode parasite. J. Immunol. 168, 6344-6351 (2002
58. Brailsford, T.J. & Mapes, C.J. Comparisons of Heligmosomoides polygyrus primary infection in protein-deficient and well-nourished mice. Parasitology 95 (Pt 2), 311-321 (1987
59. Liu, Q. et al. Helminth infection can reduce insulitis and type 1 diabetes through CD25- And IL-10-independent mechanisms. Infect. Immun. 77, 5347-5358 (2009
60. Mohrs, K., Harris, D.P., Lund, F.E. & Mohrs, M. Systemic dissemination and persistence of Th2 and type 2 cells in response to infection with a strictly enteric nematode parasite. J. Immunol. 175, 5306-5313 (2005
61. Mishra, P.K., Patel, N., Wu, W., Bleich, D. & Gause, W.C. Prevention of type 1 diabetes through infection with an intestinal nematode parasite requires IL-10 in the absence of a Th2-Type response. Mucosal Immunol. 6, 297-308 (2013
62. Perona-Wright, G., Mohrs, K. & Mohrs, M. Sustained signaling by canonical helper T cell cytokines throughout the reactive lymph node. Nat. Immunol. 11, 520-526 (2010
63. Svetic, A. et al. Cytokine gene expression after in vivo primary immunization with goat antibody to mouse IgD antibody. J. Immunol. 147, 2391-2397 (1991
64. Friberg, I.M. et al. Macroparasites at peripheral sites of infection are major and dynamic modifiers of systemic antimicrobial pattern recognition responses. Mol Ecol 22, 2810-2826 (2013
65. Massacand, J.C. et al. Helminth products bypass the need for TSLP in Th2 immune responses by directly modulating dendritic cell function. Proc. Natl. Acad. Sci. USA 106, 13968-13973 (2009
66. Al-Riyami, L. & Harnett, W. Immunomodulatory properties of ES-62, a phosphorylcholine-containing glycoprotein secreted by Acanthocheilonema viteae. Endocr. Metab. Immune Disord. Drug Targets 12, 45-52 (2012
67. Chaussabel, D. et al. Unique gene expression profiles of human macrophages and dendritic cells to phylogenetically distinct parasites. Blood 102, 672-681 (2003
68. Kane, C.M. et al. Helminth antigens modulate TLR-initiated dendritic cell activation. J. Immunol. 173, 7454-7461 (2004
69. Segura, M., Su, Z., Piccirillo, C. & Stevenson, M.M. Impairment of dendritic cell function by excretory-secretory products: A potential mechanism for nematode-induced immunosuppression. Eur. J. Immunol. 37, 1887-1904 (2007
70. Everts, B. et al. Schistosome-derived omega-1 drives Th2 polarization by suppressing protein synthesis following internalization by the mannose receptor. J. Exp. Med. 209, 1753-1767 (2012
71. McSorley, H.J., Hewitson, J.P. & Maizels, R.M. Immunomodulation by helminth parasites: Defining mechanisms and mediators. Int. J. Parasitol. 43, 301-310 (2013
72. Aranzamendi,C. et al. Trichinella spiralis-secreted products modulate DC functionality and expand regulatory T cells in vitro. Parasite Immunol. 34, 210-223 (2012
73. Grainger, J.R. et al. Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-beta pathway. J Exp Med 207, 2331-2341 (2010
74. Hartmann, W., Haben, I., Fleischer, B. & Breloer, M. Pathogenic nematodes suppress humoral responses to third-party antigens in vivo by IL-10-mediated interference with Th cell function. J. Immunol. 187, 4088-4099 (2011
75. Patel, N., Kreider, T., Urban, J.F. Jr. & Gause, W.C. Characterisation of effector mechanisms at the host:parasite interface during the immune response to tissue-dwelling intestinal nematode parasites. Int. J. Parasitol. 39, 13-21 (2009
76. Daly, C.M., Mayrhofer, G. & Dent, L.A. Trapping and immobilization of Nippostrongylus brasiliensis larvae at the site of inoculation in primary infections of interleukin-5 transgenic mice. Infect. Immun. 67, 5315-5323 (1999
