Immunotherapeutic Potential of Echinococcus granulosus Hydatid Cyst Antigens in Autoimmune Disease and Allergy
Abstract
This study explores recent advances in harnessing the immunotherapeutic potential of hydatid cyst antigens for the treatment of allergies and autoimmunity. The aim is to elucidate the immunotherapeutic mechanisms employed by these parasite antigens. The hydatid cyst is considered the larval stage of Echinococcus granulosus, a parasitic helminth with life cycles involving a carnivorous definitive host (usually dogs) and an intermediate herbivore host (human, ungulate, or rodent). The two major species of this parasite with human public health importance are E granulosus and E multilocularis. E granulosus is a highly immunogenic organism that stimulates proinflammatory responses, significant antibody production, and T cell-mediated responses. Host adaptive immune responses to the parasite are TH2 dominant, but responses are absent in one-fifth of patients. Diagnostic antigens from cyst fluid are well-known, and the high abundance of hydatid cysts in the lungs and livers of slaughtered farm animals has made it easy to access the source of cyst antigens. Emerging from current preclinical studies, antigens derived from hydatid cyst cells and fluid show potential for suppressing and regulating immune responses associated with allergic and autoimmune conditions, disorders which increase with Western-type human development.
1. Zhang W, Li J, McManus DP. Concepts in immunology and diagnosis of hydatid disease. Clin Microbiol Rev. 2003;16(1):18-36.
2. Thompson R, McManus D. Aetiology: parasites and life-cycles. World Organization Animal Health; 2001.
3. Moro P, Schantz PM. Echinococcosis: a review. International journal of Infectious diseases. 2009;13(2):125-33.
4. Díaz A, Casaravilla C, Irigoín F, Lin G, Previato JO, Ferreira F. Understanding the laminated layer of larval Echinococcus I: structure. Trends Parasitol. 2011;27(5):204-13.
5. Díaz Á. Immunology of cystic echinococcosis (hydatid disease). British Med Bulletin. 2017:1-13.
6. Korc I, Hierro J, Lasalvia E, Falco M, Calcagno M. Chemical characterization of the polysaccharide of the hydatid membrane of Echinococcus granulosus. Exp Parasitol. 1967;20(2):219-24.
7. Conchedda M, Gabriele F, Bortoletti G. Immunobiology of cystic echinococcosis. Parassitologia. 2004;46(4):375.
8. Zhang W, Wen H, Li J, Lin R, McManus DP. Immunology and immunodiagnosis of cystic echinococcosis: an update. Clin Develop Immunol. 2012;2012.
9. Díaz Á, Barrios AA, Grezzi L, Mouhape C, Jenkins SJ, Allen JE, et al. Immunology of a unique biological structure: the Echinococcus laminated layer. Protein cell. 2023;14(2):87-104.
10. Dematteis S, Baz A, Rottenbrg M, Fernandez C, Örn A, Nieto A. Antibody and Th1/Th2‐type responses in BALB/c mice inoculated with live or dead Echinococcus granulosus protoscoleces. Parasite Immunol. 1999;21(1):19-26.
11. Zhang W, Ross AG, McManus DP. Mechanisms of immunity in hydatid disease: implications for vaccine development. J Immunol. 2008;181(10):6679-85.
12. Lightowlers M. Immunology and molecular biology of Echinococcus infections. Int J Parasitol. 1990;20(4):471-8.
13. Magambo JK, Wachira TM, Wachira J, Raasen T. Cellular immunity to Echinococcus granulosus cysts. African J Health Sci. 1995;2(1):250-3.
14. Zhang W, Wen H, Li J, Lin R, McManus DP. Immunology and immunodiagnosis of cystic echinococcosis: an update. J Immunol Res. 2012;2012.
15. Rigano R, Profumo E, Di Felice O, Ortona E, Teggi A, Siracusano A. In vitro production of cytokines by peripheral blood mononuclear cells from hydatid patients. Clin Exp Immunol. 1995;99(3):433-9.
16. Rigano R, Profumo E, Teggi A, Siracusano A. Production of IL‐5 and IL‐6 by peripheral blood mononuclear cells (PBMC) from patients with Echinococcus granulosus infection. Clin Exp Immunol. 1996;105(3):456-9.
