Autoreactive responses to an environmental factor: 1. phthalate induces antibodies exhibiting anti-DNA specificity.
Environmental factors have been implicated in the induction of autoimmune disorders. We report here that a common chemical, phthalate, used widely in synthetic polymers and cosmetics induces serum anti-self DNA antibodies in BALB/c, NZB and autoimmune-prone NZB/W F1 mice. The latter group experiences a high mortality, and significantly higher anti-DNA antibody levels along with nephritis and other histopathologic changes in kidney. Comparison of amino acid sequences of an anti-phthalate BALB/c B-cell hybrid, 2C3 with the known database at the National Center for Biotechnology Information reveals a striking homology between the variable regions of 2C3-Ig (gamma1, kappa) and an anti-DNA antibody, BV04-01 (gamma2b,kappa) isolated from the lupus-prone NZB/W F1 mice. The homology is 98% for kappa light chain and 70% for gamma heavy chain. Like 2C3-Ig, BV04-01 also has specificity for d(pT)4. Furthermore, the light chains of both 2C3-Ig and BV04-01 are products of Vkappa1 gene. To understand the nature of anti-phthalate responses in general, hybridomas generated from phthalate-keyhole limpet haemocyanin-primed BALB/c splenocytes were characterized. The study identifies cross-reactive populations that strongly bind phthalate, DNA, or both. Of the 14 hybridomas evaluated, six express the same Vkappa1 gene-derived light chain as 2C3, and bind both phthalate and ds and ss-DNA. They specifically recognize the oligonucleotides, d(pT)4, and d(pT)10. Additionally, when antisera raised against idiopeptides corresponding to 2C3-Ig hypervariable regions are allowed to react with 2C3-Ig, their binding is blocked specifically by both d(pT)4 and phthalate. This study clearly demonstrates that phthalate exposure leads to activation of a significant number of autoreactive B-cells, with the consequence of a significant pathogenic progression in susceptible NZB/W F1 mice but not in non-autoimmune-prone BALB/c.
Lim
So-Yon
SY
Department of Life Sciences, Indiana State University, Terre Haute, IN 47809, USA.
Ghosh
Swapan K
SK
D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D004247:DNA / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006825:Hybridomas / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000276:immunology; D007130:Immunoglobulin Idiotypes / Q000276:immunology; D007147:Immunoglobulin Light Chains / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB; D009841:Oligonucleotides / Q000276:immunology; D010795:Phthalic Acids / Q000276:immunology*
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D007143:Immunoglobulin Heavy Chains; D007130:Immunoglobulin Idiotypes; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region; D009841:Oligonucleotides; D010795:Phthalic Acids; C032279:phthalic acid; D004247:DNA