Home LiteratureArticle Details
PMID: 23827958 Published · ppublish English Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Review

Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths.

Nature reviews. Immunology ·Vol. 13 ·No. 8 ·2013-00-00 ·Pages 607-14

Gause WC, Wynn TA, Allen JE

Abstract

Helminth-induced type 2 immune responses, which are characterized by the T helper 2 cell-associated cytokines interleukin-4 (IL-4) and IL-13, mediate host protection through enhanced tissue repair, the control of inflammation and worm expulsion. In this Opinion article, we consider type 2 immunity in the context of helminth-mediated tissue damage. We examine the relationship between the control of helminth infection and the mechanisms of wound repair, and we provide a new understanding of the adaptive type 2 immune response and its contribution to both host tolerance and resistance.

MeSH Terms
Adaptive Immunity Animals Helminthiasis/immunology,parasitology Helminths/immunology Humans Immune Tolerance Inflammation/immunology,parasitology Interleukin-10/metabolism Interleukin-13/metabolism Interleukin-4/metabolism Macrophages/immunology T-Lymphocytes, Helper-Inducer/immunology Wound Healing/immunology
Chemicals
Interleukin-13 Interleukin-10 Interleukin-4
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Gause William C
Center for Immunity and Inflammation, Department of Medicine, New Jersey Medical School, Rutgers, State University of New Jersey, Newark, New Jersey 07103-2757, USA.
Wynn Thomas A
Allen Judith E
References (92)
92 references, click to expand
  1. Immunopathology of schistosomiasis.
    Immunol Cell Biol. 2007 Feb-Mar;85(2):148-54 PMID: 17160074
  2. Eosinophils: changing perspectives in health and disease.
    Nat Rev Immunol. 2013 Jan;13(1):9-22 PMID: 23154224
  3. Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases.
    Nat Rev Immunol. 2008 Nov;8(11):889-95 PMID: 18927577
  4. Anti-inflammatory responses and oxidative stress in Nippostrongylus brasiliensis-induced pulmonary inflammation.
    Parasite Immunol. 2002 Jan;24(1):15-22 PMID: 11856442
  5. Allergic host defences.
    Nature. 2012 Apr 25;484(7395):465-72 PMID: 22538607
  6. Helminth protection against autoimmune diabetes in nonobese diabetic mice is independent of a type 2 immune shift and requires TGF-β.
    J Immunol. 2012 Jan 15;188(2):559-68 PMID: 22174447
  7. Helminths and dendritic cells: sensing and regulating via pattern recognition receptors, Th2 and Treg responses.
    Eur J Immunol. 2010 Jun;40(6):1525-37 PMID: 20405478
  8. The helminth product ES-62 protects against septic shock via Toll-like receptor 4-dependent autophagosomal degradation of the adaptor MyD88.
    Nat Immunol. 2011 Apr;12(4):344-51 PMID: 21358639
  9. An unexpected role for uric acid as an inducer of T helper 2 cell immunity to inhaled antigens and inflammatory mediator of allergic asthma.
    Immunity. 2011 Apr 22;34(4):527-40 PMID: 21474346
  10. Alternatively activated macrophage-derived RELM-{alpha} is a negative regulator of type 2 inflammation in the lung.
    J Exp Med. 2009 Apr 13;206(4):937-52 PMID: 19349464
  11. Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism.
    J Immunol. 2001 Dec 1;167(11):6533-44 PMID: 11714822
  12. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity.
    Nature. 2010 Apr 29;464(7293):1367-70 PMID: 20200518
  13. IL-33 amplifies both Th1- and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cells.
    Int Immunol. 2008 Aug;20(8):1019-30 PMID: 18550585
  14. Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway.
    J Exp Med. 2010 Oct 25;207(11):2331-41 PMID: 20876311
  15. The danger signal, extracellular ATP, is a sensor for an airborne allergen and triggers IL-33 release and innate Th2-type responses.
    J Immunol. 2011 Apr 1;186(7):4375-87 PMID: 21357533
  16. Protective immune mechanisms in helminth infection.
    Nat Rev Immunol. 2007 Dec;7(12):975-87 PMID: 18007680
  17. Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion.
    J Exp Med. 2006 Apr 17;203(4):1105-16 PMID: 16606668
  18. Micrometer-sized titanium particles can induce potent Th2-type responses through TLR4-independent pathways.
    J Immunol. 2011 Dec 15;187(12):6491-8 PMID: 22095717
  19. Review series on helminths, immune modulation and the hygiene hypothesis: mechanisms underlying helminth modulation of dendritic cell function.
