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Intermolecular spreading of antibody reactivity has been implicated in the evolution of autoimmune disease. In this study, spreading of antibody reactivity to non-thyroid autoantigens after experimental immunization with thyroglobulin (Tg) was investigated. For this purpose, two rabbits were injected with human Tg six times (stages 1–6) every 3 weeks. Animals were also bled before priming. Antisera were tested by enzyme-linked immunosorbent assay (ELISA) for reactivity to several non-thyroid antigens: bovine serum albumin (BSA), native DNA (nDNA), human myosin, human globular (G) and filamentous (F) actin and porcine tubulin. Tg-immunized animals developed the following serological reactivity pattern: (a) high reactivity to myosin from stage 2 onward, (b) significant reactivity to F-actin, remaining high up to stage 6, (c) reactivity to BSA with a peak at stage 3, (d) a small increase of reactivity to G-actin at stage 3 and (e) no increase of reactivity to nDNA and tubulin. The study of affinity-purified anti-Tg antibodies and the use of competitive assays revealed that reactivity to F-actin was not due to cross-reaction with Tg. On the contrary, reactivity to myosin during the first stages of immunization was due to cross-reaction with Tg, while at stage 6 it became myosin-specific. Reactivity to BSA at stage 3 was also due to cross-reaction with Tg. We conclude that at least part of the induced anti-Tg antibodies may result from the expansion of B cell clones producing polyreactive natural autoantibodies, and polyreactivity of anti-Tg antibodies during the first stages of Tg-immunization may be responsible for the intermolecular spreading of antibody response.