Flexibility of TCR repertoire and permissiveness of HLA-DR3 molecules in experimental autoimmune thyroiditis in nonobese diabetic mice.
Experimental autoimmune thyroiditis (EAT) is inducible in genetically susceptible mice by immunization with mouse thyroglobulin (mTg). With susceptibility linked to MHC class II, EAT is useful in studying human leukocyte antigen (HLA) associations with Hashimoto's thyroiditis. In non-obese diabetic (NOD) mice, approximately 10% thyroiditis incidence occurs with aging. This potential was exploited to examine the T cell repertoire and HLA association in EAT. Similar to B10.K-Vbeta(c)mice with TCRBV genes reduced by approximately 70%, mTg-immunized NOD-Vbeta(c)mice developed thyroiditis comparable to controls, indicating plasticity of the TCR repertoire for pathogenic epitopes. HLA association was evaluated by introducing HLA-DRA/DRB1*0301 (DR3) transgene into class II-negative NOD mice (Ab(0)/NOD). Previously, this HLA-DR3 transgene rendered EAT-resistant B10.M and Ab(0)mice susceptible to both mTg- and hTg-induced EAT. These results are now confirmed. mTg-induced thyroiditis in DR3+ Ab(0)/NOD mice was comparable to that in NOD and DR3- NOD mice, and the proliferative response was stronger. By comparison, NOD mice were only moderately susceptible to hTg-induced EAT. However, thyroiditis was more severe in DR3+ Ab(0)/NOD than in DR3- NOD mice, with no difference in proliferative response to hTg harbouring heterologous epitopes. The confirmed permissiveness of HLA-DR3 molecules on an NOD background for EAT induction by both mTg and hTg supports the importance of this class II gene implicated in some patient studies.
Flynn
J C
JC
Department of Immunology and Microbiology, Wayne State University School of Medicine, 540 E. Canfield Ave., Detroit, MI 48201, USA.
Fuller
B E
BE
Giraldo
A A
AA
Panos
J C
JC
David
C S
CS
Kong
Y C
YC
D000818:Animals; D005260:Female; D020022:Genetic Predisposition to Disease; D015803:HLA-DR3 Antigen / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D013045:Species Specificity; D013954:Thyroglobulin / Q000276:immunology; D013967:Thyroiditis, Autoimmune / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D019076:Transgenes / Q000235:genetics / Q000276:immunology
D015803:HLA-DR3 Antigen; D016693:Receptors, Antigen, T-Cell, alpha-beta; D013954:Thyroglobulin