    Immunology. 2009 Jan;126(1):28-34 PMID: 19120496
  20. Regulation of helminth-induced Th2 responses by thymic stromal lymphopoietin.
    J Immunol. 2009 May 15;182(10):6452-9 PMID: 19414799
  21. Arginase I suppresses IL-12/IL-23p40-driven intestinal inflammation during acute schistosomiasis.
    J Immunol. 2010 Jun 1;184(11):6438-46 PMID: 20483789
  22. IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses.
    Nature. 2010 Apr 29;464(7293):1362-6 PMID: 20200520
  23. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells.
    J Exp Med. 2007 Aug 6;204(8):1837-47 PMID: 17635955
  24. Evolution of Th2 immunity: a rapid repair response to tissue destructive pathogens.
    PLoS Pathog. 2011 May;7(5):e1002003 PMID: 21589896
  25. Suppression of allergic airway inflammation by helminth-induced regulatory T cells.
    J Exp Med. 2005 Nov 7;202(9):1199-212 PMID: 16275759
  26. Wound healing: an overview of acute, fibrotic and delayed healing.
    Front Biosci. 2004 Jan 01;9:283-9 PMID: 14766366
  27. Global gene expression profiles during acute pathogen-induced pulmonary inflammation reveal divergent roles for Th1 and Th2 responses in tissue repair.
    J Immunol. 2003 Oct 1;171(7):3655-67 PMID: 14500663
  28. IL-4-induced macrophage-derived IGF-I protects myofibroblasts from apoptosis following growth factor withdrawal.
    J Leukoc Biol. 2004 Nov;76(5):1019-27 PMID: 15316031
  29. Cestode regulation of inflammation and inflammatory diseases.
    Int J Parasitol. 2013 Mar;43(3-4):233-43 PMID: 23058631
  30. FcepsilonRI-mediated amphiregulin production by human mast cells increases mucin gene expression in epithelial cells.
    J Allergy Clin Immunol. 2005 Feb;115(2):272-9 PMID: 15696081
  31. Alternative activation is an innate response to injury that requires CD4+ T cells to be sustained during chronic infection.
    J Immunol. 2007 Sep 15;179(6):3926-36 PMID: 17785830
  32. Memory T(H)2 cells induce alternatively activated macrophages to mediate protection against nematode parasites.
    Nat Med. 2006 Aug;12(8):955-60 PMID: 16892038
  33. New paradigms in type 2 immunity.
    Science. 2012 Jul 27;337(6093):431-5 PMID: 22837519
  34. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus.
    Nat Immunol. 2011 Nov;12(11):1045-54 PMID: 21946417
  35. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response.
    J Clin Invest. 1999 Sep;104(6):777-85 PMID: 10491413
  36. An efferocytosis-induced, IL-4-dependent macrophage-iNKT cell circuit suppresses sterile inflammation and is defective in murine CGD.
    Blood. 2013 Apr 25;121(17):3473-83 PMID: 23426944
  37. Animal defenses against infectious agents: is damage control more important than pathogen control.
    PLoS Biol. 2008 Dec 23;6(12):e4 PMID: 19222305
  38. Control of RSV-induced lung injury by alternatively activated macrophages is IL-4R alpha-, TLR4-, and IFN-beta-dependent.
    Mucosal Immunol. 2010 May;3(3):291-300 PMID: 20404812
  39. IL-13Ralpha2 and IL-10 coordinately suppress airway inflammation, airway-hyperreactivity, and fibrosis in mice.
    J Clin Invest. 2007 Oct;117(10):2941-51 PMID: 17885690
  40. Exploring the full spectrum of macrophage activation.
    Nat Rev Immunol. 2008 Dec;8(12):958-69 PMID: 19029990
  41. Health metrics for helminthic infections.
    Adv Parasitol. 2010;73:51-69 PMID: 20627139
  42. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation.
    Science. 2011 Jun 10;332(6035):1284-8 PMID: 21566158
  43. The intraepithelial T cell response to NKG2D-ligands links lymphoid stress surveillance to atopy.
    Science. 2011 Dec 2;334(6060):1293-7 PMID: 22144628
  44. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis.
