Helminths protect against type 1 diabetes: effects and mechanisms

  • Chun-lian Tang
  • Jie-ning Zou
  • Rong-hui Zhang
  • Zhi-ming LiuEmail author
  • Cun-lan MaoEmail author
Immunology and Host-Parasite Interactions - Review


Type 1 diabetes (T1D) is an autoimmune disease in which cells of the immune system destroy pancreatic β cells, which secrete insulin. The high prevalence of T1D in developed societies may be explained by environmental changes, including lower exposure to helminths. Indeed, infection by helminths such as Schistosoma, Filaria, and Heligmosomoides polygyrus and their by-products has been reported to ameliorate or prevent the development of T1D in human and animal models. Helminths can trigger distinct immune regulatory pathways, often involving adaptive immune cells that include T helper 2 (Th2) cells and regulatory T cells (Tregs) and innate immune cells that include dendritic cells, macrophages, and invariant natural killer T cells, which may act synergistically to induce Tregs in a Toll-like receptor-dependent manner. Cytokines such as interleukin (IL)-4, IL-10, and transforming growth factor (TGF)-β also play an important role in protection from T1D. Herein, we provide a comprehensive review of the effects and mechanisms underlying protection against T1D by helminths.


Helminths Type 1 diabetes Th2 Regulatory T cells 



This research was funded by the Scientific Research Subject of the Health and Family Planning Commission of Wuhan Municipality (no. WX17A08), Hubei Provincial Planning Commission Joint Fund project (no. WJ2018H0129 and no. WJ2018H0040), and Hubei Provincial Natural Science Foundation project (no. 2017CFB570).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict interest.


  1. Ajendra J, Berbudi A, Hoerauf A, Hübner MP (2016) Combination of worm antigen and proinsulin prevents type 1 diabetes in NOD mice after the onset of insulitis. Clin Immunol 164:119–122PubMedGoogle Scholar
  2. Allender S, Foster C, Hutchinson L, Arambepola C (2008) Quantification of urbanization in relation to chronic diseases in developing countries: a systematic review. J Urban Health 85:938–951PubMedGoogle Scholar
  3. Amdare N, Khatri V, Yadav RS, Tarnekar A, Goswami K, Reddy MV (2015) Brugia malayi soluble and excretory-secretory proteins attenuate development of streptozotocin-induced type 1 diabetes in mice. Parasite Immunol 37:624–634PubMedGoogle Scholar
  4. Amdare NP, Khatri VK, Yadav RSP, Tarnekar A, Goswami K, Reddy MVR (2017) Therapeutic potential of the immunomodulatory proteins Wuchereria bancrofti L2 and Brugia malayi abundant larval transcript 2 against streptozotocin-induced type 1 diabetes in mice. J Helminthol 91:539–548PubMedGoogle Scholar
  5. Aravindhan V, Mohan V, Surendar J, Rao MM, Ranjani H, Kumaraswami V, Nutman TB, Babu S (2010) Decreased prevalence of lymphatic filariasis among subjects with type-1 diabetes. Am J Trop Med Hyg 83:1336–1339PubMedGoogle Scholar
  6. Berbudi A, Ajendra J, Wardani AP, Hoerauf A, Hübner MP (2016) Parasitic helminths and their beneficial impact on type 1 and type 2 diabetes. Diabetes Metab Res Rev 32(3):238–250PubMedGoogle Scholar
  7. Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, Herold KC, Lares A, Lee MR, Li K, Liu W, Long SA, Masiello LM, Nguyen V, Putnam AL, Rieck M, Sayre PH, Tang Q (2015) Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med 7:315ra189PubMedGoogle Scholar
  8. Blumenfeld HJ, Tohn R, Haeryfar SM, Liu Y, Savage PB, Delovitch TL (2011) Structure-guided design of an invariant natural killer T cell agonist for optimum protection from type 1 diabetes in non-obese diabetic mice. Clin Exp Immunol 166(1):121–133PubMedGoogle Scholar
