Induction of regulatory cells by helminth parasites: Exploitation for the treatment of inflammatory diseases

Immunological Reviews

Volumn 259, Issue 1, 2014, Pages 206-230

  Finlay, Conor M ^a   Walsh, Kevin P ^a   Mills, Kingston H G ^a  

^a TRINITY COLLEGE DUBLIN   (Ireland)

Author keywords

Allergy; Autoimmunity; Helminths; Hygiene hypothesis; Immune regulation; Regulatory T cells; Th1 Th2 Th17 cells

Indexed keywords

ANTHELMINTIC AGENT; ANTIINFLAMMATORY AGENT; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; GAMMA INTERFERON; GLYCOPROTEIN; INTERLEUKIN 10; INTERLEUKIN 13; INTERLEUKIN 17; INTERLEUKIN 25; INTERLEUKIN 3; INTERLEUKIN 33; INTERLEUKIN 4; INTERLEUKIN 4 RECEPTOR ALPHA; INTERLEUKIN 5; INTERLEUKIN 9; OMEGA 1 PROTEIN; STAT6 PROTEIN; THYMIC STROMAL LYMPHOPOIETIN; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG;

ADAPTIVE IMMUNITY; ANAPHYLAXIS; ARTHRITIS; ARTICLE; ASTHMA; ATHEROSCLEROSIS; ATOPY; AUTOIMMUNITY; B LYMPHOCYTE; BYSTANDER EFFECT; CD4+ T LYMPHOCYTE; CELL DIFFERENTIATION; CESTODE; COLITIS; CYTOKINE PRODUCTION; DENDRITIC CELL; DIROFILARIA IMMITIS; ECOLOGICAL NICHE; ENCEPHALITIS; EOSINOPHIL; EXPERIMENTAL AUTOIMMUNE ENCEPHALITIS; EXPERIMENTAL INFECTION; FASCIOLA HEPATICA; GENETIC DIFFERENCE; HELIGMOSOMOIDES POLYGYRUS; HELMINTH; HELMINTHIASIS; HOOKWORM; HUMAN; HYGIENE HYPOTHESIS; HYMENOLEPIS DIMINUTA; IMMUNE EVASION; IMMUNE RESPONSE; IMMUNOPATHOLOGY; IMMUNOREGULATION; INNATE IMMUNITY; INSULIN DEPENDENT DIABETES MELLITUS; INTERMEDIATE HOST; LITOMOSOIDES SIGMODONTIS; LYMPHOID CELL; LYMPHOID CELL TYPE 2; MACROPHAGE; MACROPHAGE TYPE 2; NIPPOSTRONGYLUS BRASILIENSIS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PARASITE IMMUNITY; PERIPHERAL BLOOD MONONUCLEAR CELL; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; RESPIRATORY TRACT ALLERGY; SCHISTOSOMA JAPONICUM; SCHISTOSOMA MANSONI; SCHISTOSOMIASIS MANSONI; STRONGYLOIDES VENEZUELENSIS; TH1 CELL; TH17 CELL; TH2 CELL; THERAPY WITH HELMINTHS; TREMATODE; TRICHINELLA SPIRALIS;

ALLERGY; AUTOIMMUNITY; HELMINTHS; HYGIENE HYPOTHESIS; IMMUNE REGULATION; REGULATORY T CELLS; TH1/TH2/TH17 CELLS;

ANIMALS; ANTI-INFLAMMATORY AGENTS; AUTOIMMUNITY; HELMINTHIASIS; HELMINTHS; HOST-PATHOGEN INTERACTIONS; HUMANS; HYPERSENSITIVITY; IMMUNOMODULATION; INFLAMMATION; NEOPLASMS; T-LYMPHOCYTES, HELPER-INDUCER;

EID: 84897929169     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/imr.12164     Document Type: Article

References (208)

1. Mills KH. Regulatory T cells: friend or foe in immunity to infection? Nat Rev Immunol 2004;4:841-855.
2. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986;136:2348-2357.
3. Nussbaum JC, et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 2013;502:245-248.
4. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 2010;11:889-896.
5. Spits H, et al. Innate lymphoid cells - a proposal for uniform nomenclature. Nat Rev Immunol 2013;13:145-149.
6. Maizels RM, Yazdanbakhsh M. T-cell regulation in helminth parasite infections: implications for inflammatory diseases. Chem Immunol Allergy 2008;94:112-123.
7. Nelson GS. A history of human helminthology. D. I. Grove. 1990. C·A·B International: Wallingford, UK, 1990, 848 pp. (ISBN 0-85198-689-7). J Helminthol 1991;65:120.
8. WHO. WHO world Health Statistics. Geneva, Switzerland: Organisation WH, 2009.
9. Hotez PJ, Kamath A. Neglected tropical diseases in sub-saharan Africa: review of their prevalence, distribution, and disease burden. PLoS Negl Trop Dis 2009;3:e412.
10. Lustigman S, et al. A research agenda for helminth diseases of humans: the problem of helminthiases. PLoS Negl Trop Dis 2012;6:e1582.
