Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Apr 1;99(7):1759–1766. doi: 10.1172/JCI119340

In utero exposure to helminth and mycobacterial antigens generates cytokine responses similar to that observed in adults.

I Malhotra 1, J Ouma 1, A Wamachi 1, J Kioko 1, P Mungai 1, A Omollo 1, L Elson 1, D Koech 1, J W Kazura 1, C L King 1
PMCID: PMC507997  PMID: 9120021

Abstract

Neonates exposed to parasite antigens (Ags) in utero may develop altered fetal immunity that could affect subsequent responses to infection. We hypothesized that cord blood lymphocytes (CBL) from offspring of mothers residing in an area highly endemic for schistosomiasis, filariasis, and tuberculosis in Kenya would either fail to respond or generate a predominantly Th2-associated cytokine response to helminth and mycobacterial antigens (PPD) in vitro compared to maternal PBMC. Kenyan CBL generated helminth Ag-specific IL-5 (range 29-194 pg/ml), IL-10 (121-2,115 pg/ml), and/or IFN-gamma (78 pg/ml-10.6 ng/ml) in 26, 46, and 57% of neonates, respectively (n = 40). PPD induced IFN-gamma in 30% of Kenyan CBL (range 79-1,896 pg/ml), but little or no IL-4 or IL-5. No Ag-specific IL-4, IL-5, or IFN-gamma release was detected by CBL obtained in the United States (n = 11). Ag-driven cytokine production was primarily CD4-dependent. Cytokine responses to helminth and mycobacterial Ags by maternal PBMC mirrored that observed in neonates. CBL from helminth infected and/or PPD-sensitized mothers produced more Ag-specific cytokines compared to CBL from uninfected mothers (P < 0.05). These data demonstrate that the human fetus develops similar patterns of cytokine production observed in adults and indicates that prenatal exposure may not lead to tolerance or altered fetal immunity. .

Full Text

The Full Text of this article is available as a PDF (207.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aase J. M., Noren G. R., Reddy D. V., Geme J. W., Jr Mumps-virus infection in pregnant women and the immunologic response of their offspring. N Engl J Med. 1972 Jun 29;286(26):1379–1382. doi: 10.1056/NEJM197206292862603. [DOI] [PubMed] [Google Scholar]
  2. Agarwal M., Prasad G. B., Harinath B. C., Bhatia B. D. Transplacental transfer of filarial infection. Indian Pediatr. 1986 Mar;23(3):169–174. [PubMed] [Google Scholar]
  3. BILLINGHAM R. E., BRENT L., MEDAWAR P. B. Actively acquired tolerance of foreign cells. Nature. 1953 Oct 3;172(4379):603–606. doi: 10.1038/172603a0. [DOI] [PubMed] [Google Scholar]
  4. Baker C. J., Rench M. A., Edwards M. S., Carpenter R. J., Hays B. M., Kasper D. L. Immunization of pregnant women with a polysaccharide vaccine of group B streptococcus. N Engl J Med. 1988 Nov 3;319(18):1180–1185. doi: 10.1056/NEJM198811033191802. [DOI] [PubMed] [Google Scholar]
  5. Barrios C., Brawand P., Berney M., Brandt C., Lambert P. H., Siegrist C. A. Neonatal and early life immune responses to various forms of vaccine antigens qualitatively differ from adult responses: predominance of a Th2-biased pattern which persists after adult boosting. Eur J Immunol. 1996 Jul;26(7):1489–1496. doi: 10.1002/eji.1830260713. [DOI] [PubMed] [Google Scholar]
  6. Boros D. L., Warren K. S. Delayed hypersensitivity-type granuloma formation and dermal reaction induced and elicited by a soluble factor isolated from Schistosoma mansoni eggs. J Exp Med. 1970 Sep 1;132(3):488–507. doi: 10.1084/jem.132.3.488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Camus D., Carlier Y., Bina J. C., Borojevic R., Prata A., Capron A. Sensitization to Schistosoma mansoni antigen in uninfected children born to infected mothers. J Infect Dis. 1976 Oct;134(4):405–408. doi: 10.1093/infdis/134.4.405. [DOI] [PubMed] [Google Scholar]