  9. Burton OT, Gibbs S, Miller N, Jones FM, Wen L, Dunne DW, Cooke A, Zaccone P (2010) Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens. Eur J Immunol 40:2221–2229PubMedGoogle Scholar
  10. Cooke A (2009) Review series on helminths, immune modulation and the hygiene hypothesis: how might infection modulate the onset of type 1 diabetes? Immunology 126:12–17PubMedGoogle Scholar
  11. Cooke A, Tonks P, Jones FM, O’Shea H, Hutchings P, Fulford AJ, Dunne DW (1999) Infection with Schistosoma mansoni prevents insulin dependent diabetes mellitus in non-obese diabetic mice. Parasite Immunol 21:169–176PubMedGoogle Scholar
  12. Eissa MM, Mostafa DK, Ghazy AA, El Azzouni MZ, Boulos LM, Younis LK (2016) Anti-arthritic activity of Schistosoma mansoni and Trichinella spiralis derived-antigens in adjuvant arthritis in rats: role of FOXP3+ Treg cells. PLoS One 11:e0165916PubMedGoogle Scholar
  13. Elliott DE, Weinstock JV (2012) Helminth-host immunological interactions: prevention and control of immune-mediated diseases. Ann N Y Acad Sci 1247:83–96PubMedGoogle Scholar
  14. El-Wakil HS, Aboushousha TS, El Haddad O, Gamil NB, Mansour T, El-Said H (2002) Effect of schistosoma mansoni egg deposition on multiple low doses streptozotocin induced insulin dependent diabetes. J Egypt Soc Parasitol 32:987–1002PubMedGoogle Scholar
  15. Escamilla A, Zafra R, Pérez J, McNeilly TN, Pacheco IL, Buffoni L, Martínez-Moreno FJ, Molina-Hernández V, Martínez-Moreno A (2016) Distribution of Foxp3+ T cells in the liver and hepatic lymph nodes of goats and sheep experimentally infected with Fasciola hepatica. Vet Parasitol 230:14–19PubMedGoogle Scholar
  16. Espinoza-Jiménez A, Rivera-Montoya I, Cárdenas-Arreola R, Morán L, Terrazas LI (2010) Taenia crassiceps infection attenuates multiple low-dose streptozotocin-induced diabetes. J Biomed Biotechnol 2010:850541PubMedGoogle Scholar
  17. Espinoza-Jiménez A, De Haro R, Terrazas LI (2017) Taenia crassiceps antigens control experimental type 1 diabetes by inducing alternatively activated macrophages. Mediat Inflamm 2017:8074329Google Scholar
  18. EURODIAB ACE Study Group (2000) Variation and trends in incidence of childhood diabetes in Europe. Lancet 355:873–876Google Scholar
  19. Gale EA (2002) The rise of childhood type 1 diabetes in the 20th century. Diabetes 51:3353–3361PubMedGoogle Scholar
  20. Hübner MP, Stocker JT, Mitre E (2009) 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 127:512–522PubMedGoogle Scholar
  21. Hübner MP, Shi Y, Torrero MN, Mueller E, Larson D, Soloviova K, Gondorf F, Hoerauf A, Killoran KE, Stocker JT, Davies SJ, Tarbell KV, Mitre E (2012) Helminth protection against autoimmune diabetes in nonobese diabetic mice is independent of a type 2 immune shift and requires TGF-β. J Immunol 188:559–568PubMedGoogle Scholar
  22. Hurdayal R, Ndlovu HH, Revaz-Breton M, Parihar SP, Nono JK, Govender M, Brombacher F (2017) IL-4-producing B cells regulate T helper cell dichotomy in type 1- and type 2-controlled diseases. Proc Natl Acad Sci U S A 114(40):E8430–E8439PubMedGoogle Scholar
  23. Imai S, Tezuka H, Fujita K (2001) A factor of inducing IgE from a filarial parasite prevents insulin-dependent diabetes mellitus in nonobese diabetic mice. Biochem Biophys Res Commun 286:1051–1058PubMedGoogle Scholar
  24. Ishigame H, Zenewicz LA, Sanjabi S, Licona-Limón P, Nakayama M, Leonard WJ, Flavell RA (2013) Excessive Th1 responses due to the absence of TGF-β signaling cause autoimmune diabetes and dysregulated Treg cell homeostasis. Proc Natl Acad Sci U S A 110:6961–6966PubMedGoogle Scholar