17. Vuitton DA. The ambiguous role of immunity in echinococcosis: protection of the host or of the parasite? Acta Tropica. 2003;85(2):119-32.
18. Trinchieri G. Interleukin-10 production by effector T cells: Th1 cells show self control. The J Expe Med. 2007;204(2):239-43.
19. Rigano R, Profumo E, Ioppolo S, Notargiacomo S, Ortona E, Teggi A, et al. Immunological markers indicating the effectiveness of pharmacological treatment in human hydatid disease. Clin Exp Immunol. 1995;102(2):281-5.
20. Sarkar M, Pathania R, Jhobta A, Thakur BR, Chopra R. Cystic pulmonary hydatidosis. Lung India. 2016;33(2):179-91.
21. Rigano R, Profumo E, Bruschi F, Carulli G, Azzarà A, Ioppolo S, et al. Modulation of human immune response by Echinococcus granulosus antigen B and its possible role in evading host defenses. Infect Immunity. 2001;69(1):288-96.
22. Rigano R, Buttari B, Profumo E, Ortona E, Delunardo F, Margutti P, et al. Echinococcus granulosus antigen B impairs human dendritic cell differentiation and polarizes immature dendritic cell maturation towards a Th2 cell response. Infect Immunity. 2007;75(4):1667-78.
23. Wills-Karp M, Santeliz J, Karp CL. The germless theory of allergic disease: revisiting the hygiene hypothesis. Nat Rev Immunol. 2001;1(1):69-75.
24. Wang H, Li J, Pu H, Hasan B, Ma J, Jones MK, et al. Echinococcus granulosus infection reduces airway inflammation of mice likely through enhancing IL-10 and down-regulation of IL-5 and IL-17A. Parasites Vectors. 2014;7(1):1-13.
25. Jeong MJ, Kang SA, Choi JH, Lee DI, Yu HS. Extracellular vesicles of Echinococcus granulosus have therapeutic effects in allergic airway inflammation. Parasite Immunol. 2021;43(10-11):e12872.
26. Ghabdian S, Parande Shirvan S, Maleki M, Borji H. Exacerbation of allergic asthma by somatic antigen of Echinococcus granulosus in allergic airway inflammation in BALB/c mice. Parasites Vectors 2022;15(1):1-9.
27. Kim H-J, Kang S-A, Yong T-S, Shin M-H, Lee K-J, Park G-M, et al. Therapeutic effects of Echinococcus granulosus cystic fluid on allergic airway inflammation. Exp Parasitol. 2019;198:63-70.
28. Farinon M, Oliveira P, Clarimundo V, Monteiro K, Zaha A, Ferreira H, et al. Immunomodulatory and antiinflammatory properties of antigen B, a Protein secreted by echinococcus granulosus larval stage, in experimental arthritis. Annal Rheumatic Dis. 2014;73(Suppl 2):848.
29. Bao J, Qi W, Sun C, Tian M, Jiao H, Guo G, et al. AntigenB drives M1/M2 polarization following Echinococcus granulosus infection in inflammatory bowel disease. 2022.
30. Qian Y-Y, Huang F-F, Chen S-Y, Zhang W-X, Wang Y, Du P-F, et al. Therapeutic effect of recombinant Echinococcus granulosus antigen B subunit 2 protein on sepsis in a mouse model. Parasites Vectors. 2024;17(1):467.
31. Sicherer SH, Sampson HA. Food allergy: epidemiology, pathogenesis, diagnosis, and treatment. J Allergy Clin Immunol. 2014;133(2):291-307. e5.
32. Araújo MI, Hoppe BS, Medeiros Jr M, Carvalho EM. Schistosoma mansoni infection modulates the immune response against allergic and auto-immune diseases. Memorias do Instituto Oswaldo Cruz. 2004;99:27-32.
33. Lee KH, Park HK, Jeong HJ, Park SK, Lee SJ, Choi SH, et al. Immunization of proteins from Toxascaris leonina adult worm inhibits allergic specific Th2 response. Veterinary Parasitol. 2008;156(3-4):216-25.
