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. 1995 Aug;63(8):3166–3173. doi: 10.1128/iai.63.8.3166-3173.1995

Selective neutralization of a bacterial enterotoxin by serum immunoglobulin A in response to mucosal disease.

S Johnson 1, W D Sypura 1, D N Gerding 1, S L Ewing 1, E N Janoff 1
PMCID: PMC173432  PMID: 7622244

Abstract

One-third of convalescent-phase serum samples (6 of 18) from patients with Clostridium difficle-associated diarrhea demonstrated neutralization of the clostridial enterotoxin, toxin A. Although appreciable amounts of toxin A-specific immunoglobulin G (IgG) and IgA were present in these sera, the ability to neutralize the cytotoxic activity of toxin A on OTF9-63 cells in vitro was confined to the IgA fraction and the IgA1 subclass in serum samples from all six patients. In contrast to the patients with C. difficile diarrhea, this activity was present in both the IgA and IgG fractions in sera from two C. difficile-infected patients without diarrhea, one of whom presented with a splenic abscess. Sera and purified IgA which neutralized the cytotoxicity of toxin A on OTF9-63 cell cultures in vitro also neutralized the enterotoxicity of toxin A in rabbit ileal loops in vivo. This activity was not Fc dependent, since IgA retained neutralizing activity after pepsin digestion and F(ab')2 purification. The transition from nonneutralizing toxin A-specific IgA in the acute-phase sera to neutralizing specific IgA in the convalescent-phase sera was accompanied by a shift from a polymeric to a predominantly monomeric form of specific IgA. However, the neutralizing activity in convalescent-phase sera was present as both monomeric and polymeric IgA. Convalescent-phase sera from other patients with C. difficile diarrhea that failed to neutralize toxin A also failed to produce a predominantly monomeric-form specific IgA response. We conclude that serum IgA, not IgG, characteristically neutralizes toxin A in patients with C. difficile diarrhea who develop neutralizing systemic responses. This neutralization of an enteric bacterial toxin is a unique and selective role for serum IgA which provides a novel functional link between the systemic and mucosal immune systems.

