AUTOIMMUNE-RESPONSE INDUCED BY IMMUNIZING FEMALE MICE WITH RECOMBINANT HUMAN THYROTROPIN RECEPTOR VARIES WITH THE GENETIC BACKGROUND

In a previous study, we have described the induction of thyroid blocki ng (TBAB) and thyrotropin binding inhibiting antibodies accompanied by thyroiditis in female BALBc mice (H2d) immunised with the extra-cellu lar domain (ECD) of the human thyrotropin receptor (TSHR) expressed as a maltose binding protein (MBP) fusion. In the present study we have investigated the response induced in mice of varying MHC haplotype. Tw o groups of female NOD (H2g), CBA (H2k) and C57 (H2b) mice were immuni sed intra-peritoneally with MBP-ECD or MBP on days 0 (100 mu g), 15, 3 0 and 43 (50 mu g). Blood samples from individual mice were obtained o n days 0, 22, 36 and 50 and assessed for thyroid binding inhibiting im munoglobulins (TBII), thyroid stimulating (TSAB) and TBAB. On day 50 t he treated mice and five age/sex matched NOD mice were sacrificed, the ir thyroids removed, examined histologically and any infiltrate charac terised. Induction of antibodies to the ECD was tested by ELISA in whi ch plates had been coated with either MBP-ECD or an ECD-protein A fusi on. All of the mice developed a strong antibody response to the releva nt immunogen but none of them contained TBII, TSAB or TBAB activities. No lymphocytic infiltration of the thyroid glands of the CBA or C57 m ice was observed. In contrast, all of the NOD mice displayed severe th yroiditis, whilst one of seven MBP-treated mice had moderate infiltrat ion and none of five untreated controls. Immunohistochemical analysis revealed that the infiltrate was predominantly activated T helper cell s with little evidence of B cells or the cytokines IL-10 or IL-4, indi cating that a Th1 response had been induced, contrary to our findings in BALBc mice which mount a Th2 response. In conclusion we have shown that the type and extent of response induced by immunising with the TS HR varies in mice of differing genetic background, H2d mice develop th yroiditis and TBAB/TBII, H2g mice develop thyroiditis in the absence o f functional TSHR antibodies, whilst H2b and H2k mice are resistant.