Graves' hyperthyroidism and thyroiditis in HLA-DRB1*0301 (DR3) transgenic mice after immunization with thyrotropin receptor DNA.
Familial and twin studies in Caucasians have established that the MHC class II allele HLA-DRB1*0301 (DR3) is a strong susceptibility gene in Graves' hyperthyroid disease (GD). To determine if a DR3 transgene could help establish an animal model for GD, we expressed DR3 molecules in class II-knockout NOD mice (H2Ag7-). DR3+g7- mice were given cardiotoxin prior to immunization on weeks 0, 3 and 6 with plasmid DNA encoding human thyrotropin receptor (TSHR). Two groups of mice were also coimmunized with plasmid DNA for IL-4 or GM-CSF. Serial bleeds on weeks 8, 11 and 14 showed that approximately 20% of mice produced thyroid-stimulating antibodies (Abs), and approximately 25% had elevated T4 levels. In particular, a subset displayed both signs of hyperthyroidism, resulting in approximately 30% with some aspect of GD syndrome. Additional mice had thyroid-stimulating blocking Abs and/or TSH-binding inhibitory immunoglobulins, while most mice showed strong labelling of TSHR+ cells by flow cytometry. Interestingly, lymphocytic infiltration with thyroid damage and Abs to mouse thyroglobulin were also noted. Vector controls were uniformly negative. Thus, DR3 transgenic mice can serve as a model for GD, similar to our earlier reports that this allele is permissive for the Hashimoto's thyroiditis model induced with human thyroglobulin.
Flynn
J C
JC
Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI, USA.
Rao
P V
PV
Gora
M
M
Alsharabi
G
G
Wei
W
W
Giraldo
A A
AA
David
C S
CS
Banga
J P
JP
Kong
Y M
YM
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006111:Graves Disease / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011989:Receptors, Thyrotropin / Q000235:genetics* / Q000276:immunology; D013967:Thyroiditis, Autoimmune / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D019444:Vaccines, DNA / Q000276:immunology*
D001323:Autoantibodies; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; D011989:Receptors, Thyrotropin; D019444:Vaccines, DNA