77. Knott, M.L. et al. Impaired resistance in early secondary Nippostrongylus brasiliensis infections in mice with defective eosinophilopoeisis. Int. J. Parasitol. 37, 1367-1378 (2007
78. Harvie, M. et al. The lung is an important site for priming CD4 T-cellmediated protective immunity against gastrointestinal helminth parasites. Infect. Immun. 78, 3753-3762 (2010
79. Harvie, M., Camberis, M. & Le Gros, G. Development of CD4 T cell dependent immunity against N. brasiliensis infection. Front. Immunol 4, 74 (2013
80. Herrick, C.A., Xu, L.,McKenzie, A.N., Tigelaar, R.E. & Bottomly, K. IL-13 is necessary, not simply sufficient, for epicutaneously induced Th2 responses to soluble protein antigen. J. Immunol. 170, 2488-2495 (2003
81. Liu, Z. et al. Nippostrongylus brasiliensis can induce B7-independent antigen-specific development of IL-4-producing Tcells from naive CD4 T cells in vivo. J. Immunol. 169, 6959-6968 (2002
82. Marsland, B.J., Kurrer, M., Reissmann, R., Harris, N.L. & Kopf, M. Nippostrongylus brasiliensis infection leads to the development of emphysema associated with the induction of alternatively activated macrophages. Eur. J. Immunol. 38, 479-488 (2008
83. Heitmann, L. et al. TGF-beta-responsive myeloid cells suppress type 2 immunity and emphysematous pathology after hookworm infection. Am. J. Pathol. 181, 897-906 (2012
84. Obata-Ninomiya, K. et al. The skin is an important bulwark of acquired immunity against intestinal helminths. J. Exp. Med. 210, 2583-2595 (2013
85. Potian, J.A. et al. Preexisting helminth infection induces inhibition of innate pulmonary anti-Tuberculosis defense by engaging the IL-4 receptor pathway. J. Exp Med 208, 1863-1874 (2011
86. Salgame, P., Yap, G.S. & Gause, W.C. Effect of helminth-induced immunity on infections with microbial pathogens. Nat. Immunol. 14, 1118-1126 (2013
87. Saunders, K.A., Raine, T., Cooke, A. & Lawrence, C.E. Inhibition of autoimmune type 1 diabetes by gastrointestinal helminth infection. Infect. Immun. 75, 397-407 (2007
88. Anderson, M.S. & Bluestone, J.A. The NOD mouse: A model of immune dysregulation. Annu. Rev. Immunol. 23, 447-485 (2005
89. Tisch, R. & McDevitt, H. Insulin-dependent diabetes mellitus. Cell 85, 291-297 (1996
90. Hubner, M.P. et al. Helminth protection against autoimmune diabetes in nonobese diabetic mice is independent of a type 2 immune shift and requires TGF-beta. J. Immunol. 188, 559-568 (2012
91. Suk, K. et al. IFN-gamma/TNF-Alpha synergism as the final effector in autoimmune diabetes: A key role for STAT1/IFN regulatory factor-1 pathway in pancreatic beta cell death. J. Immunol. 166, 4481-4489 (2001
92. Trembleau, S., Penna, G., Gregori, S., Giarratana, N. & Adorini, L. IL-12 administration accelerates autoimmune diabetes in both wild-Type and IFN-gamma-deficient nonobese diabetic mice, revealing pathogenic and protective effects of IL-12-induced IFN-gamma. J. Immunol. 170, 5491-5501 (2003
93. Esensten, J.H., Lee, M.R., Glimcher, L.H. & Bluestone, J.A. T-betdeficient NOD mice are protected from diabetes due to defects in both T cell and innate immune system function. J. Immunol. 183, 75-82 (2009
94. Callewaert, H.I. et al. Deletion of STAT-1 pancreatic islets protects against streptozotocin-induced diabetes and early graft failure but not against late rejection. Diabetes 56, 2169-2173 (2007
95. Lehuen, A., Diana, J., Zaccone, P. & Cooke, A. Immune cell crosstalk in type 1 diabetes. Nat. Rev. Immunol. 10, 501-513 (2010
96. Hanninen, A., Salmi, M., Simell, O. & Jalkanen, S. Mucosa-Associated (beta 7-integrinhigh) lymphocytes accumulate early in the pancreas of NOD mice and show aberrant recirculation behavior. Diabetes 45, 1173-1180 (1996