11. Hotez PJ, et al. Control of neglected tropical diseases. N Engl J Med 2007;357:1018-1027.
12. Hotez PJ, Molyneux DH, Fenwick A, Ottesen E, Ehrlich Sachs S, Sachs JD. Incorporating a rapid-impact package for neglected tropical diseases with programs for HIV/AIDS, tuberculosis, and malaria. PLoS Med 2006;3:e102.
13. Hotez PJ, Brindley PJ, Bethony JM, King CH, Pearce EJ, Jacobson J. Helminth infections: the great neglected tropical diseases. J Clin Invest 2008;118:1311-1321.
14. Fletcher RH, Fletcher SW. Clinical Epidemiology: The Essentials. 4th edn. Philadelphia, PA: Lippincott, Williams, & Wilkins, 2005.
15. Crompton DW, Nesheim MC. Nutritional impact of intestinal helminthiasis during the human life cycle. Annu Rev Nutr 2002;22:35-59.
16. McSorley HJ, Maizels RM. Helminth Infections and Host Immune Regulation. Clin Microbiol Rev 2012;25:585-608.
17. Maizels RM, Balic A, Gomez-Escobar N, Nair M, Taylor MD, Allen JE. Helminth parasites - masters of regulation. Immunol Rev 2004;201:89-116.
18. Maizels R, Hewitson J, Smith K. Susceptibility and immunity to helminth parasites. Curr Opin Immunol 2012;24:459-466.
19. Quinnell RJ. Genetics of susceptibility to human helminth infection. Int J Parasitol 2003;33:1219-1231.
20. Jackson J, et al. T helper cell type 2 responsiveness predicts future susceptibility to gastrointestinal nematodes in humans. J Infect Dis 2004;190:1804-1811.
21. Katona IM, Urban JF, Jr., Finkelman FD. The role of L3T4+ and Lyt-2+ T cells in the IgE response and immunity to Nippostrongylus brasiliensis. J Immunol 1988;140:3206-3211.
22. Nel HJ, et al. Impaired basophil induction leads to an age-dependent innate defect in type 2 immunity during helminth infection in mice. J Immunol 2011;186:4631-4639.
23. Djuardi Y, et al. The development of TH2 responses from infancy to 4 years of age and atopic sensitization in areas endemic for helminth infections. Allergy Asthma Clin Immunol 2013;9:13.
24. Urban JF, Jr., Maliszewski CR, Madden KB, Katona IM, Finkelman FD. IL-4 treatment can cure established gastrointestinal nematode infections in immunocompetent and immunodeficient mice. J Immunol 1995;154:4675-4684.
25. Kelly DS, Calman P, Dean DM. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 2010;125:S73-S80.
26. Anthony RM, Rutitzky LI, Urban JF, Jr., Stadecker MJ, Gause WC. Protective immune mechanisms in helminth infection. Nat Rev Immunol 2007;7:975-987.
27. Rodriguez-Sosa M, et al. Chronic helminth infection induces alternatively activated macrophages expressing high levels of CCR5 with low interleukin-12 production and Th2-biasing ability. Infect Immun 2002;70:3656-3664.
28. Anthony RM, et al. Memory TH2 cells induce alternatively activated macrophages to mediate protection against nematode parasites. Nat Med 2006;12:955-960.
29. Artis D, et al. RELMβ/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proc Natl Acad Sci USA 2004;101:13596-13600.
30. Maizels RM, Pearce EJ, Artis D, Yazdanbakhsh M, Wynn TA. Regulation of pathogenesis and immunity in helminth infections. J Exp Med 2009;206:2059-2066.
31. Nair MG, et al. Alternatively activated macrophage-derived RELM-α is a negative regulator of type 2 inflammation in the lung. J Exp Med 2009;206:937-952.
32. Liu T, et al. FIZZ1 stimulation of myofibroblast differentiation. Am J Pathol 2004;164:1315-1326.
33. Chen F, et al. An essential role for TH2-type responses in limiting acute tissue damage during experimental helminth infection. Nat Med 2012;18:260-266.
34. Urban J, et al. IL-13, IL-4Ralpha, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity 1998;8:255-264.
35. Liang H-E, Reinhardt R, Bando J, Sullivan B, Ho IC, Locksley R. Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat Immunol 2012;13:58-66.
36. Cliffe LJ. Accelerated intestinal epithelial cell turnover: a new mechanism of parasite expulsion. Science 2005;308:1463-1465.
37. Hasnain S, et al. Muc5ac: a critical component mediating the rejection of enteric nematodes. J Exp Med 2011;208:893-900.
38. Butterworth AE. Cell-mediated damage to helminths. In: Baker JR, Muller R, eds. Advances in Parasitology. Amsterdam: Elsevier, 1985:143-235.
39. Walsh KP, Mills KH. Dendritic cells and other innate determinants of T helper cell polarisation. Trends Immunol 2013;34:521-530.
40. Everts B, et al. Omega-1, a glycoprotein secreted by Schistosoma mansoni eggs, drives Th2 responses. J Exp Med 2009;206:1673-1680.
41. Everts B, et al. Schistosome-derived omega-1 drives Th2 polarization by suppressing protein synthesis following internalization by the mannose receptor. J Exp Med 2012;209:1753.