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Selected References

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  1. Alley C. D., Kiyono H., McGhee J. R. Murine bone marrow IgA responses to orally administered sheep erythrocytes. J Immunol. 1986 Jun 15;136(12):4414–4419. [PubMed] [Google Scholar]
  2. Blaser M. J., Duncan D. J. Human serum antibody response to Campylobacter jejuni infection as measured in an enzyme-linked immunosorbent assay. Infect Immun. 1984 May;44(2):292–298. doi: 10.1128/iai.44.2.292-298.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Clemens J. D., Ward R. L., Rao M. R., Sack D. A., Knowlton D. R., van Loon F. P., Huda S., McNeal M., Ahmed F., Schiff G. Seroepidemiologic evaluation of antibodies to rotavirus as correlates of the risk of clinically significant rotavirus diarrhea in rural Bangladesh. J Infect Dis. 1992 Jan;165(1):161–165. doi: 10.1093/infdis/165.1.161. [DOI] [PubMed] [Google Scholar]
  4. Conley M. E., Delacroix D. L. Intravascular and mucosal immunoglobulin A: two separate but related systems of immune defense? Ann Intern Med. 1987 Jun;106(6):892–899. doi: 10.7326/0003-4819-106-6-892. [DOI] [PubMed] [Google Scholar]
  5. Cover T. L., Cao P., Murthy U. K., Sipple M. S., Blaser M. J. Serum neutralizing antibody response to the vacuolating cytotoxin of Helicobacter pylori. J Clin Invest. 1992 Sep;90(3):913–918. doi: 10.1172/JCI115967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Delacroix D. L., Dehennin J. P., Vaerman J. P. Influence of molecular size of IgA on its immunoassay by various techniques. II. Solid-phase radioimmunoassays. J Immunol Methods. 1982;48(3):327–337. doi: 10.1016/0022-1759(82)90333-7. [DOI] [PubMed] [Google Scholar]
  7. Delacroix D. L., Elkom K. B., Geubel A. P., Hodgson H. F., Dive C., Vaerman J. P. Changes in size, subclass, and metabolic properties of serum immunoglobulin A in liver diseases and in other diseases with high serum immunoglobulin A. J Clin Invest. 1983 Feb;71(2):358–367. doi: 10.1172/JCI110777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gerding D. N., Olson M. M., Peterson L. R., Teasley D. G., Gebhard R. L., Schwartz M. L., Lee J. T., Jr Clostridium difficile-associated diarrhea and colitis in adults. A prospective case-controlled epidemiologic study. Arch Intern Med. 1986 Jan;146(1):95–100. [PubMed] [Google Scholar]
  9. Glass R. I., Svennerholm A. M., Stoll B. J., Khan M. R., Hossain K. M., Huq M. I., Holmgren J. Protection against cholera in breast-fed children by antibodies in breast milk. N Engl J Med. 1983 Jun 9;308(23):1389–1392. doi: 10.1056/NEJM198306093082304. [DOI] [PubMed] [Google Scholar]
  10. Griffiss J. M., Goroff D. K. IgA blocks IgM and IgG-initiated immune lysis by separate molecular mechanisms. J Immunol. 1983 Jun;130(6):2882–2885. [PubMed] [Google Scholar]
  11. Holmgren J., Andersson A., Wallerstrom G., Ouchterlony O. Experimental studies on cholera immunization. II. Evidence for protective antitoxic immunity mediated by serum antibodies as well as local antibodies. Infect Immun. 1972 May;5(5):662–667. doi: 10.1128/iai.5.5.662-667.1972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Janoff E. N., Smith P. D., Blaser M. J. Acute antibody responses to Giardia lamblia are depressed in patients with AIDS. J Infect Dis. 1988 Apr;157(4):798–804. doi: 10.1093/infdis/157.4.798. [DOI] [PubMed] [Google Scholar]
  13. Jarvis G. A., Griffiss J. M. Human IgA1 initiates complement-mediated killing of Neisseria meningitidis. J Immunol. 1989 Sep 1;143(5):1703–1709. [PubMed] [Google Scholar]
  14. Johnson S., Gerding D. N., Janoff E. N. Systemic and mucosal antibody responses to toxin A in patients infected with Clostridium difficile. J Infect Dis. 1992 Dec;166(6):1287–1294. doi: 10.1093/infdis/166.6.1287. [DOI] [PubMed] [Google Scholar]
  15. Kaetzel C. S., Robinson J. K., Chintalacharuvu K. R., Vaerman J. P., Lamm M. E. The polymeric immunoglobulin receptor (secretory component) mediates transport of immune complexes across epithelial cells: a local defense function for IgA. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8796–8800. doi: 10.1073/pnas.88.19.8796. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kerr M. A. The structure and function of human IgA. Biochem J. 1990 Oct 15;271(2):285–296. doi: 10.1042/bj2710285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Keusch G. T., Jacewicz M., Levine M. M., Hornick R. B., Kochwa S. Pathogenesis of shigella diarrhea. Serum anticytotoxin antibody response produced by toxigenic and nontoxigenic Shigella dysenteriae 1. J Clin Invest. 1976 Jan;57(1):194–202. doi: 10.1172/JCI108259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kilian M., Mestecky J., Russell M. W. Defense mechanisms involving Fc-dependent functions of immunoglobulin A and their subversion by bacterial immunoglobulin A proteases. Microbiol Rev. 1988 Jun;52(2):296–303. doi: 10.1128/mr.52.2.296-303.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kondoh H., Kobayashi K., Hagiwara K., Kajii T. Jacalin, a jackfruit lectin, precipitates IgA1 but not IgA2 subclass on gel diffusion reaction. J Immunol Methods. 1986 Apr 17;88(2):171–173. doi: 10.1016/0022-1759(86)90003-7. [DOI] [PubMed] [Google Scholar]
  20. Kutteh W. H., Koopman W. J., Conley M. E., Egan M. L., Mestecky J. Production of predominantly polymeric IgA by human peripheral blood lymphocytes stimulated in vitro with mitogens. J Exp Med. 1980 Nov 1;152(5):1424–1429. doi: 10.1084/jem.152.5.1424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kutteh W. H., Prince S. J., Mestecky J. Tissue origins of human polymeric and monomeric IgA. J Immunol. 1982 Feb;128(2):990–995. [PubMed] [Google Scholar]
