title: Immunomodulatory effects of tetrachlorobenzoquinone, a reactive metabolite of hexachlorobenzene.
abstract: Hexachlorobenzene (HCB) is an environmental pollutant that causes autoimmune-like effects in humans and rats. It is not completely clear whether T cells are involved and, if so, how they are stimulated after oral exposure to HCB. HCB as a rather inert chemical is not likely to bind covalently to macromolecules. The oxidative metabolite of HCB, tetrachlorobenzoquinone (TCBQ), which is in a redox equilibrium with tetrachlorohydroquinone (TCHQ), can bind to macromolecules, hence may form hapten-carrier complexes in vivo. We have assessed in the reporter antigen-popliteal lymph node assay whether HCB or TCHQ and TCBQ are able to induce a 2,4,6-trinitrophenyl (TNP) specific IgG1 response to the T cell-independent antigen TNP-Ficoll, which is indicative of neoantigen specific T cell help. To this end, these compounds and silica were injected into the footpad of Balb/c mice. Silica was included as an inert model compound, which causes autoimmune-like effects by activating macrophages. Seven days later, cell number and TNP specific antibody-secreting cells (ASC) in the popliteal lymph node (PLN) were determined. Furthermore, a secondary PLNA was performed to find out if TCHQ was capable of eliciting a memory response. Silica, TCHQ, and TCBQ, but not HCB, increased PLN cellularity and the number of IgM-producing ASC by ELISPOT. Both oxidative metabolites were able to induce the formation of germinal centers as assessed by immunohistochemistry and an IgG1 response to TNP-Ficoll. In the secondary PLNA, only mice primed with TCHQ and challenged with TCHQ together with TNP-Ficoll showed a significant increase in TNP specific IgG1 ASC. Present data show that TCHQ and TCBQ are capable of inducing neoantigen specific T cell help and that TCHQ can induce a compound specific memory response.
authors.affiliation: Immunotoxicology, Institute for Risk Assessment Sciences, University Utrecht, The Netherlands. J.Ezendam@iras.uu.nl
authors.forename: Janine
authors.initials: J
authors.lastname: Ezendam
authors.forename: Ischa
authors.initials: I
authors.lastname: Vissers
authors.forename: Rob
authors.initials: R
authors.lastname: Bleumink
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Vos
authors.forename: Raymond
authors.initials: R
authors.lastname: Pieters
mesh_terms: D000276:Adjuvants, Immunologic / Q000633:toxicity*; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology; D002452:Cell Count; D002703:Chloranil / Q000633:toxicity*; D005260:Female; D005434:Flow Cytometry; D005659:Fungicides, Industrial / Q000633:toxicity*; D006581:Hexachlorobenzene / Q000378:metabolism*; D006873:Hydroquinones / Q000633:toxicity; D007150:Immunohistochemistry; D023441:Local Lymph Node Assay; D008198:Lymph Nodes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D000276:Adjuvants, Immunologic; D005659:Fungicides, Industrial; D006873:Hydroquinones; D002703:Chloranil; D006581:Hexachlorobenzene; C044578:2,3,5,6-tetrachlorohydroquinone