97. Jaakkola, I., Jalkanen, S. & Hanninen, A. Diabetogenic Tcells are primed both in pancreatic and gut-Associated lymph nodes in NOD mice. Eur. J. Immunol. 33, 3255-3264 (2003
98. Rzepecka, J. et al. The helminth product, ES-62, protects against airway inflammation by resetting the Th cell phenotype. Int. J. Parasitol. 43, 211-223 (2013
99. Pineda, M.A. et al. The parasitic helminth product ES-62 suppresses pathogenesis in collagen-induced arthritis by targeting the interleukin-17- producing cellular network at multiple sites. Arthritis Rheum. 64, 3168-3178 (2012
100. McSorley, H.J. et al. Suppression of type 2 immunity and allergic airway inflammation by secreted products of the helminth Heligmosomoides polygyrus. Eur. J. Immunol. 42, 2667-2682 (2012
101. Larson, D. et al. Chronic helminth infection reduces basophil responsiveness in an IL-10-dependent manner. J. Immunol. 188, 4188-4199 (2012
102. Bach, J.F. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med. 347, 911-920 (2002
103. Asher, M.I. et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 368, 733-743 (2006
104. Cooper, P.J. Interactions between helminth parasites and allergy. Curr. Opin. Allergy Clin. Immunol. 9, 29-37 (2009
105. Hagel, I. et al. Modulation of the allergic reactivity of slum children by helminthic infection. Parasite Immunol. 15, 311-315 (1993
106. Nyan, O.A. et al. Atopy, intestinal helminth infection and total serum IgE in rural and urban adult Gambian communities. Clin. Exp. Allergy 31, 1672-1678 (2001
107. Scrivener, S. et al. Independent effects of intestinal parasite infection and domestic allergen exposure on risk of wheeze in Ethiopia: A nested casecontrol study. Lancet 358, 1493-1499 (2001
108. Cooper, P.J. et al. Reduced risk of atopy among school-Age children infected with geohelminth parasites in a rural area of the tropics. J. Allergy Clin. Immunol. 111, 995-1000 (2003
109. Cooper, P.J. et al. Ascaris lumbricoides-induced interleukin-10 is not associated with atopy in schoolchildren in a rural area of the tropics. J. Infect. Dis 197, 1333-1340 (2008
110. Wilson, M.S. et al. Suppression of allergic airway inflammation by helminth-induced regulatory Tcells. J. Exp. Med. 202, 1199-1212 (2005
111. McSorley, H.J., Blair, N.F., Smith, K.A., McKenzie, A.N. & Maizels, R.M. Blockade of IL-33 release and suppression of type 2 innate lymphoid cell responses by helminth secreted products in airway allergy. Mucosal Immunol. advance online publication, 5 February 2014; doi:10.1038/ mi.2013.123 (e-pub ahead of print
112. Wu, D. et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332, 243-247 (2011
113. Maizels, R.M. & Allen, J.E. Immunology. Eosinophils forestall obesity. Science 332, 186-187 (2011
114. Weisberg, S.P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796-1808 (2003
115. Muse, E.D. et al. Role of resistin in Diet-induced hepatic insulin resistance. J. Clin. Invest. 114, 232-239 (2004
116. Olefsky, J.M. & Glass, C.K. Macrophages, inflammation, and insulin resistance. Annu. Rev.Physiol 72, 219-246 (2010
117. Wong, T. et al. Divergent metabolic adaptations to intestinal parasitic nematode infection in mice susceptible or resistant to obesity. Gastroenterology 133, 1979-1988 (2007
118. Leung, J.M. & Loke, P. A role for IL-22 in the relationship between intestinal helminths, gut microbiota and mucosal immunity. Int. J. Parasitol. 43, 253-257 (2013
119. Devkota, S. & Chang, E.B. Nutrition, microbiomes, and intestinal inflammation. Curr. Opin Gastroenterol. 29, 603-607 (2013
120. Strober, W. Impact of the gut microbiome on mucosal inflammation. Trends Immunol. 34, 423-430 (2013
121. Brusca, S.B., Abramson, S.B. & Scher, J.U. Microbiome and mucosal inflammation as extra-Articular triggers for rheumatoid arthritis and autoimmunity. Curr. Opin. Rheumatol. 26, 101-107 (2013
