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. 1996 Nov;89(3):468–473. doi: 10.1046/j.1365-2567.1996.d01-755.x

The autoimmunogenic chemicals HgCl2 and diphenylhydantoin stimulate IgG production to TNP-Ficoll and TNP-OVA, supporting and extending the graft-versus-host hypothesis for chemical induction of autoimmunity.

R Albers 1, A van der Pijl 1, W Seinen 1, R Pieters 1, N Bloksma 1
PMCID: PMC1456546  PMID: 8958064

Abstract

Bypass of T-cell tolerance via non-cognate graft-versus-host (GVH)-like help from T-helper (Th) cells activated by chemically altered or induced epitopes, has been postulated as a mechanism underlying chemical induction of autoimmunity. To functionally test this hypothesis, we assessed whether the autoimmunogenic chemicals HgCl2 and diphenylhydantoin (DPH), like GVH reactions, stimulate specific immunoglobulin G (IgG) responses to trinitrophenyl (TNP)-Ficoll but not to TNP-ovalbumin. IgG responses were quantified in the popliteal lymph node by enzyme-linked immunosorbent spot-forming cell assay (ELISPOT) assays 7 days after s.c. injection of antigens, parental cells, chemicals or combinations thereof into the footpad of semi-allogeneic F1 mice. Antigens, chemicals, or cells alone induced few TNP-specific IgG antibody-forming cell (AFC) compared with untreated mice. Co-injection of parental cells or chemicals with TNP-Ficoll stimulated the TNP-specific response per lymph node approximately 50- and approximately 40-fold, respectively. In contrast, the IgG response to TNP-ovalbumin could not be stimulated by GVH reactions, whereas HgCl2 and DPH dose-dependently increased this response up to approximately 25- and approximately 250-fold, respectively. However, responses to TNP-ovalbumin pre-incubated with HgCl2 or DPH could be stimulated approximately 6-8 fold by GVH reactions. Observed similar adjuvanticity of chemicals and parental cells for TNP-Ficoll support a GVH-like action of autoimmunogenic chemicals. In addition, the chemicals modify TNP-ovalbumin such that B cells recognizing this antigen become susceptible to non-cognate stimulation by GVH reactions.

