Perforin expression by thyroid-infiltrating T cells in autoimmune thyroid disease

Abstract

SUMMARY Infiltration of the thyroid gland by lymphocytes is a hall‐mark of autoimmune thyroid disease; it is particularly evident in Hashimoto's thyroiditis but is also seen in most patients with Graves’ disease. Infiltrating cells are comprised primarily of T lymphocytes., of which only a minority appears to be activated. Their precise pathogenic role is largely unknown. Since perforin has been a marker for functionally activated cytotoxic T cells in situ we elected to assess the presence of perforin‐containing cells in thyroid‐infiltrating lymphocytes and establish their phenotype. Cells were isolated from seven subtotal thyroidectomy specimens, five from patients with Graves” disease and two with Hashimoto's thyroiditis. The novel findings were as follows: CD4+ perforin‐containing T cells occurred only in Hashimoto's glands, suggesting a class II‐restricted component of cytotoxicity; in Graves' disease, and to a lesser extent in Hashimoto's, perforin‐expressing cells were primarily T cell receptor αβ+ CD4‐ CD8‐ (double negative); double negative perforin‐containing cells in peripheral blood of normal individuals were largely γδ+T cells. In Hashimoto's samples, the predominant population of T cells expressing perforin was CD8+. By comparison, in studies of the synovial fluid of knee joints from patients with rheumatoid arthritis only a minor population of the perforin‐containing cells was double‐negative. The data suggest significant differences in cytotoxic autoimmune mechanisms between the two autoimmune thyroid diseases. Functional characterization of double‐negative T cells is necessary to define their role in autoimmunity.

Dose-specific transcriptional responses in thyroid tissue in mice after 131I administration

“…increasing or decreasing gene expression with absorbed dose throughout the entire absorbed dose range. The Prf1 gene, involved in T-cell mediated cytolysis, belongs to the autoimmune thyroid disease signaling pathway, and the S100a8 gene product may induce apoptosis under inflammatory conditions [31,32]. These genes are interesting biomarker candidate genes that might be useful to predict absorbed dose to thyroid in mice injected with 131 I, at least in the interval 0.85-17 Gy.…”

Thyroid autoimmunity

“…There is a combination, likely in variable proportions along the evolution of the disease and from one patient to another, of cellular, humoral (thyroid antibodies) and cytokine effects. The impact of specific cytotoxic perforin-expressing CD8+ T cells is relatively poorly documented in human AITD [49]. As to the implication of the Fas-Fas-ligand system in thyroid cell apoptosis, it remains so far unclear.…”

Juvenile Autoimmune Thyroiditis

“…Initial studies on thyroid autoimmunity were centered around the discovery of antibodies to thyroid-related antigens, such as thyroglobulin, microsomal fraction, and the thyrotropin (TSH) receptor 15 . Once activated, cell-mediated immune mechanisms mediate thyrocyte destruction, which is further exacerbated by humoral immunity, either by complement fixation or antibody directed cellular cytotoxicity (ADCC) 18 ' 19 . Since children diagnosed with JAT have developed thyroid autoimmunity at an early age, it is logical to think that they constitute a genetically predisposed population.…”