34. Wang Y, Zhou H, Shen Y, Wang Y, Wu W, Liu H, et al. Impairment of dendritic cell function and induction of CD4+ CD25+ Foxp3+ T cells by excretory-secretory products: a potential mechanism of immune evasion adopted by Echinococcus granulosus. BMC Immunol. 2015;16(1):1-10.
35. Tuxun T, Wang JH, Lin RY, SHAN JY, TAI QW, Li T, et al. Th17/Treg imbalance in patients with liver cystic echinococcosis. Parasite Immunol. 2012;34(11):520-7.
36. Zhang Y, Yue Y, Cheng Y, Jiao H, Yan M. Antigen B from Echinococcus granulosus regulates macrophage phagocytosis by controlling TLR4 endocytosis in immune thrombocytopenia. Chem Biol Interact. 2024:111350.
37. Benazzouz S, Amri M, Wang J, Bouaziz S, Ameur F, Djebbara S, et al. In vitro immunoregulatory activity and anti-inflammatory effect of Echinococcus granulosus laminated layer. Acta Tropica. 2021;218:105886.
38. Zakariaei Z, Fakhar M, Sharifpour A, Banimostafavi ES, Soleymani M, Zakariaei A. Anaphylactic shock due to ruptured pulmonary hydatid cyst in a young patient from Iran. Annals Med Surgery. 2021;68.
39. Shameem M, Akhtar J, Bhargava R, Ahmed Z, Khan NA, Baneen U. Ruptured pulmonary hydatid cyst with anaphylactic shock and pneumothorax. Resp Care. 2011;56(6):863-5.
40. Yilmaz I, Aydin O, Okoh A, Misirligil Z. Late onsCet anaphylaxis in a hydatid cyst case presenting with chronic urticaria. Case Reports in Med. 2013;2013(1):658393.
41. Ozkan F, Yesilkaya Y, Peker O, Yuksel M. Anaphylaxis due to spontaneous rupture of primary isolated splenic hydatid cyst. Int J Critical Illness Injury Sci. 2013;3(2):152-4.
42. Belhaj A, Et-Tayeb O, Majdoub KI, Toughrai I, Laalim SA, Mazaz K. Anaphylactic shock during splenic hydatid cyst surgery: A case report. J Surgery Med. 2018;2(2):154-6.
43. Hanalioglu D, Terzi K, Ozkan S, Sivri M, Kurt F, Misirlioglu ED. Anaphylactic shock following minor abdominal trauma as the initial presentation of Echinococcus cyst: a case report. BMC pediatrics. 2022;22(1):89.
44. Wang M, Wu L, Weng R, Zheng W, Wu Z, Lv Z. Therapeutic potential of helminths in autoimmune diseases: helminth-derived immune-regulators and immune balance. Parasitol Res. 2017;116:2065-74.
45. Hübner MP, Layland LE, Hoerauf A. Helminths and their implication in sepsis–a new branch of their immunomodulatory behaviour? Pathogens Dis. 2013;69(2):127-41.
46. Bao J, Qi W, Sun C, Tian M, Jiao H, Guo G, et al. Echinococcus granulosus sensu stricto and antigen B may decrease inflammatory bowel disease through regulation of M1/2 polarization. Parasites Vectors 2022;15(1):391.
47. Xie H, Wu L, Chen X, Gao S, Li H, Yuan Y, et al. Schistosoma japonicum cystatin alleviates sepsis through activating regulatory macrophages. Front Cell Infect Microbiol. 2021;11:617461.
48. Walsh KP, Brady MT, Finlay CM, Boon L, Mills KH. Infection with a helminth parasite attenuates autoimmunity through TGF-β-mediated suppression of Th17 and Th1 responses. J Immunol. 2009;183(3):1577-86.
49. Aslan M, Oner Y, Saribas S, Polat E, Cakan H, Yuksel P, et al. Can cystic Echinococcosis trigger autoimmunity? Int J Infect Dis. 2010;14:e292-e3.
50. Lightowlers MW, Haralambous A, Rickard MD. Amino acid sequence homology between cyclophilin and a cDNA-cloned antigen of Echinococcus granulosus. Mol Biochem Parasitol. 1989;36(3):287-9.