    Nature. 2011 Nov 20;480(7375):104-8 PMID: 22101429
  45. IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis.
    J Immunol. 2000 Jun 15;164(12):6406-16 PMID: 10843696
  46. T1/ST2-deficient mice demonstrate the importance of T1/ST2 in developing primary T helper cell type 2 responses.
    J Exp Med. 2000 Mar 20;191(6):1069-76 PMID: 10727469
  47. Efficient colonic mucosal wound repair requires Trem2 signaling.
    Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):256-61 PMID: 19109436
  48. Schistosome-derived omega-1 drives Th2 polarization by suppressing protein synthesis following internalization by the mannose receptor.
    J Exp Med. 2012 Sep 24;209(10):1753-67, S1 PMID: 22966004
  49. Necessity of IgE antibodies and mast cells for manifestation of resistance against larval Haemaphysalis longicornis ticks in mice.
    J Immunol. 1990 Jan 1;144(1):259-62 PMID: 2295794
  50. IL-13 effector functions.
    Annu Rev Immunol. 2003;21:425-56 PMID: 12615888
  51. TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation.
    Nature. 2011 Aug 14;477(7363):229-33 PMID: 21841801
  52. Helminth-host immunological interactions: prevention and control of immune-mediated diseases.
    Ann N Y Acad Sci. 2012 Jan;1247:83-96 PMID: 22239614
  53. Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis.
    Nature. 2007 Mar 29;446(7135):552-6 PMID: 17322906
  54. Schistosoma mansoni in IL-4-deficient mice.
    Int Immunol. 1996 Apr;8(4):435-44 PMID: 8671630
  55. Innate immune responses to lung-stage helminth infection induce alternatively activated alveolar macrophages.
    Infect Immun. 2006 Sep;74(9):4970-81 PMID: 16926388
  56. IL-33, a potent inducer of adaptive immunity to intestinal nematodes.
    J Immunol. 2008 Feb 15;180(4):2443-9 PMID: 18250453
  57. Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells.
    Nature. 2010 Jan 28;463(7280):540-4 PMID: 20023630
  58. An essential role for TH2-type responses in limiting acute tissue damage during experimental helminth infection.
    Nat Med. 2012 Jan 15;18(2):260-6 PMID: 22245779
  59. The intestinal nematode Trichuris arvicolae affects the fecundity of its host, the common vole Microtus arvalis.
    Parasitol Res. 2007 Sep;101(4):1161-4 PMID: 17520287
  60. Inflammation in wound repair: molecular and cellular mechanisms.
    J Invest Dermatol. 2007 Mar;127(3):514-25 PMID: 17299434
  61. Inflammatory monocytes recruited to allergic skin acquire an anti-inflammatory M2 phenotype via basophil-derived interleukin-4.
    Immunity. 2013 Mar 21;38(3):570-80 PMID: 23434060
  62. Systemically dispersed innate IL-13-expressing cells in type 2 immunity.
    Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11489-94 PMID: 20534524
  63. MyD88-dependent induction of allergic Th2 responses to intranasal antigen.
    J Clin Invest. 2005 Feb;115(2):459-67 PMID: 15650773
  64. Retnla (relmalpha/fizz1) suppresses helminth-induced Th2-type immunity.
    PLoS Pathog. 2009 Apr;5(4):e1000393 PMID: 19381262
  65. Studies of murine schistosomiasis reveal interleukin-13 blockade as a treatment for established and progressive liver fibrosis.
    Hepatology. 2001 Aug;34(2):273-82 PMID: 11481612
  66. The role of nematode parasites in Soay sheep (Ovis aries L.) mortality during a population crash.
    Parasitology. 1992 Dec;105 ( Pt 3):493-503 PMID: 1461688
  67. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis.
    Science. 2011 Apr 8;332(6026):243-7 PMID: 21436399
  68. Innate lymphoid cells wield a double-edged sword.
    Nat Immunol. 2011 Oct 19;12(11):1025-7 PMID: 22012433
  69. Insulin-like growth factor-I (IGF-I) stimulates protein synthesis and collagen gene expression in monolayer and lattice cultures of fibroblasts.
    J Cell Physiol. 1992 Aug;152(2):389-96 PMID: 1639869
  70. To B or not to B: B cells and the Th2-type immune response to helminths.
    Trends Immunol. 2011 Feb;32(2):80-8 PMID: 21159556
  71. Forum: Immunology: Allergy challenged.
    Nature. 2012 Apr 25;484(7395):458-9 PMID: 22538601
  72. Helminth products bypass the need for TSLP in Th2 immune responses by directly modulating dendritic cell function.
    Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13968-73 PMID: 19666528
  73. The pathogenesis of schistosomiasis is controlled by cooperating IL-10-producing innate effector and regulatory T cells.