  25. Jakobsen OAJ, Szereday L (2018) The “three amigos” lurking behind type 1 diabetes: hygiene, gut microbiota and viruses. Acta Microbiol Immunol Hung 28:1–18Google Scholar
  26. Johnson MC, Garland AL, Nicolson SC, Li C, Samulski RJ, Wang B, Tisch R (2013) β-cell-specific IL-2 therapy increases islet Foxp3+ Treg and suppresses type 1 diabetes in NOD mice. Diabetes 62:3775–3784PubMedGoogle Scholar
  27. Kikodze N, Pantsulaia I, Rekhviashvili K, Iobadze M, Dzhakhutashvili N, Pantsulaia N, Kukuladze N, Bikashvili N, Metreveli D, Chikovani T (2013) Cytokines and T regulatory cells in the pathogenesis of type 1 diabetes. Georgian Med News 222:29–35Google Scholar
  28. Kondrashova A, Reunanen A, Romanov A, Karvonen A, Viskari H, Vesikari T, Ilonen J, Knip M, Hyöty H (2005) A six-fold gradient in the incidence of type 1 diabetes at the eastern border of Finland. Ann Med 37(1):67–72PubMedGoogle Scholar
  29. Lee IF, Wang X, Hao J, Akhoundsadegh N, Chen L, Liu L, Langermann S, Ou D, Warnock GL (2013) B7-H4.Ig inhibits the development of type 1 diabetes by regulating Th17 cells in NOD mice. Cell Immunol 282(1):1–8PubMedGoogle Scholar
  30. Lehuen A, Diana J, Zaccone P, Cooke A (2010) Immune cell crosstalk in type 1 diabetes. Nat Rev Immunol 10(7):501–513PubMedGoogle Scholar
  31. Li C, Zhang L, Chen Y, Lin X, Li T (2016) Protective role of adenovirus vector-mediated interleukin-10 gene therapy on endogenous islet β-cells in recent-onset type 1 diabetes in NOD mice. Exp Ther Med 11(5):1625–1632PubMedGoogle Scholar
  32. Lin MS, Tse HM, Delmastro MM, Bertera S, Wong CT, Lakomy R, He J, Sklavos MM, Coudriet GM, Pietropaolo M, Trucco MM, Piganelli JD (2011) A multivalent vaccine for type 1 diabetes skews T cell subsets to Th2 phenotype in NOD mice. Immunol Res 50:213–220PubMedGoogle Scholar
  33. Liu Q, Sundar K, Mishra PK, Mousavi G, Liu Z, Gaydo A, Alem F, Lagunoff D, Bleich D, Gause WC (2009) Helminth infection can reduce insulitis and type 1 diabetes through CD25- and IL-10-independent mechanisms. Infect Immun 77:5347–5358PubMedGoogle Scholar
  34. Lund ME, O’Brien BA, Hutchinson AT, Robinson MW, Simpson AM, Dalton JP, Donnelly S (2014) Secreted proteins from the helminth Fasciola hepatica inhibit the initiation of autoreactive T cell responses and prevent diabetes in the NOD mouse. PLoS One 9:e86289PubMedGoogle Scholar
  35. Maizels RM (2016) Parasitic helminth infections and the control of human allergic and autoimmune disorders. Clin Microbiol Infect 22(6):481–486PubMedGoogle Scholar
  36. Maizels RM, McSorley HJ, Smyth DJ (2014) Helminths in the hygiene hypothesis: sooner or later? Clin Exp Immunol 177(1):38–46PubMedGoogle Scholar
  37. Mishra PK, Patel N, Wu W, Bleich D, Gause WC (2013) 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 6:297–308PubMedGoogle Scholar
  38. Nagayama Y, Saitoh O, McLachlan SM, Rapoport B, Kano H, Kumazawa Y (2004) TSH receptor-adenovirus-induced Graves’ hyperthyroidism is attenuated in both interferon-gamma and interleukin-4 knockout mice; implications for the Th1/Th2 paradigm. Clin Exp Immunol 138(3):417–422PubMedGoogle Scholar
  39. Osada Y, Yamada S, Nabeshima A, Yamagishi Y, Ishiwata K, Nakae S, Sudo K, Kanazawa T (2013) Heligmosomoides polygyrus infection reduces severity of type 1 diabetes induced by multiple low-dose streptozotocin in mice via STAT6- and IL-10-independent mechanisms. Exp Parasitol 135:388–396. PubMedGoogle Scholar
