Cellular thyroid peroxidase (TPO), unlike purified TPO and adjuvant, induces antibodies in mice that resemble autoantibodies in human autoimmune thyroid disease.
Autoantibodies to several protein antigens in human autoimmunity interact with a restricted range of epitopes, whereas diverse epitopes are recognized by antibodies induced in animals using antigen and adjuvant. To examine the basis for this difference, we compared the qualitative nature of antibodies developing in AKR/N mice injected with purified thyroid peroxidase (TPO) and adjuvant or with TPO expressed on major histocompatibility complex (MHC) class II+ fibroblasts. Mice injected with purified TPO had higher TPO antibody levels than TPO+/class II+ fibroblast-treated mice. Despite lower titers, recipients of TPO+/class II+ cells developed very high affinity antibodies (Kd = approximately 10(-10) M), comparable with those of human TPO autoantibodies and about 10-fold higher than those in purified TPO plus adjuvant-immunized mice. Moreover, more than 90% of TPO antibodies in TPO+/class II+ fibroblast-injected mice, compared with only approximately 50% in TPO plus adjuvant-immunized mice, were to the immunodominant region recognized by patients' autoantibodies. Consistent with this epitopic restriction, TPO+/class II+ fibroblast-injected mice had TPO antibody epitopic fingerprints similar to those of human autoantibodies. In conclusion, mice injected with TPO+/class II+ fibroblasts, but not those injected with purified TPO and adjuvant, develop antibodies closely resembling autoantibodies in human disease. These observations indicate that some animal models based on conventional immunization may not be representative of human diseases with a major humoral component.
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001323:Autoantibodies / Q000737:chemistry* / Q000276:immunology; D018604:Epitope Mapping; D005347:Fibroblasts; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D005802:Genes, MHC Class II / Q000235:genetics / Q000276:immunology; D006111:Graves Disease / Q000201:enzymology* / Q000276:immunology*; D006801:Humans; D007453:Iodide Peroxidase / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics; D051379:Mice; D008806:Mice, Inbred AKR