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Thyroglobulin-Thyroperoxidase Autoantibodies Are Polyreactive, Not Bispecific: Analysis Using Human Monoclonal Autoantibodies

Autoimmune Disease Unit, Cedars-Sinai Research Institute and the University of California, Los Angeles School of Medicine, Los Angeles, California 90048

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

Autoantibodies (Ab) to thyroglobulin (Tg) and to thyroid peroxidase (TPO) are reported to share common epitopes, and an assay for bispecific TgPOAb has been developed that may distinguish between different clinical presentations of thyroid autoimmunity. We sought to clone TgPOAb from an Ig gene combinatorial library constructed from B cells infiltrating the thyroid of a patient with TgPOAb. As described for isolating serum TgPOAb, we panned the phage display library by alternating from Tg- to TPO-coated ELISA wells. After panning, the library was enriched for TgPO-binding phage. Of 526 clones tested for expressed Ab, most were negative; 3 clones were specific for Tg, and 5 clones specifically recognized TPO. Antibody from a single clone, encoded by a non-Tg, non-TPO Ig heavy chain gene, bound both Tg and TPO (TgPO activity). However, this antibody also bound equally well to nonthyroid antigens. In conclusion, enrichment for Tg- and TPO-binding phage was largely attributable to phage specific for either Tg or TPO. This finding, albeit from a single patient, questions previous observations of serum TgPOAb prepared by affinity chromatography. Combined with the isolation of a polyreactive monoclonal antibody, our data provide powerful evidence against shared, cross-reactive epitopes on 2 major thyroid autoantigens.

These studies were supported by NIH Grant DK-36182.

Abbreviations: Ab, Autoantibody (or autoantibodies); CDR3, complementarity determining region 3; Gluc, glucagon; H chain, heavy chain; JH (or JK), joining region for the H (or kappa) chain; K chain, kappa chain; KLH, keyhole limpet hemocyanin; L chain, light chain; LPO, lactoperoxidase; R-I, -II, etc., round I, II, etc.; Tg, thyroglobulin; TPO, thyroid peroxidase; VH, variable region of H chain; V gene, variable region gene; VL (VK), variable region of L (or kappa) L chain.

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