title: 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.
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.
authors.affiliation: Utrecht University, Research Institute of Toxicology, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Albers
authors.forename: A
authors.initials: A
authors.lastname: van der Pijl
authors.forename: W
authors.initials: W
authors.lastname: Seinen
authors.forename: R
authors.initials: R
authors.lastname: Pieters
authors.forename: N
authors.initials: N
authors.lastname: Bloksma
mesh_terms: D000818:Animals; D000921:Antibody-Producing Cells / Q000276:immunology; D015551:Autoimmunity / Q000187:drug effects*; D005260:Female; D005362:Ficoll / Q000031:analogs & derivatives / Q000276:immunology; D006087:Graft vs Host Reaction / Q000276:immunology*; D007074:Immunoglobulin G / Q000096:biosynthesis*; D008627:Mercuric Chloride / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010047:Ovalbumin / Q000276:immunology; D010672:Phenytoin / Q000494:pharmacology*; D014301:Trinitrobenzenes / Q000276:immunology
chemical_list: D007074:Immunoglobulin G; C020529:TNP-ficoll; D014301:Trinitrobenzenes; C038600:trinitrophenyl-ovalbumin; D005362:Ficoll; D008627:Mercuric Chloride; D010672:Phenytoin; D010047:Ovalbumin