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Relationship between Thyroid Peroxidase T Cell Epitope Restriction and Antibody Recognition of the Autoantibody Immunodominant Region in Human Leukocyte Antigen DR3 Transgenic Mice

Autoimmune Disease Unit (J.G., S.M.M., P.N.P., C.-R.C., N.P., H.A.A., B.R.), Cedars-Sinai Research Institute and University of California, Los Angeles School of Medicine, Los Angeles, California 90048; and Department of Immunology (C.S.D.), Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Basil Rapoport, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite B-131, Los Angeles, California 90048. E-mail: rapoportb{at}cshs.org.

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 (10⁷ vs. 10⁹) 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- response to TPO in vitro) were highly diverse and variable in different animals. In contrast, DR3 mice immunized the higher TPO-Ad dose (10⁹ 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.