Thyroid autoimmune disease - Demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers

Autoimmune thyroid disease-Hashimoto thyroiditis and Graves' disease-patien ts produce high levels of thyroid autoantibodies and contain lymphoid tissu e that resembles secondary lymphoid follicles (LFs). We compared the specif icity, structure, and function of tonsil and lymph node LFs with those of t he intrathyroidal LFs to assess the latter's capability to contribute to au toimmune response. Thyroglobulin and thyroperoxidase binding to LFs indicat ed that most intrathyroidal LFs were committed to response to thyroid self- antigens and were associated to higher levels of antibodies to thyroglobuli n, thyroperoxidase, and thyroid-stimulating hormone receptor. Intrathyroida l LFs were microanatomically very similar to canonical LFs, ie, they had we ll-developed germinal centers with mantle, light, and dark zones and each o f these zones contained B and T lymphocytes, follicular dendritic and inter digitating dendritic cells with typical phenotypes. Careful assessment of p roliferation (Ki67) and apoptosis (terminal dUTP nick-end labeling) indicat ors and of the occurrence of secondary immunoglobulin gene rearrangements ( RAGI and RAG2) confirmed the parallelism. Unexpected high levels of RAG exp ression suggested that receptor revision occurs in intrathyroidal LFs and m ay contribute to generate high-affinity thyroid autoantibodies. Well-formed high endothelial. venules and a congruent pattern of adhesion molecules an d chemokine expression in intrathyroidal LFs were also detected. These data suggest that ectopic intrathyroidal LFs contain all of the elements needed to drive the autoimmune response and also that their microenvironment may favor the expansion and perpetuation of autoimmune response.