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Selected References

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  1. Bloksma N., Kubicka-Muranyi M., Schuppe H. C., Gleichmann E., Gleichmann H. Predictive immunotoxicological test systems: suitability of the popliteal lymph node assay in mice and rats. Crit Rev Toxicol. 1995;25(5):369–396. doi: 10.3109/10408449509049338. [DOI] [PubMed] [Google Scholar]
  2. Christensen M. M., Ellermann-Eriksen S., Rungby J., Mogensen S. C. Comparison of the interaction of methyl mercury and mercuric chloride with murine macrophages. Arch Toxicol. 1993;67(3):205–211. doi: 10.1007/BF01973309. [DOI] [PubMed] [Google Scholar]
  3. Gleichmann H. Studies on the mechanism of drug sensitization: T-cell-dependent popliteal lymph node reaction to diphenylhydantoin. Clin Immunol Immunopathol. 1981 Feb;18(2):203–211. doi: 10.1016/0090-1229(81)90026-x. [DOI] [PubMed] [Google Scholar]
  4. Golding H., Rittenberg M. B. In vitro and in vivo allogeneic effects: differential modulation of B cell subpopulations. J Immunol. 1982 Apr;128(4):1625–1630. [PubMed] [Google Scholar]
  5. Harding C. V., Roof R. W., Allen P. M., Unanue E. R. Effects of pH and polysaccharides on peptide binding to class II major histocompatibility complex molecules. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2740–2744. doi: 10.1073/pnas.88.7.2740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Inman J. K. Thymus-independent antigens: the preparation of covalent, hapten-ficoll conjugates. J Immunol. 1975 Feb;114(2 Pt 1):704–709. [PubMed] [Google Scholar]
  7. Kammüller M. E., Thomas C., De Bakker J. M., Bloksma N., Seinen W. The popliteal lymph node assay in mice to screen for the immune disregulating potential of chemicals--a preliminary study. Int J Immunopharmacol. 1989;11(3):293–300. doi: 10.1016/0192-0561(89)90167-7. [DOI] [PubMed] [Google Scholar]
  8. Katz D. H., Osborne D. P., Jr The allogeneic effect in inbred mice. II. Establishment of the cellular interactions required for enhancement of antibody production by the graft-versus-host reaction. J Exp Med. 1972 Sep 1;136(3):455–465. doi: 10.1084/jem.136.3.455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kubicka-Muranyi M., Behmer O., Uhrberg M., Klonowski H., Bister J., Gleichmann E. Murine systemic autoimmune disease induced by mercuric chloride (HgCl2): Hg-specific helper T-cells react to antigen stored in macrophages. Int J Immunopharmacol. 1993 Feb;15(2):151–161. doi: 10.1016/0192-0561(93)90091-c. [DOI] [PubMed] [Google Scholar]
  10. Kubicka-Muranyi M., Kremer J., Rottmann N., Lübben B., Albers R., Bloksma N., Lührmann R., Gleichmann E. Murine systemic autoimmune disease induced by mercuric chloride: T helper cells reacting to self proteins. Int Arch Allergy Immunol. 1996 Jan;109(1):11–20. doi: 10.1159/000237226. [DOI] [PubMed] [Google Scholar]
  11. Lehmann P. V., Sercarz E. E., Forsthuber T., Dayan C. M., Gammon G. Determinant spreading and the dynamics of the autoimmune T-cell repertoire. Immunol Today. 1993 May;14(5):203–208. doi: 10.1016/0167-5699(93)90163-F. [DOI] [PubMed] [Google Scholar]
  12. Letvin N. L., Benacerraf B., Germain R. N. B-lymphocyte responses to trinitrophenyl-conjugated Ficoll: requirement for T lymphocytes and Ia-bearing adherent cells. Proc Natl Acad Sci U S A. 1981 Aug;78(8):5113–5117. doi: 10.1073/pnas.78.8.5113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Mongini P. K., Paul W. E., Metcalf E. S. T cell regulation of immunoglobulin class expression in the antibody response to trinitrophenyl-ficoll. Evidence for T cell enhancement of the immunoglobulin class switch. J Exp Med. 1982 Mar 1;155(3):884–902. doi: 10.1084/jem.155.3.884. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Murdoch R. D., Pepys J. Enhancement of antibody production by mercury and platinum group metal halide salts. Kinetics of total and ovalbumin-specific IgE synthesis. Int Arch Allergy Appl Immunol. 1986;80(4):405–411. doi: 10.1159/000234089. [DOI] [PubMed] [Google Scholar]
  15. Osborne D. P., Jr, Katz D. H. The allogeneic effect in inbred mice. I. Experimental conditions for the enhancement of hapten-specific secondary antibody responses by the graft-versus-host reaction. J Exp Med. 1972 Sep 1;136(3):439–454. doi: 10.1084/jem.136.3.439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Peterson G. L. A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal Biochem. 1977 Dec;83(2):346–356. doi: 10.1016/0003-2697(77)90043-4. [DOI] [PubMed] [Google Scholar]
  17. Prouvost-Danon A., Abadie A., Sapin C., Bazin H., Druet P. Induction of IgE synthesis and potentiation of anti-ovalbumin IgE antibody response by HgCl2 in the rat. J Immunol. 1981 Feb;126(2):699–792. [PubMed] [Google Scholar]
  18. Reuter R., Tessars G., Vohr H. W., Gleichmann E., Lührmann R. Mercuric chloride induces autoantibodies against U3 small nuclear ribonucleoprotein in susceptible mice. Proc Natl Acad Sci U S A. 1989 Jan;86(1):237–241. doi: 10.1073/pnas.86.1.237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Schielen P., van Rodijnen W., Tekstra J., Albers R., Seinen W. Quantification of natural antibody producing B cells in rats by an improved ELISPOT technique using the polyvinylidene difluoride membrane as the solid support. J Immunol Methods. 1995 Dec 15;188(1):33–41. doi: 10.1016/0022-1759(95)00199-9. [DOI] [PubMed] [Google Scholar]
  20. Sercarz E. E., Lehmann P. V., Ametani A., Benichou G., Miller A., Moudgil K. Dominance and crypticity of T cell antigenic determinants. Annu Rev Immunol. 1993;11:729–766. doi: 10.1146/annurev.iy.11.040193.003501. [DOI] [PubMed] [Google Scholar]
  21. Stiller-Winkler R., Radaszkiewicz T., Gleichmann E. Immunopathological signs in mice treated with mercury compounds--I. Identification by the popliteal lymph node assay of responder and nonresponder strains. Int J Immunopharmacol. 1988;10(4):475–484. doi: 10.1016/0192-0561(88)90136-1. [DOI] [PubMed] [Google Scholar]
  22. Via C. S., Shearer G. M. T-cell interactions in autoimmunity: insights from a murine model of graft-versus-host disease. Immunol Today. 1988 Jul-Aug;9(7-8):207–213. doi: 10.1016/0167-5699(88)91215-7. [DOI] [PubMed] [Google Scholar]

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