Effects of Helminth Eradication on the Immune System

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Ziva Weisman
Alexander Kalinkovich
Miguel Stein
Zalman Greenberg
Gad Borkow
David Adlerstein
Jemal Ali Mahdi
Zvi Bentwich

Abstract

Introduction: Helminth infection has a profound effect on the immune system. However, the precise nature of the immune changes that are elicited by helminth infection have not been sufficiently characterized. Furthermore, the reversibility of these changes after treatment has not been documented sufficiently. We studied the immune profiles of Ethiopian immigrants to Israel at baseline, that is on arrival and at one-year follow-up and compared individuals who received antihelminthic treatment during the study period with those who missed the treatment.

Methods: A longitudinal follow up study involving different groups of subjects was conducted. Baseline data was recorded from the newly arrived Ethiopian immigrants for a series of peripheral blood tests, including: IgE and Eosinophil levels, T-cell populations, T-cell receptor phenotypes, and cytokine measurement. These tests were all repeated after a 1-year interval. Results were compared between the newly arrived Ethiopian immigrants (NEW-Eth-Il), long term Ethiopian immigrants (LT-Eth-Il), and non Ethiopian Israeli controls (NON-Imm-Il).

Results: Of the 184 individuals, 111 were NEW-Eth-Il, who had a high prevalence of helminth infection, the immunological changes were elevated IgE levels and eosinophil counts, decreased CD4/CD8 ratio, increased proportion of HLA-DR+CD3+, HLA-DR+CD4+ and HLA-DR+CD8+ cells, decreased proportion of CD45RA+CD4+ (naive) and CD28+CD8+ cells, increased proportion of CD45RO+CD4+ (memory) cells, and increased secretion of IL-4 and IL-5 (Th2 type cytokines). In the 42 LT-Eth-Il participants, who all had negative tests for helminth infection, we did not observe these immune changes and their immune profile did not differ markedly from that of the NON-Imm-Il controls. The follow-up immune profiles of 33 NEW-Eth-Il who received succesful antihelminth treatment, showed a significant normalization in the above-mentioned variables that was not observed in the 19 NEW-Eth-Il who missed and did not receive the antihelminth treatment.

Conclusions: These findings demonstrate that helminth infection is associated with profound immune changes that are normalized within a short time after helminth eradication. They also strengthen the hypothesis that effective antihelminth interventions, in areas endemic for intestinal helminths, may have an impact on AIDS and tuberculosis epidemics.

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Author Biography

Jemal Ali Mahdi, Department of Microbiology, Immunology and Parasitology, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; Department of Microbiology Immunology and Genetics, Center for Emerging and Tropical Diseases and AIDS, Ben Gurion University of the Negev, Beer Sheba, Israel

Currently, I am a PhD student of Molecular Microbiology and Immunology in Ben Gurion University. I am academic staff in the department of Microbiology Immunology and Parasitology with academic rank of Assistant professor of Medical Microbiology.

References

1. Bundy DA, de Silva NR. Can we deworm this wormy world? Br Med Bull. 1998;54(2):421-32. PubMed PMID: 9830207.

2. Bundy DA, Medley GF. Immuno-epidemiology of human geohelminthiasis: ecological and immunological determinants of worm burden. Parasitology. 1992;104 Suppl:S105-19. PubMed PMID: 1589298.

3. Chan MS. The global burden of intestinal nematode infections--fifty years on. Parasitol Today. 1997;13(11):438-43. PubMed PMID: 15275146.

4. Araujo MI, de Jesus AR, Bacellar O, Sabin E, Pearce E, Carvalho EM. Evidence of a T helper type 2 activation in human schistosomiasis. Eur J Immunol. 1996;26(6):1399-403. PubMed PMID: 8647223. doi: 10.1002/eji.1830260633

5. Maizels RM, Bundy DA, Selkirk ME, Smith DF, Anderson RM. Immunological modulation and evasion by helminth parasites in human populations. Nature. 1993;365(6449):797-805. PubMed PMID: 8413664. doi: 10.1038/365797a0

6. Montenegro SM, Miranda P, Mahanty S, Abath FG, Teixeira KM, Coutinho EM, Brinkman J, Goncalves I, Domingues LA, Domingues AL, Sher A, Wynn TA. Cytokine production in acute versus chronic human Schistosomiasis mansoni: the cross-regulatory role of interferon-gamma and interleukin-10 in the responses of peripheral blood mononuclear cells and splenocytes to parasite antigens. J Infect Dis. 1999;179(6):1502-14. PubMed PMID: 10228073. doi: 10.1086/314748

7. Sher A, Gazzinelli RT, Oswald IP, Clerici M, Kullberg M, Pearce EJ, Berzofsky JA, Mosmann TR, James SL, Morse HC, 3rd. Role of T-cell derived cytokines in the downregulation of immune responses in parasitic and retroviral infection. Immunol Rev. 1992;127:183-204. PubMed PMID: 1354651.

