Distinct immunomodulation by autoimmunogenic xenobiotics in susceptible and resistant mice.
HgCl(2) and diphenylhydantoin (DPH) are prototype chemicals associated with diverse (auto)immune effects in genetically susceptible individuals. Both chemicals activate T cells, and the balance of Th1 versus Th2 activation may influence the clinical outcome of exposure. It is unknown which chemically created neoantigens are responsible for Th activation. We therefore investigated the effect of DPH and HgCl(2) on specific responses to TNP-ovalbumin, in mouse strains with varying sensitivity for the adverse effects. HgCl(2) was found to enhance Th2-driven antibody responses in susceptible B10.s, but protective type 1 responses in resistant B10.d2 mice. This was chemical-specific, as DPH enhanced type 2 responses in both strains. DBA/2 mice were relatively unresponsive to HgCl(2), whereas DPH stimulated type 1 responses in these mice. Interestingly, prior exposure to HgCl(2), but not DPH, facilitated IC deposition in B10.s mice only. Thus, we demonstrate that, depending on MHC-II and background genes, HgCl(2) and DPH preferentially adjuvate type 1 or type 2 responses. In case of HgCl(2), the type of response corresponds with susceptibility to antibody-mediated autoimmunity induced by this chemical. In addition, we demonstrate that, within one strain, different autoimmunogenic chemicals can enhance distinct responses to the same antigen.
Albers
R
R
Research Institute of Toxicology, Utrecht University, Utrecht, 3508 TD, The Netherlands.
van der Pijl
A
A
Bol
M
M
Bleumink
R
R
Seinen
W
W
Pieters
R
R
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000936:Antigen-Antibody Complex / Q000032:analysis; D015551:Autoimmunity; D003176:Complement C3 / Q000032:analysis; D005260:Female; D006968:Hypersensitivity, Delayed / Q000209:etiology; D007114:Immunization; D007132:Immunoglobulin Isotypes / Q000097:blood; D007684:Kidney Tubules / Q000276:immunology; D008627:Mercuric Chloride / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains / Q000097:blood / Q000235:genetics* / Q000276:immunology; D010047:Ovalbumin / Q000008:administration & dosage*; D010672:Phenytoin / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D013997:Time Factors; D015262:Xenobiotics / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D000936:Antigen-Antibody Complex; D003176:Complement C3; D007132:Immunoglobulin Isotypes; D015262:Xenobiotics; C038600:trinitrophenyl-ovalbumin; D008627:Mercuric Chloride; D010672:Phenytoin; D010047:Ovalbumin