Immunotargeting of Thyroglobulin on Antigen Presenting Cells Abrogates Natural Tolerance in the Absence of Adjuvant

Mice usually develop strong IgG responses to self-thyroglobulin (Tg) following immunization with mouse Tg (mTg) emulsified in complete Freundʹs adjuvant (CFA). Here we report that adjuvant-free challenge of mice with small doses of mTg conjugated onto a monoclonal antibody (MAb) specific for class II MHC determinants (anti-I-Ak) induces an mTg-specific IgG response in CBA (H-2k) but not in B6 (H-2b) mice. This is not a result of nonspecific uptake of immunoconjugate or chemical modification of mTg because mTg conjugated in a similar manner to a control MAb (specific for influenza nucleoprotein) of the same IgG subclass as the anti-I-Ak MAb did not elicit an autoimmune response. Despite the presence of mTg-specific IgG with titers equal to those observed after challenge with mTg in CFA, thyroid lesions were not detected in CBA mice that received mTg-(anti-I-Ak Mab) conjugate indicating a clear divergence in the requirements for autoantibody production and disease. The data suggest that small amounts of soluble autoantigen, conjugated onto MAbs specific for determinants expressed on antigen-presenting cells (APC), can effectively abrogate natural tolerance perhaps via a targeting mechanism that focuses autoantigen on APC. This approach may help elucidate the role of various APC subsets in autoimmunity and allow the study of initial events that trigger autoreactivity outside a CFA-induced granuloma site.