8. Yazdanbakhsh M. Common features of T cell reactivity in persistent helminth infections: lymphatic filariasis and schistosomiasis. Immunol Lett. 1999;65(1-2):109-15. PubMed PMID: 10065636.

9. Kalinkovich A, Weisman Z, Greenberg Z, Nahmias J, Eitan S, Stein M, Bentwich Z. Decreased CD4 and increased CD8 counts with T cell activation is associated with chronic helminth infection. Clin Exp Immunol. 1998;114(3):414-21. PubMed PMID: 9844052. Pubmed Central PMCID: PMC1905129.

10. Messele T, Abdulkadir M, Fontanet AL, Petros B, Hamann D, Koot M, Roos MT, Schellekens PT, Miedema F, Rinke de Wit TF. Reduced naive and increased activated CD4 and CD8 cells in healthy adult Ethiopians compared with their Dutch counterparts. Clin Exp Immunol. 1999;115(3):443-50. PubMed PMID: 10193416. Pubmed Central PMCID: PMC1905237.

11. Grogan JL, Kremsner PG, Deelder AM, Yazdanbakhsh M. Antigen-specific proliferation and interferon-gamma and interleukin-5 production are down-regulated during Schistosoma haematobium infection. J Infect Dis. 1998;177(5):1433-7. PubMed PMID: 9593042.

12. Sabin EA, Araujo MI, Carvalho EM, Pearce EJ. Impairment of tetanus toxoid-specific Th1-like immune responses in humans infected with Schistosoma mansoni. J Infect Dis. 1996;173(1):269-72. PubMed PMID: 8537675.

13. Borkow G, Leng Q, Weisman Z, Stein M, Galai N, Kalinkovich A, Bentwich Z. Chronic immune activation associated with intestinal helminth infections results in impaired signal transduction and anergy. J Clin Invest. 2000;106(8):1053-60. PubMed PMID: 11032865. Pubmed Central PMCID: 314342. doi: 10.1172/JCI10182

14. Villa OF, Kuhn RE. Mice infected with the larvae of Taenia crassiceps exhibit a Th2-like immune response with concomitant anergy and downregulation of Th1-associated phenomena. Parasitology. 1996;112 ( Pt 6):561-70. PubMed PMID: 8684830.

15. Bentwich Z. Good worms or bad worms: do worm infections affect the epidemiological patterns of other diseases? Parasitol Today. 2000;16(7):312. PubMed PMID: 10858652.

16. Bentwich Z, Kalinkovich A, Weisman Z, Borkow G, Beyers N, Beyers AD. Can eradication of helminthic infections change the face of AIDS and tuberculosis? Immunol Today. 1999;20(11):485-7. PubMed PMID: 10529774.

17. Soboslay PT, Geiger SM, Weiss N, Banla M, Luder CG, Dreweck CM, Batchassi E, Boatin BA, Stadler A, Schulz-Key H. The diverse expression of immunity in humans at distinct states of Onchocerca volvulus infection. Immunology. 1997;90(4):592-9. PubMed PMID: 9176114. Pubmed Central PMCID: PMC1456700.

18. Bentwich Z, Weisman Z., Grossman Z., Galai N, and Kalinkovich A. Pathogenesis of AIDS in Africa: lessons from the Ethiopian immigrants in Israel. Immunologist. 1997; 5:21-26

19. Bentwich Z, Kalinkovich A, Weisman Z. Immune activation is a dominant factor in the pathogenesis of African AIDS. Immunol Today. 1995;16(4):187-91. PubMed PMID: 7734046.

20. Bentwich Z, Weisman Z, Moroz C, Bar-Yehuda S, Kalinkovich A. Immune dysregulation in Ethiopian immigrants in Israel: relevance to helminth infections? Clin Exp Immunol. 1996;103(2):239-43. PubMed PMID: 8565306. Pubmed Central PMCID: PMC2200340.

21. Bentwich Z, Kalinkovich A, Weisman Z, Grossman Z. Immune activation in the context of HIV infection. Clin Exp Immunol. 1998;111(1):1-2. PubMed PMID: 9472654. Pubmed Central PMCID: PMC1904872.

22. Shapira-Nahor O, Kalinkovich A, Weisman Z, Greenberg Z, Nahmias J, Shapiro M, Panet A, Bentwich Z. Increased susceptibility to HIV-1 infection of peripheral blood mononuclear cells from chronically immune-activated individuals. AIDS. 1998;12(13):1731-3. PubMed PMID: 9764802.

23. Borkow G, Bentwich Z. Eradication of helminthic infections may be essential for successful vaccination against HIV and tuberculosis. Bull World Health Organ. 2000;78(11):1368-9. PubMed PMID: 11143198. Pubmed Central PMCID: PMC2560630.

24. Borkow G, Weisman Z, Leng Q, Stein M, Kalinkovich A, Wolday D, Bentwich Z. Helminths, human immunodeficiency virus and tuberculosis. Scand J Infect Dis. 2001;33(8):568-71. PubMed PMID: 11525348.

