T-CELL RESTRICTION IN THYROID EYE DISEASE

Infiltrating immunocompetent cells act to establish and perpetuate the orbital autoimmune process in thyroid eye disease (TED). Until recent ly, it has remained unclear whether T cells infiltrating the orbital c onnective/fatty tissue and extraocular muscles represent a primary imm une response that is specifically directed against orbital antigens. I n addition, despite a close clinical and temporal association of the t hyroidal and extrathyroidal manifestations in Graves' disease (GD), it has not been proven whether T cells infiltrating thyroid, orbital, an d pretibial tissue in patients with TED and pretibial dermopathy (PTD) are directed against certain antigenic determinants shared between th ese anatomically distinct tissues. Using polymerase chain reaction (PC R)-based molecular analysis of T-cell antigen receptor (TcR) variable (V) region genes, we have demonstrated marked restriction of orbital a nd pretibial TcR V alpha and V beta genes in patients with active TED and PTD. In addition, molecular analysis of T cells in paired samples of extraocular muscle and orbital connective/fatty tissue revealed usa ge of similar TcR V genes. In contrast, TcR V gene restriction was eit her absent or much less pronounced in patients with longstanding TED a nd PTD. Comparison of TcR V genes in T cells obtained from thyroid gla nd, orbital tissue, pretibial tissue, and peripheral blood of three in dividual patients with active GD, TED, and PTD also revealed marked re striction and, in addition, striking similarities of TcR V gene usage. Sequencing of complementarity determining regions 3 (CDR3) and juncti onal domains of TcR V beta genes confirmed oligoclonality of intrathyr oidal, orbital, and pretibial T cells. Moreover, several conserved jun ctional motifs were shared by T cells infiltrating the thyroid gland a nd the extrathyroidal sites. Taken together, these data suggest that, in patients with GD and extrathyroidal manifestations, similar antigen ic determinants may be responsible for recruitment and oligoclonal exp ansion of T cells both within the thyroid gland and in the involved ex trathyroidal sites.