    J Immunol. 2004 Mar 1;172(5):3157-66 PMID: 14978122
  74. Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis.
    PLoS Pathog. 2009 Apr;5(4):e1000371 PMID: 19360123
  75. Infectious triggers protect from autoimmunity.
    Semin Immunol. 2011 Apr;23(2):122-9 PMID: 21296592
  76. The lung is an important site for priming CD4 T-cell-mediated protective immunity against gastrointestinal helminth parasites.
    Infect Immun. 2010 Sep;78(9):3753-62 PMID: 20605978
  77. IL-10 is critical for host resistance and survival during gastrointestinal helminth infection.
    J Immunol. 2002 Mar 1;168(5):2383-92 PMID: 11859129
  78. Alum adjuvant: some of the tricks of the oldest adjuvant.
    J Med Microbiol. 2012 Jul;61(Pt 7):927-934 PMID: 22174375
  79. Accelerated and progressive and lethal liver fibrosis in mice that lack interleukin (IL)-10, IL-12p40, and IL-13Rα2.
    Gastroenterology. 2011 Dec;141(6):2200-9 PMID: 21864478
  80. TLR-dependent T cell activation in autoimmunity.
    Nat Rev Immunol. 2011 Nov 18;11(12):807-22 PMID: 22094985
  81. IgE enhances parasite clearance and regulates mast cell responses in mice infected with Trichinella spiralis.
    J Immunol. 2004 Jan 15;172(2):1139-45 PMID: 14707089
  82. Influence of host nutrition on the development and consequences of nematode parasitism in ruminants.
    Trends Parasitol. 2001 Jul;17(7):325-30 PMID: 11423375
  83. 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. 2013 Mar;6(2):297-308 PMID: 22806101
  84. The biology of nematode- and IL4Rα-dependent murine macrophage polarization in vivo as defined by RNA-Seq and targeted lipidomics.
    Blood. 2012 Dec 13;120(25):e93-e104 PMID: 23074280
  85. Review series on helminths, immune modulation and the hygiene hypothesis: immunity against helminths and immunological phenomena in modern human populations: coevolutionary legacies?
    Immunology. 2009 Jan;126(1):18-27 PMID: 19120495
  86. A role for human skin-resident T cells in wound healing.
    J Exp Med. 2009 Apr 13;206(4):743-50 PMID: 19307328
  87. Silica crystals and aluminum salts regulate the production of prostaglandin in macrophages via NALP3 inflammasome-independent mechanisms.
    Immunity. 2011 Apr 22;34(4):514-26 PMID: 21497116
  88. Diversity and dialogue in immunity to helminths.
    Nat Rev Immunol. 2011 Jun;11(6):375-88 PMID: 21610741
  89. Mechanisms of fibrosis: therapeutic translation for fibrotic disease.
    Nat Med. 2012 Jul 06;18(7):1028-40 PMID: 22772564
  90. Alternative activation of macrophages by IL-4 impairs phagocytosis of pathogens but potentiates microbial-induced signalling and cytokine secretion.
    Blood. 2010 Jan 14;115(2):353-62 PMID: 19880493
  91. Protective immunity and mast cell and eosinophil responses in mice infested with larval Haemaphysalis longicornis ticks.
    Parasite Immunol. 1993 Apr;15(4):209-14 PMID: 8506116
  92. Review series on helminths, immune modulation and the hygiene hypothesis: how might infection modulate the onset of type 1 diabetes?
    Immunology. 2009 Jan;126(1):12-7 PMID: 19120494
Article Info
Journal
Nature reviews. Immunology
Abbr.
Nat Rev Immunol
ISSN
1474-1741
DOI
10.1038/nri3476
Published
2013-00-00
Epub
2013-00-05
Pages
607-14
Language
English
Region
England
NLM ID
101124169
PMCID
PMC3789590
Subset
IM
Grants
NIAID NIH HHS · R01 AI031678 · United States
NIAID NIH HHS · R01AI031678 · United States
Medical Research Council · G0600818 · United Kingdom
Intramural NIH HHS · ZIA AI000829-15 · United States
Wellcome Trust · 095831 · United Kingdom
NIAID NIH HHS · R01AI066188 · United States
NIAID NIH HHS · R01 AI066188 · United States
Intramural NIH HHS · ZIA AI001019-06 · United States
Medical Research Council · MR/J001929/1 · United Kingdom
External Links
PubMed source DOI: 10.1038/nri3476 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2