  8. Carlier Y., Bout D., Bina J. C., Camus D., Figueiredo J. F., Capron A. Immunological studies in human schistosomiasis. I. Parasitic antigen in urine. Am J Trop Med Hyg. 1975 Nov;24(6 Pt 1):949–954. doi: 10.4269/ajtmh.1975.24.949. [DOI] [PubMed] [Google Scholar]
  9. Carlier Y., Nzeyimana H., Bout D., Capron A. Evaluation of circulating antigens by a sandwich radioimmunoassay, and of antibodies and immune complexes, in Schistosoma mansoni-infected African parturients and their newborn children. Am J Trop Med Hyg. 1980 Jan;29(1):74–81. doi: 10.4269/ajtmh.1980.29.74. [DOI] [PubMed] [Google Scholar]
  10. Eloi-Santos S. M., Novato-Silva E., Maselli V. M., Gazzinelli G., Colley D. G., Correa-Oliveira R. Idiotypic sensitization in utero of children born to mothers with schistosomiasis or Chagas' disease. J Clin Invest. 1989 Sep;84(3):1028–1031. doi: 10.1172/JCI114225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Forsthuber T., Yip H. C., Lehmann P. V. Induction of TH1 and TH2 immunity in neonatal mice. Science. 1996 Mar 22;271(5256):1728–1730. doi: 10.1126/science.271.5256.1728. [DOI] [PubMed] [Google Scholar]
  12. Fried M., Duffy P. E. Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta. Science. 1996 Jun 7;272(5267):1502–1504. doi: 10.1126/science.272.5267.1502. [DOI] [PubMed] [Google Scholar]
  13. GELFAND M. THE HYPERSENSITIVE RESPONSE OF THE EUROPEAN TO SCHISTOSOMIASIS. J Trop Med Hyg. 1964 Oct;67:255–256. [PubMed] [Google Scholar]
  14. Gill T. J., 3rd, Repetti C. F., Metlay L. A., Rabin B. S., Taylor F. H., Thompson D. S., Cortese A. L. Transplacental immunization of the human fetus to tetanus by immunization of the mother. J Clin Invest. 1983 Sep;72(3):987–996. doi: 10.1172/JCI111071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Grogan T. M., Broughton D. D., Doyle W. F. Graft-versus-host reaction (GVHR). A case report suggesting GVHR occurred as a result of maternofetal cell transfer. Arch Pathol. 1975 Jun;99(6):330–334. [PubMed] [Google Scholar]
  16. Hang L. M., Boros D. L., Warren K. S. Induction of immunological hyporesponsiveness to granulomatous hypersensitivity in Schistosoma mansoni infection. J Infect Dis. 1974 Nov;130(5):515–522. doi: 10.1093/infdis/130.5.515. [DOI] [PubMed] [Google Scholar]
  17. Haque A., Capron A. Transplacental transfer of rodent microfilariae induces antigen-specific tolerance in rats. Nature. 1982 Sep 23;299(5881):361–363. doi: 10.1038/299361a0. [DOI] [PubMed] [Google Scholar]
  18. Haque A., Cuna W., Pestel J., Capron A., Bonnel B. Tolerance in rats by transplacental transfer of Dipetalonema viteae microfilariae: recognition of putative tolerogen(s) by antibodies that inhibit antigen-specific lymphocyte proliferation. Eur J Immunol. 1988 Aug;18(8):1167–1172. doi: 10.1002/eji.1830180804. [DOI] [PubMed] [Google Scholar]
  19. Hara T., Ohashi S., Yamashita Y., Abe T., Hisaeda H., Himeno K., Good R. A., Takeshita K. Human V delta 2+ gamma delta T-cell tolerance to foreign antigens of Toxoplasma gondii. Proc Natl Acad Sci U S A. 1996 May 14;93(10):5136–5140. doi: 10.1073/pnas.93.10.5136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hussain R., Hamilton R. G., Kumaraswami V., Adkinson N. F., Jr, Ottesen E. A. IgE responses in human filariasis. I. Quantitation of filaria-specific IgE. J Immunol. 1981 Oct;127(4):1623–1629. [PubMed] [Google Scholar]
  21. Iskander R., Das P. K., Aalberse R. C. IgG4 antibodies in Egyptian patients with schistosomiasis. Int Arch Allergy Appl Immunol. 1981;66(2):200–207. doi: 10.1159/000232819. [DOI] [PubMed] [Google Scholar]