25. Elias D, Wolday D, Akuffo H, Petros B, Bronner U, Britton S. Effect of deworming on human T cell responses to mycobacterial antigens in helminth-exposed individuals before and after bacille Calmette-Guerin (BCG) vaccination. Clin Exp Immunol. 2001;123(2):219-25. PubMed PMID: 11207651. Pubmed Central PMCID: 1905995.

26. Nahmias J, Greenberg Z, Berger SA, Hornstein L, Bilgury B, Abel B, Kutner S. Health profile of Ethiopian immigrants in Israel: an overview. Isr J Med Sci. 1993;29(6-7):338-43. PubMed PMID: 8349445.

27. Knight WB, Hiatt RA, Cline BL, Ritchie LS. A modification of the formol-ether concentration technique for increased sensitivity in detecting Schistosoma mansoni eggs. Am J Trop Med Hyg. 1976;25(6):818-23. PubMed PMID: 1008127.

28. Roberts M, Butterworth AE, Kimani G, Kamau T, Fulford AJ, Dunne DW, Ouma JH, Sturrock RF. Immunity after treatment of human schistosomiasis: association between cellular responses and resistance to reinfection. Infect Immun. 1993;61(12):4984-93. PubMed PMID: 8225573. Pubmed Central PMCID: 281273.

29. Feldmeier H, Gastl GA, Poggensee U, Daffalla AA, Nogueira-Queiroz JA, Capron A, Peter HH. Immune response in chronic Schistosomiasis haematobium and mansoni. Reversibility of alterations after anti-parasitic treatment with praziquantel. Scand J Immunol. 1988;28(2):147-55. PubMed PMID: 3137653.

30. Williams MA, Rhoades CJ, Newland AC, Kelsey SM. The potential for monocyte-mediated immunotherapy during infection and malignancy--Part II: in vivo activation by exogenous cytokines and clinical applications. Leuk Lymphoma. 1999;34(3-4):207-30. PubMed PMID: 10439359. doi: 10.3109/10428199909050947

31. Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996;17(3):138-46. PubMed PMID: 8820272.

32. Williams ME, Montenegro S, Domingues AL, Wynn TA, Teixeira K, Mahanty S, Coutinho A, Sher A. Leukocytes of patients with Schistosoma mansoni respond with a Th2 pattern of cytokine production to mitogen or egg antigens but with a Th0 pattern to worm antigens. J Infect Dis. 1994;170(4):946-54. PubMed PMID: 7930740.

33. Fallon PG, Smith P, Dunne DW. Type 1 and type 2 cytokine-producing mouse CD4+ and CD8+ T cells in acute Schistosoma mansoni infection. Eur J Immunol. 1998;28(4):1408-16. PubMed PMID: 9565381. doi: 10.1002/(SICI)1521-4141(199804)28:04<1408::AID-IMMU1408>3.0.CO;2-H

34. Grzych JM, Pearce E, Cheever A, Caulada ZA, Caspar P, Heiny S, Lewis F, Sher A. Egg deposition is the major stimulus for the production of Th2 cytokines in murine schistosomiasis mansoni. J Immunol. 1991;146(4):1322-7. PubMed PMID: 1825109.

35. Mwatha JK, Kimani G, Kamau T, Mbugua GG, Ouma JH, Mumo J, Fulford AJ, Jones FM, Butterworth AE, Roberts MB, Dunne DW. High levels of TNF, soluble TNF receptors, soluble ICAM-1, and IFN-gamma, but low levels of IL-5, are associated with hepatosplenic disease in human schistosomiasis mansoni. J Immunol. 1998;160(4):1992-9. PubMed PMID: 9469463.

36. Wolday D, Mayaan S, Mariam ZG, Berhe N, Seboxa T, Britton S, Galai N, Landay A, Bentwich Z. Treatment of intestinal worms is associated with decreased HIV plasma viral load. J Acquir Immune Defic Syndr. 2002;31(1):56-62. PubMed PMID: 12352151.

37. Walson JL, Herrin BR, John-Stewart G. Deworming helminth co-infected individuals for delaying HIV disease progression. Cochrane Database Syst Rev. 2009 (3):CD006419. PubMed PMID: 19588389. Pubmed Central PMCID: 2871762. doi: 10.1002/14651858.CD006419.pub3

38. Lawn SD, Karanja DM, Mwinzia P, Andove J, Colley DG, Folks TM, Secor WE. The effect of treatment of schistosomiasis on blood plasma HIV-1 RNA concentration in coinfected individuals. AIDS. 2000;14(16):2437-43. PubMed PMID: 11101053.

39. Modjarrad K, Zulu I, Redden DT, Njobvu L, Lane HC, Bentwich Z, Vermund SH. Treatment of intestinal helminths does not reduce plasma concentrations of HIV-1 RNA in coinfected Zambian adults. J Infect Dis. 2005;192(7):1277-83. PubMed PMID: 16136473. Pubmed Central PMCID: PMC2730764. doi: 10.1086/444543