  40. Osada Y, Fujiyama T, Kamimura N, Kaji T, Nakae S, Sudo K, Ishiwata K, Kanazawa T (2017) Dual genetic absence of STAT6 and IL-10 does not abrogate anti-hyperglycemic effects of Schistosoma mansoni in streptozotocin-treated diabetic mice. Exp Parasitol 177:1–12PubMedGoogle Scholar
  41. Ottesen EA, Hiatt RA, Cheever AW, Sotomayor ZR, Neva FA (1978) The acquisition and loss of antigen-specific cellular immune responsiveness in acute and chronic schistosomiasis in man. Clin Exp Immunol 33:37–47PubMedGoogle Scholar
  42. Palomares O, Martín-Fontecha M, Lauener R, Traidl-Hoffmann C, Cavkaytar O, Akdis M, Akdis CA (2014) Regulatory T cells and immune regulation of allergic diseases: roles of IL-10 and TGF-β. Genes Immun 15:511–520PubMedGoogle Scholar
  43. Parsa R, Andresen P, Gillett A, Mia S, Zhang XM, Mayans S, Holmberg D, Harris RA (2012) Adoptive transfer of immunomodulatory M2 macrophages prevents type 1 diabetes in NOD mice. Diabetes 61(11):2881–2892PubMedGoogle Scholar
  44. Pazzagli L, Möllsten A, Waernbaum I (2017) Marginal structural model to evaluate the joint effect of socioeconomic exposures on the risk of developing end-stage renal disease in patients with type 1 diabetes: a longitudinal study based on data from the Swedish childhood diabetes study group. Ann Epidemiol 27(8):479–484PubMedGoogle Scholar
  45. Peres RS, Chiuso-Minicucci F, da Rosa LC, Domingues A, Zorzella-Pezavento SF, França TG, Ishikawa LL, do Amarante AF, Sartori A (2013) Previous contact with Strongyloides venezuelensis contributed to prevent insulitis in MLD-STZ diabetes. Exp Parasitol 134:183–189PubMedGoogle Scholar
  46. Precechtelova J, Borsanyiova M, Sarmirova S, Bopegamage S (2014) Type I diabetes mellitus: genetic factors and presumptive enteroviral etiology or protection. J Pathog 2014:738512PubMedGoogle Scholar
  47. Pugliese A (2016) Insulitis in the pathogenesis of type 1 diabetes. Pediatr Diabetes 22:31–36Google Scholar
  48. Reddy SM, Reddy PM, Amdare N, Khatri V, Tarnekar A, Goswami K, Reddy MVR (2017) Filarial abundant larval transcript protein ALT-2: an immunomodulatory therapeutic agent for type 1 diabetes. Indian J Clin Biochem 32:45–52PubMedGoogle Scholar
  49. Reyes JL, Espinoza-Jiménez AF, González MI, Verdin L, Terrazas L (2011) Taenia crassiceps infection abrogates experimental autoimmune encephalomyelitis. Cell Immunol 267:77–87PubMedGoogle Scholar
  50. Ruffner MA, Robbins PD (2010) Dendritic cells transduced to express interleukin 4 reduce diabetes onset in both normoglycemic and prediabetic nonobese diabetic mice. PLoS One 5(7):e11848PubMedGoogle Scholar
  51. Ruyssers NE, De Winter BY, De Man JG, Ruyssers ND, Van Gils AJ, Loukas A, Pearson MS, Weinstock JV, Pelckmans PA, Moreels TG (2010) Schistosoma mansoni proteins attenuate gastrointestinal motility disturbances during experimental colitis in mice. World J Gastroenterol 16(6):703–712PubMedGoogle Scholar
  52. Saunders KA, Raine T, Cooke A, Lawrence CE (2007) Inhibition of autoimmune type 1 diabetes by gastrointestinal helminth infection. Infect Immun 75:397–407PubMedGoogle Scholar
  53. Sgouroudis E, Piccirillo CA (2009) Control of type 1 diabetes by CD4+Foxp3+ regulatory T cells: lessons from mouse models and implications for human disease. Diabetes Metab Res Rev 25(3):208–218PubMedGoogle Scholar
  54. Strachan DP (1989) Hay fever, hygiene, and household size. BMJ 299(6710):1259–1260PubMedGoogle Scholar
  55. Surendar J, Indulekha K, Hoerauf A, Hübner MP (2017) Immunomodulation by helminths: Similar impact on type 1 and type 2 diabetes? Parasite Immunol 39(5):1–15Google Scholar