  22. King C. L., Hakimi J., Shata M. T., Medhat A. IL-12 regulation of parasite antigen-driven IgE production in human helminth infections. J Immunol. 1995 Jul 1;155(1):454–461. [PubMed] [Google Scholar]
  23. King C. L., Mahanty S., Kumaraswami V., Abrams J. S., Regunathan J., Jayaraman K., Ottesen E. A., Nutman T. B. Cytokine control of parasite-specific anergy in human lymphatic filariasis. Preferential induction of a regulatory T helper type 2 lymphocyte subset. J Clin Invest. 1993 Oct;92(4):1667–1673. doi: 10.1172/JCI116752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. King C. L., Medhat A., Malhotra I., Nafeh M., Helmy A., Khaudary J., Ibrahim S., El-Sherbiny M., Zaky S., Stupi R. J. Cytokine control of parasite-specific anergy in human urinary schistosomiasis. IL-10 modulates lymphocyte reactivity. J Immunol. 1996 Jun 15;156(12):4715–4721. [PubMed] [Google Scholar]
  25. King C. L., Nutman T. B. Regulation of the immune response in lymphatic filariasis and onchocerciasis. Immunol Today. 1991 Mar;12(3):A54–A58. doi: 10.1016/S0167-5699(05)80016-7. [DOI] [PubMed] [Google Scholar]
  26. King C. L., Stupi R. J., Craighead N., June C. H., Thyphronitis G. CD28 activation promotes Th2 subset differentiation by human CD4+ cells. Eur J Immunol. 1995 Feb;25(2):587–595. doi: 10.1002/eji.1830250242. [DOI] [PubMed] [Google Scholar]
  27. Klei T. R., Blanchard D. P., Coleman S. U. Development of Brugia pahangi infections and lymphatic lesions in male offspring of female jirds with homologous infections. Trans R Soc Trop Med Hyg. 1986;80(2):214–216. doi: 10.1016/0035-9203(86)90014-3. [DOI] [PubMed] [Google Scholar]
  28. Lal R. B., Ottesen E. A. Enhanced diagnostic specificity in human filariasis by IgG4 antibody assessment. J Infect Dis. 1988 Nov;158(5):1034–1037. doi: 10.1093/infdis/158.5.1034. [DOI] [PubMed] [Google Scholar]
  29. Lammie P. J., Hitch W. L., Walker Allen E. M., Hightower W., Eberhard M. L. Maternal filarial infection as risk factor for infection in children. Lancet. 1991 Apr 27;337(8748):1005–1006. doi: 10.1016/0140-6736(91)92661-k. [DOI] [PubMed] [Google Scholar]
  30. Lewert R. M., Mandlowitz S. Schistosomiasis: prenatal induction of tolerance to antigens. Nature. 1969 Dec 6;224(5223):1029–1030. doi: 10.1038/2241029a0. [DOI] [PubMed] [Google Scholar]
  31. Li Z., King C. L., Ogundipe J. O., Licate L. S., Blanton R. E. Preferential recognition by human IgE and IgG4 of a species-specific Schistosoma haematobium serine protease inhibitor. J Infect Dis. 1995 Feb;171(2):416–422. doi: 10.1093/infdis/171.2.416. [DOI] [PubMed] [Google Scholar]
  32. Mahanty S., Abrams J. S., King C. L., Limaye A. P., Nutman T. B. Parallel regulation of IL-4 and IL-5 in human helminth infections. J Immunol. 1992 Jun 1;148(11):3567–3571. [PubMed] [Google Scholar]
  33. McCormick J. B., Gusmão H. H., Nakamura S., Freire J. B., Veras J., Gorman G., Feeley J. C., Wingo P. Antibody response to serogroup A and C meningococcal polysaccharide vaccines in infants born of mothers vaccinated during pregnancy. J Clin Invest. 1980 May;65(5):1141–1144. doi: 10.1172/JCI109768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Nash T. E., Deelder A. M. Comparison of four schistosome excretory-secretory antigens: phenol sulfuric test active peak, cathodic circulating antigen, gut-associated proteoglycan, and circulating anodic antigen. Am J Trop Med Hyg. 1985 Mar;34(2):236–241. doi: 10.4269/ajtmh.1985.34.236. [DOI] [PubMed] [Google Scholar]