51. 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(9):1199-212.
52. Ranasinghe S, McManus D. Echinococcus granulosus: Cure for Cancer Revisited. Front Med (Lausanne). 2018; 5: 60. 2018.
53. De Rosa FG, Amoroso A, Teggi A, Paparo SB, Franchi C, Ferri GM, et al. Anti-neutrophil cytoplasmic antibodies in echinococcus granulosus hydatid disease. Hum Immunol. 2001;62(10):1122-6.
2. Thompson R, McManus D. Aetiology: parasites and life-cycles. World Organization Animal Health; 2001.
3. Moro P, Schantz PM. Echinococcosis: a review. International journal of Infectious diseases. 2009;13(2):125-33.
4. Díaz A, Casaravilla C, Irigoín F, Lin G, Previato JO, Ferreira F. Understanding the laminated layer of larval Echinococcus I: structure. Trends Parasitol. 2011;27(5):204-13.
5. Díaz Á. Immunology of cystic echinococcosis (hydatid disease). British Med Bulletin. 2017:1-13.
6. Korc I, Hierro J, Lasalvia E, Falco M, Calcagno M. Chemical characterization of the polysaccharide of the hydatid membrane of Echinococcus granulosus. Exp Parasitol. 1967;20(2):219-24.
7. Conchedda M, Gabriele F, Bortoletti G. Immunobiology of cystic echinococcosis. Parassitologia. 2004;46(4):375.
8. Zhang W, Wen H, Li J, Lin R, McManus DP. Immunology and immunodiagnosis of cystic echinococcosis: an update. Clin Develop Immunol. 2012;2012.
9. Díaz Á, Barrios AA, Grezzi L, Mouhape C, Jenkins SJ, Allen JE, et al. Immunology of a unique biological structure: the Echinococcus laminated layer. Protein cell. 2023;14(2):87-104.
10. Dematteis S, Baz A, Rottenbrg M, Fernandez C, Örn A, Nieto A. Antibody and Th1/Th2‐type responses in BALB/c mice inoculated with live or dead Echinococcus granulosus protoscoleces. Parasite Immunol. 1999;21(1):19-26.
11. Zhang W, Ross AG, McManus DP. Mechanisms of immunity in hydatid disease: implications for vaccine development. J Immunol. 2008;181(10):6679-85.
12. Lightowlers M. Immunology and molecular biology of Echinococcus infections. Int J Parasitol. 1990;20(4):471-8.
13. Magambo JK, Wachira TM, Wachira J, Raasen T. Cellular immunity to Echinococcus granulosus cysts. African J Health Sci. 1995;2(1):250-3.
14. Zhang W, Wen H, Li J, Lin R, McManus DP. Immunology and immunodiagnosis of cystic echinococcosis: an update. J Immunol Res. 2012;2012.
15. Rigano R, Profumo E, Di Felice O, Ortona E, Teggi A, Siracusano A. In vitro production of cytokines by peripheral blood mononuclear cells from hydatid patients. Clin Exp Immunol. 1995;99(3):433-9.
16. Rigano R, Profumo E, Teggi A, Siracusano A. Production of IL‐5 and IL‐6 by peripheral blood mononuclear cells (PBMC) from patients with Echinococcus granulosus infection. Clin Exp Immunol. 1996;105(3):456-9.
17. Vuitton DA. The ambiguous role of immunity in echinococcosis: protection of the host or of the parasite? Acta Tropica. 2003;85(2):119-32.
18. Trinchieri G. Interleukin-10 production by effector T cells: Th1 cells show self control. The J Expe Med. 2007;204(2):239-43.
19. Rigano R, Profumo E, Ioppolo S, Notargiacomo S, Ortona E, Teggi A, et al. Immunological markers indicating the effectiveness of pharmacological treatment in human hydatid disease. Clin Exp Immunol. 1995;102(2):281-5.
