T-Cell Restriction in Thyroid Eye Disease

Abstract

Infiltrating immunocompetent cells act to establish and perpetuate the orbital autoimmune process in thyroid eye disease (TED). Until recently, it has remained unclear whether T cells infiltrating the orbital connective/fatty tissue and extraocular muscles represent a primary immune response that is specifically directed against orbital antigens. In addition, despite a close clinical and temporal association of the thyroidal and extrathyroidal manifestations in Graves' disease (GD), it has not been proven whether T cells infiltrating thyroid, orbital, and pretibial tissue in patients with TED and pretibial dermopathy (PTD) are directed against certain antigenic determinants shared between these anatomically distinct tissues. Using polymerase chain reaction (PCR)-based molecular analysis of T-cell antigen receptor (TcR) variable (V) region genes, we have demonstrated marked restriction of orbital and pretibial TcR Valpha and Vbeta 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 usage of similar TcR V genes. In contrast, TcR V gene restriction was either absent or much less pronounced in patients with longstanding TED and PTD. Comparison of TcR V genes in T cells obtained from thyroid gland, orbital tissue, pretibial tissue, and peripheral blood of three individual patients with active GD, TED, and PTD also revealed marked restriction and, in addition, striking similarities of TcR V gene usage. Sequencing of complementarity determining regions 3 (CDR3) and junctional domains of TcR Vbeta genes confirmed oligoclonality of intrathyroidal, orbital, and pretibial T cells. Moreover, several conserved junctional motifs were shared by T cells infiltrating the thyroid gland and the extrathyroidal sites. Taken together, these data suggest that, in patients with GD and extrathyroidal manifestations, similar antigenic determinants may be responsible for recruitment and oligoclonal expansion of T cells both within the thyroid gland and in the involved extrathyroidal sites.

Management of Graves' Ophthalmopathy: Reality and Perspectives

“…After infiltration of the orbit by T cells, the shared antigen could then be recognized by a T cell receptor on CD4ϩ T lymphocytes: the finding of a biased usage of the T cell receptor variable gene (14,15) supports the concept of an antigen-specific immune reaction (9). After antigen recognition, CD4ϩ T lymphocytes could secrete cytokines that amplify the immune reaction by either activating CD8ϩ T lymphocytes or autoantibody-producing B cells (16).…”

Influence of cigarette smoking on thyroid function, goiter formation and autoimmune thyroid disorders

“…Graves' ophthalmopathy, or thyroid eye disease (TED) 58,59 , is the most frequent extrathyroidal clinical manifestation of Graves' disease and constitutes a major and complex pathogenetic and therapeutic dilemma 26 . The first possible connection between cigarette smoking and Graves' ophthalmopathy was made by Hagg and Asplund 60 who showed that 10 out of 12 patients were current smokers, a figure much higher than that observed in Graves' patients without ophthalmopathy (46%) or in control subjects (31%).…”

Mechanisms That Underly T Cell Immunity in Graves’ Orbitopathy

“…Development of diversity or polyclonality of the TCR gene repertoire indicates that orbital inflammation is at the burnout stage. Heufelder summarized data from three severe active GO patients with GD and dermopathy and reported not only marked TCR restriction, but also several conserved junctional motifs shared by T cells in the orbit, thyroid, and pretibial tissue despite obvious heterogeneity of the TCR genes in each patient ( 12 , 51 ). This highlights the presence of certain oligoclonal T cell populations stimulated by the analogous antigenic determinants shared by the thyroid and the involved extrathyroidal compartments.…”