T helper cell subsets in autoimmune thyroid disease

TOPIC: A role for Th17 T cells in AITD

Title: Increases of the Th1/Th2 cell ratio in severe Hashimoto’s disease and in the proportion of Th17 cells in intractable Graves’ disease.

Authors: Nanba T , Watanabe M , Inoue N , & Iwatani Y .

Reference: Thyroid 19: 495-501, 2009

Summary

Background

CD4+ T cells have been divided into subsets such as Th1 and Th2, based on their pattern of cytokine production, although it remains to be understood how well such subdivisions identified in mice are applicable to man. A recently identified additional subset has been termed Th17, because such T cells are characterised by the production of the cytokine interleukin-17 (1L-17). These T cells seem to have a major defence role against extracellular microbes and are involved in the inflammatory phase of many immune processes, including autoimmunity. So far, no study has examined the role of Th17 cells in autoimmune thyroid disease (AITD).

Objectives

To carry out a phenotypic analysis of CD17+ T cells in human AITD, and at the same time to examine the ratio of Th1 and Th2 cells.

Methods

The authors studied peripheral blood lymphocytes (PBL) from 18 patients with Graves’ disease (GD), still active after treatment and termed ‘intractable GD’, 17 patients with Graves’ disease in remission after treatment, 17 patients with Hashimoto’s thyroiditis (HT) requiring thyroxine treatment and termed ‘severe HT’, 17 patients with HT who were still euthyroid, and finally 10 control subjects. PBL were polyclonally activated by culture with ionomycin and phorbol myristate acetate for 4 hours before staining with monoclonal antibodies and then analyzed by flow cytometry. Th1 cells were defined as those that were positive for interferon-γ, Th2 cells as those positive for IL-4 and Th17 as those positive for IL-17.

Results

Patients with severe HT had a higher proportion of Th1 cells and a lower proportion of Th2 cells than those with mild HT. There was no difference between the 2 GD groups with regard to Th1 and Th2 cells. The proportion of Th17 cells was higher in those with AITD (either GD or HT) than in controls. Patients with intractable GD had a higher proportion of Th17 cells than those in remission.

Conclusions

There are significant alterations in the T helper cell subsets in severe HT, and Th17 cells are elevated in the circulation of all patients with AITD, although those with GD in remission appear to have lower levels of these cells. The results support a role for Th17 cells in AITD.

Commentary

Th1 cells promote autoimmune inflammatory reactions and Th2 cells enhance the production of autoantibodies, although teleologically the prime purpose of these subsets is in the defence mechanisms against microbial and protozoal infections, respectively. It would therefore ‘make sense’ if Th1 cells predominated in Hashimoto’s thyroiditis (HT) and Th2 cells predominated in Graves’ disease (GD). However, such a neat dichotomy would not explain the huge levels of thyroid autoantibodies in HT compared to the distinctive TSH receptor stimulating antibodies in GD. We also know that the thyroid is a major site of autoantibody synthesis in AITD and, yet, the analysis of intrathyroidal cell populations has not shown any clear Th1 or Th2 predominance in either disease (see Ajjan & Weetman, in Autoimmunity 2003). This may be because the notion of Th1 and Th2 is too simplistic for application to human pathological processes, which are chronic and complex. It is not always appreciated that even the exact cytokine profile of murine and human putative Th1 and Th2 cells differ. Moreover, there are many T cells which defy neat categorisation: CD8+ and NK cells can secrete similar cytokines and other populations like Th0 and Th3 have been described. Non-lymphoid cells including thyrocytes can produce cytokines, which adds to the complexity of the cytokine milieu. Thus, the finding of an expansion of Th1 and a decline of Th2 peripheral blood cells in severe HT is interesting but cannot tell us much about what is going on in the thyroid where much of the autoimmune pathogenesis occurs. It should also be noted that the authors of the present article classified their Th1 & Th2 cells rigorously as only those secreting either interferon- γ or IL-4. When they took into account the co-production of other cytokines, there was no overall difference between disease groups. Other issues which require addressing in future studies would include the fact that the cells were polyclonally activated and thus not in the ex vivo state (such activation is necessary to amplify the cytokine signal), also that the patients were not followed sequentially, and finally that there are no absolute numbers given for the T cell subsets, but only relative proportions.

That said, the data on Th17 cells are especially interesting as this is the first study to show that these cells are likely to play a role in AITD. It is interesting that there was an increase in these cells in both GD and HT, although the proportion of Th17 was somewhat reduced when GD went into remission. This fits with the known immuno-modulatory actions of antithyroid drugs, but other mechanisms could also be involved. It is noteworthy that even in remission Th17 cells remained elevated. Could these be the harbingers of autoimmune hypothyroidism which is known to arise in some patients with GD late on in remission? Further studies on the role of Th17 cells in AITD are clearly warranted.

Summary and Commentary prepared by Anthony Weetman (Related to Chapter 7 of TDM)