20. Sarkar M, Pathania R, Jhobta A, Thakur BR, Chopra R. Cystic pulmonary hydatidosis. Lung India. 2016;33(2):179-91.
21. Rigano R, Profumo E, Bruschi F, Carulli G, Azzarà A, Ioppolo S, et al. Modulation of human immune response by Echinococcus granulosus antigen B and its possible role in evading host defenses. Infect Immunity. 2001;69(1):288-96.
22. Rigano R, Buttari B, Profumo E, Ortona E, Delunardo F, Margutti P, et al. Echinococcus granulosus antigen B impairs human dendritic cell differentiation and polarizes immature dendritic cell maturation towards a Th2 cell response. Infect Immunity. 2007;75(4):1667-78.
23. Wills-Karp M, Santeliz J, Karp CL. The germless theory of allergic disease: revisiting the hygiene hypothesis. Nat Rev Immunol. 2001;1(1):69-75.
24. Wang H, Li J, Pu H, Hasan B, Ma J, Jones MK, et al. Echinococcus granulosus infection reduces airway inflammation of mice likely through enhancing IL-10 and down-regulation of IL-5 and IL-17A. Parasites Vectors. 2014;7(1):1-13.
25. Jeong MJ, Kang SA, Choi JH, Lee DI, Yu HS. Extracellular vesicles of Echinococcus granulosus have therapeutic effects in allergic airway inflammation. Parasite Immunol. 2021;43(10-11):e12872.
26. Ghabdian S, Parande Shirvan S, Maleki M, Borji H. Exacerbation of allergic asthma by somatic antigen of Echinococcus granulosus in allergic airway inflammation in BALB/c mice. Parasites Vectors 2022;15(1):1-9.
27. Kim H-J, Kang S-A, Yong T-S, Shin M-H, Lee K-J, Park G-M, et al. Therapeutic effects of Echinococcus granulosus cystic fluid on allergic airway inflammation. Exp Parasitol. 2019;198:63-70.
28. Farinon M, Oliveira P, Clarimundo V, Monteiro K, Zaha A, Ferreira H, et al. Immunomodulatory and antiinflammatory properties of antigen B, a Protein secreted by echinococcus granulosus larval stage, in experimental arthritis. Annal Rheumatic Dis. 2014;73(Suppl 2):848.
29. Bao J, Qi W, Sun C, Tian M, Jiao H, Guo G, et al. AntigenB drives M1/M2 polarization following Echinococcus granulosus infection in inflammatory bowel disease. 2022.
30. Qian Y-Y, Huang F-F, Chen S-Y, Zhang W-X, Wang Y, Du P-F, et al. Therapeutic effect of recombinant Echinococcus granulosus antigen B subunit 2 protein on sepsis in a mouse model. Parasites Vectors. 2024;17(1):467.
31. Sicherer SH, Sampson HA. Food allergy: epidemiology, pathogenesis, diagnosis, and treatment. J Allergy Clin Immunol. 2014;133(2):291-307. e5.
32. Araújo MI, Hoppe BS, Medeiros Jr M, Carvalho EM. Schistosoma mansoni infection modulates the immune response against allergic and auto-immune diseases. Memorias do Instituto Oswaldo Cruz. 2004;99:27-32.
33. Lee KH, Park HK, Jeong HJ, Park SK, Lee SJ, Choi SH, et al. Immunization of proteins from Toxascaris leonina adult worm inhibits allergic specific Th2 response. Veterinary Parasitol. 2008;156(3-4):216-25.
34. Wang Y, Zhou H, Shen Y, Wang Y, Wu W, Liu H, et al. Impairment of dendritic cell function and induction of CD4+ CD25+ Foxp3+ T cells by excretory-secretory products: a potential mechanism of immune evasion adopted by Echinococcus granulosus. BMC Immunol. 2015;16(1):1-10.
35. Tuxun T, Wang JH, Lin RY, SHAN JY, TAI QW, Li T, et al. Th17/Treg imbalance in patients with liver cystic echinococcosis. Parasite Immunol. 2012;34(11):520-7.
36. Zhang Y, Yue Y, Cheng Y, Jiao H, Yan M. Antigen B from Echinococcus granulosus regulates macrophage phagocytosis by controlling TLR4 endocytosis in immune thrombocytopenia. Chem Biol Interact. 2024:111350.