  35. Novato-Silva E., Gazzinelli G., Colley D. G. Immune responses during human schistosomiasis mansoni. XVIII. Immunologic status of pregnant women and their neonates. Scand J Immunol. 1992 Apr;35(4):429–437. doi: 10.1111/j.1365-3083.1992.tb02878.x. [DOI] [PubMed] [Google Scholar]
  36. Nutman T. B., Kumaraswami V., Ottesen E. A. Parasite-specific anergy in human filariasis. Insights after analysis of parasite antigen-driven lymphokine production. J Clin Invest. 1987 May;79(5):1516–1523. doi: 10.1172/JCI112982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Ottesen E. A. Immunological aspects of lymphatic filariasis and onchocerciasis in man. Trans R Soc Trop Med Hyg. 1984;78 (Suppl):9–18. doi: 10.1016/0035-9203(84)90309-2. [DOI] [PubMed] [Google Scholar]
  38. Partono F., Pribadi P. W., Soewarta A. Epidemiological and clinical features of Brugia timori in a newly established village. Karakuak, West Flores, Indonesia. Am J Trop Med Hyg. 1978 Sep;27(5):910–915. doi: 10.4269/ajtmh.1978.27.910. [DOI] [PubMed] [Google Scholar]
  39. Pennisi E. Teetering on the brink of danger. Science. 1996 Mar 22;271(5256):1665–1667. doi: 10.1126/science.271.5256.1665. [DOI] [PubMed] [Google Scholar]
  40. Prost A., Gorim de Ponsay E. Importance épidémiologique du parasitisme neo-natal par microfilaires d'Onchocerca volvulus. Tropenmed Parasitol. 1979 Dec;30(4):477–481. [PubMed] [Google Scholar]
  41. Ridge J. P., Fuchs E. J., Matzinger P. Neonatal tolerance revisited: turning on newborn T cells with dendritic cells. Science. 1996 Mar 22;271(5256):1723–1726. doi: 10.1126/science.271.5256.1723. [DOI] [PubMed] [Google Scholar]
  42. Roncarolo M. G., Bigler M., Ciuti E., Martino S., Tovo P. A. Immune responses by cord blood cells. Blood Cells. 1994;20(2-3):573–586. [PubMed] [Google Scholar]
  43. Santoro F., Carlier Y., Borojevic R., Bout D., Tachon P., Capron A. Parasite 'M' antigen in milk from mothers infected with Schistosoma mansoni (preliminary report). Ann Trop Med Parasitol. 1977 Mar;71(1):121–123. doi: 10.1080/00034983.1977.11687169. [DOI] [PubMed] [Google Scholar]
  44. Schrater A. F., Spielman A., Piessens W. F. Predisposition to Brugia malayi microfilaremia in progeny of infected gerbils. Am J Trop Med Hyg. 1983 Nov;32(6):1306–1308. doi: 10.4269/ajtmh.1983.32.1306. [DOI] [PubMed] [Google Scholar]
  45. Schröder J. Passage of leukocytes from mother to fetus. Scand J Immunol. 1974;3(3):369–373. doi: 10.1111/j.1365-3083.1974.tb01267.x. [DOI] [PubMed] [Google Scholar]
  46. Steel C., Guinea A., McCarthy J. S., Ottesen E. A. Long-term effect of prenatal exposure to maternal microfilaraemia on immune responsiveness to filarial parasite antigens. Lancet. 1994 Apr 9;343(8902):890–893. doi: 10.1016/s0140-6736(94)90009-4. [DOI] [PubMed] [Google Scholar]
  47. Tachon P., Borojevic R. Mother-child relation in human schistosomiasis mansoni : skin test and cord blood reactivity to schistosomal antigens. Trans R Soc Trop Med Hyg. 1978;72(6):605–609. doi: 10.1016/0035-9203(78)90011-1. [DOI] [PubMed] [Google Scholar]
  48. Weil G. J., Hussain R., Kumaraswami V., Tripathy S. P., Phillips K. S., Ottesen E. A. Prenatal allergic sensitization to helminth antigens in offspring of parasite-infected mothers. J Clin Invest. 1983 May;71(5):1124–1129. doi: 10.1172/JCI110862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. de Waal Malefyt R., Haanen J., Spits H., Roncarolo M. G., te Velde A., Figdor C., Johnson K., Kastelein R., Yssel H., de Vries J. E. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med. 1991 Oct 1;174(4):915–924. doi: 10.1084/jem.174.4.915. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES