Relationship between thyroid peroxidase T cell epitope restriction and antibody recognition of the autoantibody immunodominant region in human leukocyte antigen DR3 transgenic mice.
We investigated the relationship between thyroid peroxidase (TPO) antibody and T lymphocyte epitopes in TPO-adenovirus (TPO-Ad) immunized BALB/c mice and mice transgenic for the human class II molecule DR3 associated with human thyroid autoimmunity. TPO autoantibodies are largely restricted to an immunodominant region (IDR). BALB/c mice immunized with fewer (10(7) vs. 10(9)) TPO-Ad particles developed TPO antibodies with lower titers that displayed greater restriction to the IDR. However, as with higher-dose TPO-Ad immunization, T cell epitopes (assessed by splenocyte interferon-gamma response to TPO in vitro) were highly diverse and variable in different animals. In contrast, DR3 mice immunized the higher TPO-Ad dose (10(9) particles) had high TPO antibody levels that showed relative focus on the IDR. Moreover, T cell epitopes recognized by splenocytes from DR3 mice showed greater restriction than BALB/c mice. Antibody affinities for TPO were higher in DR3 than in BALB/c mice. The present study indicates that weak TPO-Ad immunization of BALB/c mice (with consequent low TPO antibody titers) is required for enhanced IDR focus yet is not associated with T cell epitopic restriction. Humanized DR3 transgenic mice, despite stronger TPO-Ad immunization, develop higher titer TPO antibodies that do focus on the autoantibody IDR with T cells that recognize a more limited range of TPO peptides. These data suggest a relationship between major histocompatibility complex class II molecules and the development of antibodies to the IDR, a feature of human thyroid autoimmunity.
Guo
Jin
J
Autoimmune Disease Unit, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite B-131, Los Angeles, California 90048, USA.
McLachlan
Sandra M
SM
Pichurin
Pavel N
PN
Chen
Chun-Rong
CR
Pham
Nancy
N
Aliesky
Holly A
HA
David
Chella S
CS
Rapoport
Basil
B
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D005822:Genetic Vectors; D015803:HLA-DR3 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007114:Immunization; D016056:Immunodominant Epitopes / Q000276:immunology*; D007453:Iodide Peroxidase / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D013154:Spleen / Q000166:cytology / Q000276:immunology
D001323:Autoantibodies; D018984:Epitopes, T-Lymphocyte; D015803:HLA-DR3 Antigen; D016056:Immunodominant Epitopes; D007453:Iodide Peroxidase