  56. Tang CL, Yang J, Cheng LY, Cheng LF, Liu ZM (2017a) Anti-CD25 monoclonal antibody enhances the protective efficacy of Schistosoma japonicum GST vaccine via inhibition of CD4+CD25+Foxp3+ regulatory T cells. Parasitol Res 116(10):2727–2732PubMedGoogle Scholar
  57. Tang H, Liang YB, Chen ZB, Du LL, Zeng LJ, Wu JG, Yang W, Liang HP, Ma ZF (2017b) Soluble egg antigen activates M2 macrophages via the STAT6 and PI3K pathways, and Schistosoma japonicum alternatively activates macrophage polarization to improve the survival rate of septic mice. J Cell Biochem 118(12):4230–4239PubMedGoogle Scholar
  58. Tang CL, Liu ZM, Gao Y, Xiong F (2018) Schistosoma infection and Schistosoma-derived products modulate the immune responses associated with protection against type 2 diabetes. Front Immunol 8:1990PubMedGoogle Scholar
  59. Taylor MD, van der Werf N, Harris A, Graham AL, Bain O, Allen JE, Maizels RM (2009) Early recruitment of natural CD4+ Foxp3+ Treg cells by infective larvae determines the outcome of filarial infection. Eur J Immunol 39:192–206PubMedGoogle Scholar
  60. Thabet HS, Saleh NK, Thabet SS, Abdel-Aziz M, Kalleny NK (2008) Decreased basal non-insulin-stimulated glucose uptake by diaphragm in streptozotocin-induced diabetic mice infected with Schistosoma mansoni. Parasitol Res 103:595–601PubMedGoogle Scholar
  61. Tritt M, Sgouroudis E, d’Hennezel E, Albanese A, Piccirillo CA (2008) Functional waning of naturally occurring CD4+ regulatory T-cells contributes to the onset of autoimmune diabetes. Diabetes 57:113–123PubMedGoogle Scholar
  62. Wan YY, Flavell RA (2007) Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 445:766–770PubMedGoogle Scholar
  63. Weinstock JV, Elliott DE (2014) Helminth infections decrease host susceptibility to immune-mediated diseases. J Immunol 193:3239–3247PubMedGoogle Scholar
  64. Xiang AH, Wang X, Martinez MP, Getahun D, Page KA, Buchanan TA, Feldman K (2018) Maternal gestational diabetes mellitus, type 1 diabetes, and type 2 diabetes during pregnancy and risk of ADHD in offspring. Diabetes Care 41(12):2502–2508PubMedGoogle Scholar
  65. Zaccone P, Fehérvári Z, Jones FM, Sidobre S, Kronenberg M, Dunne DW, Cooke A (2003) Schistosoma mansoni antigens modulate the activity of the innate immune response and prevent onset of type 1 diabetes. Eur J Immunol 33:1439–1449PubMedGoogle Scholar
  66. Zaccone P, Fehervari Z, Phillips JM, Dunne DW, Cooke A (2006) Parasitic worms and inflammatory diseases. Parasite Immunol 28:515–523PubMedGoogle Scholar
  67. Zaccone P, Burton O, Miller N, Jones FM, Dunne DW, Cooke A (2009) Schistosoma mansoni egg antigens induce Treg that participate in diabetes prevention in NOD mice. Eur J Immunol 39:1098–1107PubMedGoogle Scholar
  68. Zaccone P, Burton OT, Gibbs S, Miller N, Jones FM, Dunne DW, Cooke A (2010) Immune modulation by Schistosoma mansoni antigens in NOD mice: effects on both innate and adaptive immune systems. J Biomed Biotechnol 2010:795210PubMedGoogle Scholar
  69. Zaccone P, Burton OT, Gibbs SE, Miller N, Jones FM, Schramm G, Haas H, Doenhoff MJ, Dunne DW, Cooke A (2011) The S. mansoni glycoprotein ω-1 induces Foxp3 expression in NOD mouse CD4+ T cells. Eur J Immunol 41:2709–2718PubMedGoogle Scholar
  70. Zhou X, Kong N, Zou H, Brand D, Li X, Liu Z, Zheng SG (2011) Therapeutic potential of TGF-β-induced CD4+Foxp3+ regulatory T cells in autoimmune diseases. Autoimmunity 44:43–50PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Wuchang Hospital affiliated to Wuhan University of Science and TechnologyWuhanChina
  2. 2.Department of Obstetrics and GynecologyPeople’s Hospital of Songzi CitySongziChina

Personalised recommendations