37. Benazzouz S, Amri M, Wang J, Bouaziz S, Ameur F, Djebbara S, et al. In vitro immunoregulatory activity and anti-inflammatory effect of Echinococcus granulosus laminated layer. Acta Tropica. 2021;218:105886.
38. Zakariaei Z, Fakhar M, Sharifpour A, Banimostafavi ES, Soleymani M, Zakariaei A. Anaphylactic shock due to ruptured pulmonary hydatid cyst in a young patient from Iran. Annals Med Surgery. 2021;68.
39. Shameem M, Akhtar J, Bhargava R, Ahmed Z, Khan NA, Baneen U. Ruptured pulmonary hydatid cyst with anaphylactic shock and pneumothorax. Resp Care. 2011;56(6):863-5.
40. Yilmaz I, Aydin O, Okoh A, Misirligil Z. Late onsCet anaphylaxis in a hydatid cyst case presenting with chronic urticaria. Case Reports in Med. 2013;2013(1):658393.
41. Ozkan F, Yesilkaya Y, Peker O, Yuksel M. Anaphylaxis due to spontaneous rupture of primary isolated splenic hydatid cyst. Int J Critical Illness Injury Sci. 2013;3(2):152-4.
42. Belhaj A, Et-Tayeb O, Majdoub KI, Toughrai I, Laalim SA, Mazaz K. Anaphylactic shock during splenic hydatid cyst surgery: A case report. J Surgery Med. 2018;2(2):154-6.
43. Hanalioglu D, Terzi K, Ozkan S, Sivri M, Kurt F, Misirlioglu ED. Anaphylactic shock following minor abdominal trauma as the initial presentation of Echinococcus cyst: a case report. BMC pediatrics. 2022;22(1):89.
44. Wang M, Wu L, Weng R, Zheng W, Wu Z, Lv Z. Therapeutic potential of helminths in autoimmune diseases: helminth-derived immune-regulators and immune balance. Parasitol Res. 2017;116:2065-74.
45. Hübner MP, Layland LE, Hoerauf A. Helminths and their implication in sepsis–a new branch of their immunomodulatory behaviour? Pathogens Dis. 2013;69(2):127-41.
46. Bao J, Qi W, Sun C, Tian M, Jiao H, Guo G, et al. Echinococcus granulosus sensu stricto and antigen B may decrease inflammatory bowel disease through regulation of M1/2 polarization. Parasites Vectors 2022;15(1):391.
47. Xie H, Wu L, Chen X, Gao S, Li H, Yuan Y, et al. Schistosoma japonicum cystatin alleviates sepsis through activating regulatory macrophages. Front Cell Infect Microbiol. 2021;11:617461.
48. Walsh KP, Brady MT, Finlay CM, Boon L, Mills KH. Infection with a helminth parasite attenuates autoimmunity through TGF-β-mediated suppression of Th17 and Th1 responses. J Immunol. 2009;183(3):1577-86.
49. Aslan M, Oner Y, Saribas S, Polat E, Cakan H, Yuksel P, et al. Can cystic Echinococcosis trigger autoimmunity? Int J Infect Dis. 2010;14:e292-e3.
50. Lightowlers MW, Haralambous A, Rickard MD. Amino acid sequence homology between cyclophilin and a cDNA-cloned antigen of Echinococcus granulosus. Mol Biochem Parasitol. 1989;36(3):287-9.
51. 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(9):1199-212.
52. Ranasinghe S, McManus D. Echinococcus granulosus: Cure for Cancer Revisited. Front Med (Lausanne). 2018; 5: 60. 2018.
53. De Rosa FG, Amoroso A, Teggi A, Paparo SB, Franchi C, Ferri GM, et al. Anti-neutrophil cytoplasmic antibodies in echinococcus granulosus hydatid disease. Hum Immunol. 2001;62(10):1122-6.
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How to Cite
1.
Samei A, khedri M. Immunotherapeutic Potential of Echinococcus granulosus Hydatid Cyst Antigens in Autoimmune Disease and Allergy. Iran J Allergy Asthma Immunol. 2025;:1-9.