122. Vinje, S., Stroes, E., Nieuwdorp, M. & Hazen, S.L. The gut microbiome as novel cardio-metabolic target: The time has come!. Eur. Heart J. advance online publication, 11 November 2013; doi:10.1093/eurheartj/ eht467 (e-pub ahead of print
123. Naseer, M.I. et al. Role of gut microbiota in obesity, type 2 diabetes and Alzheimer's disease. CNS Neurol. Disord. Drug Targets advance online publication, 18 September 2013 (e-pub ahead of print
124. Walk, S.T., Blum, A.M., Ewing, S.A., Weinstock, J.V. & Young, V.B. Alteration of the murine gut microbiota during infection with the parasitic helminth Heligmosomoides polygyrus. Inflamm. Bowel Dis. 16, 1841-1849 (2010
125. Hayes, K.S. et al. Exploitation of the intestinal microflora by the parasitic nematode Trichuris muris. Science 328, 1391-1394 (2010
126. De Filippo, C. et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc. Natl. Acad. Sci. USA 107, 14691-14696 (2010
127. Broadhurst, M.J. et al. IL-22+ CD4+ T cells are associated with therapeutic trichuris trichiura infection in an ulcerative colitis patient. Sci. Transl. Med. 2, 60ra88 (2010
128. Sonnenberg, G.F., Fouser, L.A. & Artis, D. Border patrol: Regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat. Immunol. 12, 383-390 (2011
129. Sonnenberg, G.F. et al. Pathological versus protective functions of IL-22 in airway inflammation are regulated by IL-17A. J. Exp. Med. 207, 1293-1305 (2010
130. Turner, J.E., Stockinger, B. & Helmby, H. IL-22 mediates goblet cell hyperplasia and worm expulsion in intestinal helminth infection. PLoS Pathog. 9, e1003698 (2013
131. Zenewicz, L.A. & Flavell, R.A. Recent advances in IL-22 biology. Int. Immunol. 23, 159-163 (2011
132. Wolk, K. et al. IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: A potential role in psoriasis. Eur. J. Immunol. 36, 1309-1323 (2006
133. Zindl, C.L. et al. IL-22-producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis. Proc. Natl. Acad. Sci. USA 110, 12768-12773 (2013
134. Liang, S.C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271-2279 (2006
135. Sonnenberg, G.F. et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336, 1321-1325 (2012
136. Wilson, M.S. et al. Redundant and pathogenic roles for IL-22 in mycobacterial, protozoan, and helminth infections. J. Immunol. 184, 4378-4390 (2010
137. Wolff, M.J., Broadhurst, M.J. & Loke, P. Helminthic therapy: Improving mucosal barrier function. Trends Parasitol. 28, 187-194 (2012
138. Summers, R.W., Elliott, D.E., Urban, J.F. Jr., Thompson, R. &Weinstock, J.V. Trichuris suis therapy in Crohn's disease. Gut 54, 87-90 (2005
139. Summers, R.W. et al. Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease. Am. J. Gastroenterol. 98, 2034-2041 (2003
140. Fleming, J.O. et al. Probiotic helminth administration in relapsing-remitting multiple sclerosis: A phase 1 study. Mult. Scler. 17, 743-754 (2011
141. Bager, P. et al. Trichuris suis ova therapy for allergic rhinitis: A randomized, double-blind, placebo-controlled clinical trial. J. Allergy Clin. Immunol. 125, 123-130. e121-123 (2010
142. Summers,R.W., Elliott,D.E.&Weinstock, J.V. Trichuris suis mightbe effective in treating allergic rhinitis. J. Allergy Clin. Immunol. 125, 766-767 (2010
143. Hepworth, M.R., Hamelmann, E., Lucius, R. & Hartmann, S. Looking into the future of Trichuris suis therapy. J. Allergy Clin. Immunol. 125, 767-768. author reply 768-769 (2010
144. Pritchard,D.I., Blount, D.G., Schmid-Grendelmeier, P. & Till, S.J. Parasitic worm therapy for allergy: Is this incongruous or avant-garde medicine? Clin. Exp. Allergy 42, 505-512 (2012.