  22. Levett P. N. Clostridium difficile in habitats other than the human gastro-intestinal tract. J Infect. 1986 May;12(3):253–263. doi: 10.1016/s0163-4453(86)94294-5. [DOI] [PubMed] [Google Scholar]
  23. Lyerly D. M., Phelps C. J., Toth J., Wilkins T. D. Characterization of toxins A and B of Clostridium difficile with monoclonal antibodies. Infect Immun. 1986 Oct;54(1):70–76. doi: 10.1128/iai.54.1.70-76.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lyerly D. M., Saum K. E., MacDonald D. K., Wilkins T. D. Effects of Clostridium difficile toxins given intragastrically to animals. Infect Immun. 1985 Feb;47(2):349–352. doi: 10.1128/iai.47.2.349-352.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Mai U. E., Perez-Perez G. I., Allen J. B., Wahl S. M., Blaser M. J., Smith P. D. Surface proteins from Helicobacter pylori exhibit chemotactic activity for human leukocytes and are present in gastric mucosa. J Exp Med. 1992 Feb 1;175(2):517–525. doi: 10.1084/jem.175.2.517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mascart-Lemone F. O., Duchateau J. R., Oosterom J., Butzler J. P., Delacroix D. L. Kinetics of anti-Campylobacter jejuni monomeric and polymeric immunoglobulin A1 and A2 responses in serum during acute enteritis. J Clin Microbiol. 1987 Jul;25(7):1253–1257. doi: 10.1128/jcm.25.7.1253-1257.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Mascart-Lemone F., Carlsson B., Jalil F., Hahn-Zoric M., Duchateau J., Hanson L. A. Polymeric and monomeric IgA response in serum and milk after parenteral cholera and oral typhoid vaccination. Scand J Immunol. 1988 Oct;28(4):443–448. doi: 10.1111/j.1365-3083.1988.tb01474.x. [DOI] [PubMed] [Google Scholar]
  28. Mascart-Lemone F., Duchateau J., Conley M. E., Delacroix D. L. A polymeric IgA response in serum can be produced by parenteral immunization. Immunology. 1987 Aug;61(4):409–413. [PMC free article] [PubMed] [Google Scholar]
  29. Mazanec M. B., Kaetzel C. S., Lamm M. E., Fletcher D., Nedrud J. G. Intracellular neutralization of virus by immunoglobulin A antibodies. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6901–6905. doi: 10.1073/pnas.89.15.6901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Mestecky J., Kilian M. Immunoglobulin A (IgA). Methods Enzymol. 1985;116:37–75. doi: 10.1016/s0076-6879(85)16005-2. [DOI] [PubMed] [Google Scholar]
  31. Nayak N., Ganguly N. K., Walia B. N., Wahi V., Kanwar S. S., Mahajan R. C. Specific secretory IgA in the milk of Giardia lamblia-infected and uninfected women. J Infect Dis. 1987 Apr;155(4):724–727. doi: 10.1093/infdis/155.4.724. [DOI] [PubMed] [Google Scholar]
  32. Negro Ponzi A., Merlino C., Angeretti A., Penna R. Virus-specific polymeric immunoglobulin A antibodies in serum from patients with rubella, measles, varicella, and herpes zoster virus infections. J Clin Microbiol. 1985 Oct;22(4):505–509. doi: 10.1128/jcm.22.4.505-509.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Russell M. W., Brown T. A., Claflin J. L., Schroer K., Mestecky J. Immunoglobulin A-mediated hepatobiliary transport constitutes a natural pathway for disposing of bacterial antigens. Infect Immun. 1983 Dec;42(3):1041–1048. doi: 10.1128/iai.42.3.1041-1048.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Russell M. W., Reinholdt J., Kilian M. Anti-inflammatory activity of human IgA antibodies and their Fab alpha fragments: inhibition of IgG-mediated complement activation. Eur J Immunol. 1989 Dec;19(12):2243–2249. doi: 10.1002/eji.1830191210. [DOI] [PubMed] [Google Scholar]
  35. SCHROHENLOHER R. E., KUNKEL H. G., TOMASI T. B. ACTIVITY OF DISSOCIATED AND REASSOCIATED 19S ANTI-GAMMA-GLOBULINS. J Exp Med. 1964 Dec 1;120:1215–1229. doi: 10.1084/jem.120.6.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Smith P. D., Quinn T. C., Strober W., Janoff E. N., Masur H. NIH conference. Gastrointestinal infections in AIDS. Ann Intern Med. 1992 Jan 1;116(1):63–77. doi: 10.7326/0003-4819-116-1-63. [DOI] [PubMed] [Google Scholar]
  37. Stieglbauer K. T., Gruber S. A., Johnson S. Elevated serum antibody response to toxin A following splenic abscess due to Clostridium difficile. Clin Infect Dis. 1995 Jan;20(1):160–162. doi: 10.1093/clinids/20.1.160. [DOI] [PubMed] [Google Scholar]
  38. Tarkowski A., Lue C., Moldoveanu Z., Kiyono H., McGhee J. R., Mestecky J. Immunization of humans with polysaccharide vaccines induces systemic, predominantly polymeric IgA2-subclass antibody responses. J Immunol. 1990 May 15;144(10):3770–3778. [PubMed] [Google Scholar]
  39. Tarkowski A., Moldoveanu Z., Koopman W. J., Radl J., Haaijman J. J., Mestecky J. Cellular origins of human polymeric and monomeric IgA: enumeration of single cells secreting polymeric IgA1 and IgA2 in peripheral blood, bone marrow, spleen, gingiva and synovial tissue. Clin Exp Immunol. 1991 Aug;85(2):341–348. doi: 10.1111/j.1365-2249.1991.tb05730.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Tucker K. D., Carrig P. E., Wilkins T. D. Toxin A of Clostridium difficile is a potent cytotoxin. J Clin Microbiol. 1990 May;28(5):869–871. doi: 10.1128/jcm.28.5.869-871.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Underdown B. J., Schiff J. M. Immunoglobulin A: strategic defense initiative at the mucosal surface. Annu Rev Immunol. 1986;4:389–417. doi: 10.1146/annurev.iy.04.040186.002133. [DOI] [PubMed] [Google Scholar]
  42. Vincent C., Cozon G., Zittoun M., Mellquist M., Kazatchkine M. D., Czerkinsky C., Revillard J. P. Secretory immunoglobulins in serum from human immunodeficiency virus (HIV)-infected patients. J Clin Immunol. 1992 Sep;12(5):381–388. doi: 10.1007/BF00920796. [DOI] [PubMed] [Google Scholar]

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