42. Holland MJ, Harcus YM, Riches PL, Maizels RM. Proteins secreted by the parasitic nematode Nippostrongylus brasiliensis act as adjuvants for Th2 responses. Eur J Immunol 2000;30:1977-1987.
43. Schramm G, et al. Cutting edge: IPSE/alpha-1, a glycoprotein from Schistosoma mansoni eggs, induces IgE-dependent, antigen-independent IL-4 production by murine basophils in vivo. J Immunol 2007;178:6023-6027.
44. Donnelly S, Stack CM, O'Neill SM, Sayed AA, Williams DL, Dalton JP. Helminth 2-Cys peroxiredoxin drives Th2 responses through a mechanism involving alternatively activated macrophages. FASEB J 2008;22:4022-4032.
45. Neill DR, et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 2010;464:1367-1370.
46. Hsu C-L, Neilsen CV, Bryce PJ. IL-33 is produced by mast cells and regulates IgE-dependent inflammation. PLoS One 2010;5:e11944.
47. Yasuda K, et al. Contribution of IL-33-activated type II innate lymphoid cells to pulmonary eosinophilia in intestinal nematode-infected mice. Proc Natl Acad Sci USA 2012;109:3451-3456.
48. Giacomin PR, et al. Thymic stromal lymphopoietin-dependent basophils promote Th2 cytokine responses following intestinal helminth infection. J Immunol 2012;189:4371-4378.
49. Else KJ, Grencis RK. Cellular immune responses to the murine nematode parasite Trichuris muris. I. Differential cytokine production during acute or chronic infection. Immunology 1991;72:508-513.
50. Artis D, Potten C, Else K, Finkelman F, Grencis R. Trichuris muris: host intestinal epithelial cell hyperproliferation during chronic infection is regulated by interferon-gamma. Exp Parasitol 1999;92:144-153.
51. Rutitzky LI, Bazzone L, Shainheit MG, Joyce-Shaikh B, Cua DJ, Stadecker MJ. IL-23 is required for the development of severe egg-induced immunopathology in schistosomiasis and for lesional expression of IL-17. J Immunol 2008;180:2486-2495.
52. Mbow M, et al. T-helper 17 cells are associated with pathology in human schistosomiasis. J Infect Dis 2013;207:186-195.
53. Herbert DBR, et al. Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity 2004;20:623-635.
54. Rick M. Maizels ABNG-EMNMDTJEA. Helminth parasites; masters of regulation. Immunol Rev 2004;201:89-116.
55. Turner J, et al. Intensity of intestinal infection with multiple worm species is related to regulatory cytokine output and immune hyporesponsiveness. J Infect Dis 2008;197:1204-1212.
56. Doetze A, et al. Antigen-specific cellular hyporesponsiveness in a chronic human helminth infection is mediated by Th3/Tr1-type cytokines IL-10 and transforming growth factor-β but not by a Th1 to Th2 shift. Int Immunol 2000;12:623-630.
57. HaÇAriz O, Sayers G, Flynn RJ, Lejeune A, Mulcahy G. IL-10 and TGF-β1 are associated with variations in fluke burdens following experimental fasciolosis in sheep. Parasite Immunol 2009;31:613-622.
58. Waldvogel AS, Lepage MF, Zakher A, Reichel MP, Eicher R, Heussler VT. Expression of interleukin 4, interleukin 4 splice variants and interferon gamma mRNA in calves experimentally infected with Fasciola hepatica. Vet Immunol Immunopathol 2004;97:53-63.
59. Flynn RJ, Mulcahy G. The roles of IL-10 and TGF-[beta] in controlling IL-4 and IFN-[gamma] production during experimental Fasciola hepatica infection. Int J Parasitol 2008;38:1673-1680.
60. Wynn TA, et al. IL-10 regulates liver pathology in acute murine schistosomiasis mansoni but is not required for immune down-modulation of chronic disease. J Immunol 1998;160:4473-4480.
61. McCoy K, Camberis M, Gros GL. Protective immunity to nematode infection is induced by CTLA-4 blockade. J Exp Med 1997;186:183-187.
62. van der Werf N, Redpath SA, Azuma M, Yagita H, Taylor MD. Th2 cell-intrinsic hypo-responsiveness determines susceptibility to helminth infection. PLoS Pathog 2013;9:e1003215.
63. Taylor MD, LeGoff L, Harris A, Malone E, Allen JE, Maizels RM. Removal of regulatory T cell activity reverses hyporesponsiveness and leads to filarial parasite clearance in vivo. J Immunol 2005;174:4924-4933.
64. Taylor MD, et al. Early recruitment of natural CD4+Foxp3+ Treg cells by infective larvae determines the outcome of filarial infection. Eur J Immunol 2009;39:192-206.
65. Nausch N, Midzi N, Mduluza T, Maizels R, Mutapi F. Regulatory and activated T cells in human Schistosoma haematobium infections. PLoS One 2011;6:e16860.
66. Alves Oliveira L, et al. Cytokine production associated with periportal fibrosis during chronic schistosomiasis mansoni in humans. Infect Immun 2006;74:1215-1221.
67. Achim H, Susanne K, Norbert WB, Andrea H, Bertram M-M, Klaus AD. The variant Arg110Gln of human IL-13 is associated with an immunologically hyper-reactive form of onchocerciasis (sowda). Microbes Infect 2002;4:37-42.
68. Korten S, Hoerauf A, Kaifi J, Büttner D. Low levels of transforming growth factor-beta (TGF-beta) and reduced suppression of Th2-mediated inflammation in hyperreactive human onchocerciasis. Parasitology 2011;138:35-45.
69. Turner J, et al. CD4+CD25+ regulatory cells contribute to the regulation of colonic Th2 granulomatous pathology caused by schistosome infection. PLoS Negl Trop Dis 2011;5:e1269.
70. D'Elia R, Behnke JM, Bradley JE, Else KJ. Regulatory T cells: a role in the control of helminth-driven intestinal pathology and worm survival. J Immunol 2009;182:2340-2348.
71. Babu S, et al. Filarial lymphedema is characterized by antigen-specific Th1 and th17 proinflammatory responses and a lack of regulatory T cells. PLoS Negl Trop Dis 2009;3:e420.
72. Korten S, Büttner D, Schmetz C, Hoerauf A, Mand S, Brattig N. The nematode parasite Onchocerca volvulus generates the transforming growth factor-beta (TGF-beta). Parasitology Res 2009;105:731-741.
73. Su Z, Segura M, Morgan K, Loredo-Osti JC, Stevenson MM. Impairment of protective immunity to blood-stage malaria by concurrent nematode infection. Infect Immun 2005;73:3531-3539.
74. Gomez-Escobar N, Gregory WF, Maizels RM. Identification of tgh-2, a filarial nematode homolog of Caenorhabditis elegans daf-7 and human transforming growth factor beta, expressed in microfilarial and adult stages of Brugia malayi. Infect Immun 2000;68:6402-6410.
75. Gantt KR, et al. Activation of TGF-β by Leishmania chagasi: importance for parasite survival in macrophages. J Immunol 2003;170:2613-2620.
76. Grainger J, et al. Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway. J Exp Med 2010;207:2331-2341.
77. Zaccone P, Burton O, Miller N, Jones FM, Dunne DW, Cooke A. Schistosoma mansoni egg antigens induce Treg that participate in diabetes prevention in NOD mice. Eur J Immunol 2009;39:1098-1107.
78. Smith K, Hochweller K, Hämmerling GJ, Boon L, MacDonald AS, Maizels RM. Chronic helminth infection promotes immune regulation in vivo through dominance of CD11cloCD103- dendritic cells. J Immunol 2011;186:7098-7109.
79. Zaccone P, et al. The S. mansoni glycoprotein ω-1 induces Foxp3 expression in NOD mouse CD4 T cells. Eur J Immunol 2011;41:2709-2718.
80. Whelan M, Harnett MM, Houston KM, Patel V, Harnett W, Rigley KP. A filarial nematode-secreted product signals dendritic cells to acquire a phenotype that drives development of Th2 cells. J Immunol 2000;164:6453-6460.
81. Jenkins SJ, Mountford AP. Dendritic cells activated with products released by schistosome larvae drive Th2-type immune responses, which can be inhibited by manipulation of CD40 costimulation. Infect Immun 2005;73:395-402.
82. Goodridge HS, Harnett W, Liew FY, Harnett MM. Differential regulation of interleukin-12 p40 and p35 induction via Erk mitogen-activated protein kinase-dependent and -independent mechanisms and the implications for bioactive IL-12 and IL-23 responses. Immunology 2003;109:415-425.
83. Terrazas LI, et al. Helminth excreted/secreted antigens repress expression of LPS-induced Let-7i but not miR-146a and miR-155 in human dendritic cells. BioMed Res Intl 2013;2013:972506.
84. Hamilton CM, Dowling DJ, Loscher CE, Morphew RM, Brophy PM, O'Neill SM. The Fasciola hepatica tegumental antigen suppresses dendritic cell maturation and function. Infect Immun 2009;77:2488-2498.
85. Falcón C, et al. Excretory-secretory products (ESP) from Fasciola hepatica induce tolerogenic properties in myeloid dendritic cells. Vet Immunol Immunopathol 2010;137:36-46.
86. Donnelly S, et al. Helminth cysteine proteases inhibit TRIF-dependent activation of macrophages via degradation of TLR3. J Biol Chem 2010;285:3383-3392.
87. Robinson MW, et al. A helminth cathelicidin-like protein suppresses antigen processing and presentation in macrophages via inhibition of lysosomal vATPase. FASEB J 2012;26:4614-4627.
88. van der Kleij D, et al. A novel host-parasite lipid cross-talk. Schistosomal lyso-phosphatidylserine activates toll-like receptor 2 and affects immune polarization. J Biol Chem 2002;277:48122-48129.
89. Layland LE, Rad R, Wagner H, da Costa CUP. Immunopathology in schistosomiasis is controlled by antigen-specific regulatory T cells primed in the presence of TLR2. Eur J Immunol 2007;37:2174-2184.
90. Rodriguez PC, et al. L-Arginine consumption by macrophages modulates the expression of CD3ζ chain in T lymphocytes. J Immunol 2003;171:1232-1239.
91. Rodriguez PC, Quiceno DG, Ochoa AC. L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 2007;109:1568-1573.
92. Pesce JT, et al. Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. PLoS Pathog 2009;5:e1000371.
93. Li H, Han Y, Guo Q, Zhang M, Cao X. Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-β1. J Immunol 2009;182:240-249.
94. Loke P, MacDonald AS, Allen JE. Antigen-presenting cells recruited by Brugia malayi induce Th2 differentiation of naive CD4(+) T cells. Eur J Immunol 2000;30:1127-1135.
95. Martinez-Forero I, et al. IL-10 suppressor activity and ex vivo Tr1 cell function are impaired in multiple sclerosis. Eur J Immunol 2008;38:576-586.
96. Pesce JT, et al. Retnla (Relmα/Fizz1) suppresses helminth-induced Th2-type immunity. PLoS Pathog 2009;5:e1000393.
97. Fumagalli M, et al. Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions. J Exp Med 2009;206:1395-1408.
98. Allen JE, Wynn TA. Evolution of Th2 immunity: a rapid repair response to tissue destructive pathogens. PLoS Pathog 2011;7:e1002003.
99. Nacher M, et al. Intestinal helminth infections are associated with increased incidence of Plasmodium falciparum malaria in Thailand. J Parasitol 2002;88:55-58.
100. Potian JA, Rafi W, Bhatt K, McBride A, Gause WC, Salgame P. Preexisting helminth infection induces inhibition of innate pulmonary anti-tuberculosis defense by engaging the IL-4 receptor pathway. J Exp Med 2011;208:1863-1874.
101. Hubner MP, et al. Chronic helminth infection does not exacerbate Mycobacterium tuberculosis infection. PLoS Negl Trop Dis 2012;6:e1970.
102. Flynn RJ, Mannion C, Golden O, Hacariz O, Mulcahy G. Experimental Fasciola hepatica infection alters responses to tests used for diagnosis of bovine tuberculosis. Infect Immun 2007;75:1373-1381.
103. Brady MT, O'Neill SM, Dalton JP, Mills KH. Fasciola hepatica suppresses a protective Th1 response against Bordetella pertussis. Infect Immun 1999;67:5372-5378.
104. Miller CMD, Smith NC, Ikin RJ, Boulter NR, Dalton JP, Donnelly S. Immunological interactions between 2 common pathogens, Th1-inducing protozoan Toxoplasma gondii and the Th2-inducing helminth Fasciola hepatica. PLoS ONE 2009;4:e5692.
105. Kamal SM, et al. Acute hepatitis C without and with schistosomiasis: correlation with hepatitis C-specific CD4(+) T-cell and cytokine response. Gastroenterology 2001;121:646-656.
106. Walson JL, et al. Albendazole treatment of HIV-1 and helminth co-infection: a randomized, double-blind, placebo-controlled trial. AIDS 2008;22:1601-1609.
107. Fried B, Reddy A, Mayer D. Helminths in human carcinogenesis. Cancer Lett 2011;305:239-249.
108. Botelho M, et al. Tumourigenic effect of Schistosoma haematobium total antigen in mammalian cells. Int J Exp Pathol 2009;90:448-453.
109. Gale EAM. The rise of childhood type 1 diabetes in the 20th century. Diabetes 2002;51:3353-3361.
110. Strachan DP. Family size, infection and atopy: the first decade of the "hygiene hypothesis". Thorax 2000;55(Suppl):S2-S10.
111. Emanuel MB. Hay fever, a post industrial revolution epidemic: a history of its growth during the 19th century. Clin Exp Allergy 1988;18:295-304.
112. Strachan DP. Hay fever, hygiene, and household size. BMJ 1989;299:1259-1260.
113. Greenwood BM. Autoimmune disease and parastic infections in Nigerians. Lancet 1968;292:380-382.
114. Leibowitz U, Antonovsky A, Medalie JM, Smith HA, Halpern L, Alter M. Epidemiological study of multiple sclerosis in Israel. II. Multiple sclerosis and level of sanitation. J Neurol Neurosurg Psychiatry 1966;29:60-68.
115. Correale J, Farez M. Association between parasite infection and immune responses in multiple sclerosis. Ann Neurol 2007;61:97-108.
116. Jorge C, Mauricio F, Gabriela R. Helminth infections associated with multiple sclerosis induce regulatory B cells. Ann Neurol 2008;64:187-199.
117. Mutapi F, et al. Schistosome infection intensity is inversely related to auto-reactive antibody levels. PLoS One 2011;6:e19149.
118. Medeiros M, et al. Schistosoma mansoni infection is associated with a reduced course of asthma. J Allergy Clin Immunol 2003;111:947-951.
119. Feary J, Britton J, Leonardi-Bee J. Atopy and current intestinal parasite infection: a systematic review and meta-analysis. Allergy 2011;66:569-578.
120. Figueiredo CA, et al. Coassociations between IL10 polymorphisms, IL-10 production, helminth infection, and asthma/wheeze in an urban tropical population in Brazil. J Allergy Clin Immunol 2013;131:1683-1690.
121. van den Biggelaar A, et al. Long-term treatment of intestinal helminths increases mite skin-test reactivity in Gabonese schoolchildren. J Infect Dis 2004;189:892-900.
122. Dittrich AM, et al. Helminth infection with Litomosoides sigmodontis induces regulatory T cells and inhibits allergic sensitization, airway inflammation, and hyperreactivity in a murine asthma model. J Immunol 2008;180:1792-1799.
123. Mo HM, et al. Schistosoma japonicum infection modulates the development of allergen-induced airway inflammation in mice. Parasitol Res 2008;103:1183-1189.
124. Wilson MS, Taylor MD, Balic A, Finney CA, Lamb JR, Maizels RM. Suppression of allergic airway inflammation by helminth-induced regulatory T cells. J Exp Med 2005;202:1199-1212.
125. Wohlleben G, et al. Helminth infection modulates the development of allergen-induced airway inflammation. Int Immunol 2004;16:585-596.
126. McSorley HJ, O'Gorman MT, Blair N, Sutherland TE, Filbey KJ, Maizels RM. Suppression of type 2 immunity and allergic airway inflammation by secreted products of the helminth Heligmosomoides polygyrus. Eur J Immunol 2012;42:2667-2682.
127. Trujillo-Vargas CM, et al. Helminth-derived products inhibit the development of allergic responses in mice. Am J Respir Crit Care Med 2007;175:336-344.
128. Danilowicz-Luebert E, et al. A nematode immunomodulator suppresses grass pollen-specific allergic responses by controlling excessive Th2 inflammation. Int J Parasitol 2013;43:201-210.
129. Schnoeller C, et al. A helminth immunomodulator reduces allergic and inflammatory responses by induction of IL-10-producing macrophages. J Immunol 2008;180:4265-4272.
130. Mangan NE, Fallon RE, Smith P, van Rooijen N, McKenzie AN, Fallon PG. Helminth infection protects mice from anaphylaxis via IL-10-producing B cells. J Immunol 2004;173:6346-6356.
131. Hartmann S, et al. Gastrointestinal nematode infection interferes with experimental allergic airway inflammation but not atopic dermatitis. Clin Exp Allergy 2009;39:1585-1596.
132. Pearson D, Taylor G. The influence of the nematode Syphacia oblevata on adjuvant arthritis in the rat. Immunology 1975;29:391-396.
133. Osada Y, Shimizu S, Kumagai T, Yamada S, Kanazawa T. Schistosoma mansoni infection reduces severity of collagen-induced arthritis via down-regulation of pro-inflammatory mediators. Int J Parasitol 2009;39:457-464.
134. Song X, et al. Impact of Schistosoma japonicum infection on collagen-induced arthritis in DBA/1 mice: a murine model of human rheumatoid arthritis. PLoS One 2011;6:e23453.
135. Shi M, et al. Infection with an intestinal helminth parasite reduces Freund's complete adjuvant-induced monoarthritis in mice. Arthritis Rheum 2011;63:434-444.
136. Salinas-Carmona MC, et al. Spontaneous arthritis in MRL/lpr mice is aggravated by Staphylococcus aureus and ameliorated by Nippostrongylus brasiliensis infections. Autoimmunity 2009;42:25-32.
137. McInnes I, Leung B, Harnett M, Gracie J, Liew F, Harnett W. A novel therapeutic approach targeting articular inflammation using the filarial nematode-derived phosphorylcholine-containing glycoprotein ES-62. J Immunol 2003;171:2127-2133.
138. Gruden-Movsesijan A, Ilic N, Mostarica-Stojkovic M, Stosic-Grujicic S, Milic M, Sofronic-Milosavljevic L. Trichinella spiralis: modulation of experimental autoimmune encephalomyelitis in DA rats. Exp Parasitol 2008;118:641-647.
139. Wilson M, et al. Helminth-induced CD19+CD23hi B cells modulate experimental allergic and autoimmune inflammation. Eur J Immunol 2010;40:1682-1696.
140. Walsh KP, Brady MT, Finlay CM, Boon L, Mills KHG. Infection with a helminth parasite attenuates autoimmunity through TGF-β-mediated suppression of Th17 and Th1 responses. J Immunol 2009;183:1577-1586.
141. La Flamme A, Ruddenklau K, Bäckström B. Schistosomiasis decreases central nervous system inflammation and alters the progression of experimental autoimmune encephalomyelitis. Infect Immun 2003;71:4996-5004.
142. Chiuso-Minicucci F, et al. Experimental autoimmune encephalomyelitis evolution was not modified by multiple infections with Strongyloides venezuelensis. Parasite Immunol 2011;33:303-308.
143. Zheng X, et al. Soluble egg antigen from Schistosoma japonicum modulates the progression of chronic progressive experimental autoimmune encephalomyelitis via Th2-shift response. J Neuroimmunol 2008;194:107-114.
144. Saunders KA, Raine T, Cooke A, Lawrence CE. Inhibition of autoimmune type 1 diabetes by gastrointestinal helminth infection. Infect Immun 2007;75:397-407.
145. Hübner M, Stocker J, Mitre E. Inhibition of type 1 diabetes in filaria-infected non-obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3+ regulatory T cells. Immunology 2009;127:512-522.
146. Cooke A, et al. Infection with Schistosoma mansoni prevents insulin dependent diabetes mellitus in non-obese diabetic mice. Parasite Immunol 1999;21:169-176.
147. Zaccone P, et al. Schistosoma mansoni antigens modulate the activity of the innate immune response and prevent onset of type 1 diabetes. Eur J Immunol 2003;33:1439-1449.
148. Wirtz S, Neufert C, Weigmann B, Neurath MF. Chemically induced mouse models of intestinal inflammation. Nat Protocols 2007;2:541-546.
149. Moreels TG, et al. Concurrent infection with Schistosoma mansoni attenuates inflammation induced changes in colonic morphology, cytokine levels, and smooth muscle contractility of trinitrobenzene sulphonic acid induced colitis in rats. Gut 2004;53:99-107.
150. Elliott DE, et al. Exposure to schistosome eggs protects mice from TNBS-induced colitis. Am J Physiol Gastrointest Liver Physiol 2003;284:G385-G391.
151. Elliott DE, et al. Colonization with Heligmosomoides polygyrus suppresses mucosal IL-17 production. J Immunol 2008;181:2414-2419.
152. Motomura Y, Wang H, Deng Y, El-Sharkawy RT, Verdu EF, Khan WI. Helminth antigen-based strategy to ameliorate inflammation in an experimental model of colitis. Clin Exp Immunol 2009;155:88-95.
153. Weng M, et al. Alternatively activated macrophages in intestinal helminth infection: effects on concurrent bacterial colitis. J Immunol 2007;179:4721-4731.
154. Wang A, Fernando M, Leung G, Phan V, Smyth D, McKay DM. Exacerbation of oxazolone colitis by infection with the helminth hymenolepis diminuta: involvement of IL-5 and eosinophils. Am J Pathol 2010;177:2850-2859.
155. Heller F, Fuss IJ, Nieuwenhuis EE, Blumberg RS, Strober W. Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 2002;17:629-638.
156. Wolfs IM, et al. Reprogramming macrophages to an anti-inflammatory phenotype by helminth antigens reduces murine atherosclerosis. FASEB J 2014;28:288-299.
157. Wu D, et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 2011;332:243-247.
158. Imai S, Tezuka H, Fujita K. A factor of inducing IgE from a filarial parasite prevents insulin-dependent diabetes mellitus in nonobese diabetic mice. Biochem Biophys Res Commun 2001;286:1051-1058.
159. Sewell D, et al. Immunomodulation of experimental autoimmune encephalomyelitis by helminth ova immunization. Int Immunol 2003;15:59-69.
160. Tran GT, et al. IL-5 promotes induction of antigen-specific CD4+CD25+ T regulatory cells that suppress autoimmunity. Blood 2012;119:4441-4450.
161. Jager A, Dardalhon V, Sobel RA, Bettelli E, Kuchroo VK. Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol 2009;183:7169-7177.
162. Seidl A, Panzer M, Voehringer D. Protective immunity against the gastrointestinal nematode Nippostrongylus brasiliensis requires a broad T-cell receptor repertoire. Immunology 2011;134:214-223.
163. Hübner MP, et al. Helminth protection against autoimmune diabetes in nonobese diabetic mice is independent of a type 2 immune shift and requires TGF-β. J Immunol 2012;188:559-568.
164. Yazdanbakhsh M, Kremsner PG, van Ree R. Allergy, parasites, and the hygiene hypothesis. Science 2002;296:490-494.
165. Setiawan T, et al. Heligmosomoides polygyrus promotes regulatory T-cell cytokine production in the murine normal distal intestine. Infect Immun 2007;75:4655-4663.
166. Liu Q, et al. Helminth infection can reduce insulitis and type 1 diabetes through CD25- and IL-10-independent mechanisms. Infect Immun 2009;77:5347-5358.
167. Mishra PK, Patel N, Wu W, Bleich D, Gause WC. 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;6:297-308.
168. Racke MK, Dhib-Jalbut S, Cannella B, Albert PS, Raine CS, McFarlin DE. Prevention and treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-beta 1. J Immunol 1991;146:3012-3017.
169. Ince MN, et al. Role of T cell TGF-β signaling in intestinal cytokine responses and helminthic immune modulation. Eur J Immunol 2009;39:1870-1878.
170. Letterio JJ, Roberts AB. Regulation of immune responses by TGF-β. Annu Rev Immunol 1998;16:137-161.
171. Sagara H, et al. Activation of TGF-β/Smad2 signaling is associated with airway remodeling in asthma. J Allergy Clin Immunol 2002;110:249-254.
172. Aranzamendi C, et al. Trichinella spiralis-secreted products modulate DC functionality and expand regulatory T cells in vitro. Parasite Immunol 2012;34:210-223.
173. Hang L, et al. Heligmosomoides polygyrus infection can inhibit colitis through direct interaction with innate immunity. J Immunol 2010;185:3184-3189.
174. Blum AM, et al. Heligmosomoides polygyrus bakeri induces tolerogenic dendritic cells that block colitis and prevent antigen-specific gut T cell responses. J Immunol 2012;189:2512-2520.
175. Nolting J, et al. Retinoic acid can enhance conversion of naive into regulatory T cells independently of secreted cytokines. J Exp Med 2009;206:2131-2139.
176. Mielke LA, et al. Retinoic acid expression associates with enhanced IL-22 production by γδ T cells and innate lymphoid cells and attenuation of intestinal inflammation. J Exp Med 2013;210:1117-1124.
177. Correale J, Farez MF. Parasite infections in multiple sclerosis modulate immune responses through a retinoic acid-dependent pathway. J Immunol 2013;191:3827-3837.
178. Carranza F, et al. Helminth antigens enable CpG-activated dendritic cells to inhibit the symptoms of collagen-induced arthritis through Foxp3+ regulatory T cells. PLoS One 2012;7:e40356.
179. Liu JY, et al. Adoptive transfer of dendritic cells isolated from helminth-infected mice enhanced T regulatory cell responses in airway allergic inflammation. Parasite Immunol 2011;33:525-534.
180. Smith P, et al. Infection with a helminth parasite prevents experimental colitis via a macrophage-mediated mechanism. J Immunol 2007;178:4557-4566.
181. Klotz C, et al. A helminth immunomodulator exploits host signaling events to regulate cytokine production in macrophages. PLoS Pathog 2011;7:e1001248.
182. Summers R, Elliott D, Qadir K, Urban J, Thompson R, Weinstock J. Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease. Am J Gastroenterol 2003;98:2034-2041.
183. Summers RW, Elliott DE, Urban JF, Jr., Thompson R, Weinstock JV. Trichuris suis therapy in Crohn's disease. Gut 2005;54:87-90.
184. Summers RW, Elliott DE, Urban JF, Jr., Thompson RA, Weinstock JV. Tri churis suis therapy for active ulcerative colitis: a randomized controlled trial. Gastroenterology 2005;128:825-832.
185. Croese J, et al. A proof of concept study establishing Necator americanus in Crohn's patients and reservoir donors. Gut 2006;55:136-137.
186. Broadhurst M, et al. IL-22+ CD4+ T cells are associated with therapeutic trichuris trichiura infection in an ulcerative colitis patient. Sci Transl Med 2010;2:60ra88.
187. Daveson AJ, et al. Effect of hookworm infection on wheat challenge in celiac disease-a randomised double-blinded placebo controlled trial. PLoS One 2011;6:e17366.
188. McSorley HJ, et al. Suppression of inflammatory immune responses in celiac disease by experimental hookworm infection. PLoS One 2011;6:e24092.
189. Correale J, Farez MF. The impact of parasite infections on the course of multiple sclerosis. J Neuroimmunol 2011;233:6-11.
190. Fleming J, et al. Probiotic helminth administration in relapsing-remitting multiple sclerosis: a phase 1 study. Multiple sclerosis 2011;17:743-754.
191. Bager P, et al. Symptoms after ingestion of pig whipworm Trichuris suis eggs in a randomized placebo-controlled double-blind clinical trial. PLoS One 2011;6:e22346.
192. King CL, et al. B cell sensitization to helminthic infection develops in utero in humans. J Immunol 1998;160:3578-3584.
193. Mortimer K, et al. Dose-ranging study for trials of therapeutic infection with Necator americanus in humans. Am J Trop Med Hygeine 2006;75:914-920.
194. Hübner M, Layland L, Hoerauf A. Helminths and their implication in sepsis - a new branch of their immunomodulatory behaviour? Pathogens Dis 2013;69:127-141.
195. McGuirk P, McCann C, Mills KH. Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis. J Exp Med 2002;195:221-231.
196. Harnett M, Melendez A, Harnett W. The therapeutic potential of the filarial nematode-derived immunodulator, ES-62 in inflammatory disease. Clin Exp Immunol 2010;159:256-267.
197. Atochina O, Harn D. Prevention of psoriasis-like lesions development in fsn/fsn mice by helminth glycans. Exp Dermatol 2006;15:461-468.
198. Dutta P, et al. Lacto-N-fucopentaose III, a pentasaccharide, prolongs heart transplant survival. Transplantation 2010;90:1071-1078.
199. Harris NL. Advances in helminth immunology: optimism for future vaccine design? Trends Parasitol 2011;27:288-293.
200. Jones SA, Sutton CE, Cua D, Mills KH. Therapeutic potential of targeting IL-17. Nat Immunol 2012;13:1022-1025.
201. Keane J, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345:1098-1104.
202. Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol 2008;7:796-804.
203. Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353:375-381.
204. Elliott DE, Setiawan T, Metwali A, Blum A, Urban JF, Weinstock JV. Heligmosomoides polygyrus inhibits established colitis in IL-10-deficient mice. Eur J Immunol 2004;34:2690-2698.
205. Reardon C, Sanchez A, Hogaboam CM, McKay DM. Tapeworm infection reduces epithelial ion transport abnormalities in murine dextran sulfate sodium-induced colitis. Infect Immun 2001;69:4417-4423.
206. Johnston MJG, et al. Extracts of the rat tapeworm, hymenolepis diminuta, suppress macrophage activation in vitro and alleviate chemically induced colitis in mice. Infect Immun 2010;78:1364-1375.
207. Khan W, et al. Intestinal nematode infection ameliorates experimental colitis in mice. Infect Immun 2002;70:5931-5937.
208. Kuijk LM, et al. Soluble helminth products suppress clinical signs in murine experimental autoimmune encephalomyelitis and differentially modulate human dendritic cell activation. Mol Immunol 2012;51:210-218.