TOPIC: Thymus contribution to thyroid autoimmunity
Title: Influx of recent thymic emigrants into autoimmune thyroid disease glands in humans.
Authors: Armengol MP, Sabater L, Fernandez M, Ruiz M, Alonso M, Otero MJ, Martinez-Caceres E, Jaraquemada E, & Pujol-Borrell R.
Reference: Clinical & Experimental Immunology 153: 338-350, 2008
Summary
Background
The aetiology of autoimmune thyroid disease remains poorly understood although most recent attention has focussed on failure of peripheral tolerance mechanisms as an explanation. Amongst these mechanisms, the recent finding of T regulatory cells has opened up the possibility that a defect in their function might allow the emergence of autoimmunity which is exacerbated by the failure of thyroid cells to impose tolerance through MHC class II molecule expression. The idea that a defect in central (thymic) tolerance is involved in aetiology has received much less attention.
Purpose
In order to assess the contribution of the thymus to thyroid autoimmunity, peripheral blood lymphocytes (PBL) and intrathyroidal lymphocytes (ITL) from patients were examined for surface markers indicating that they are recent thymic emigrants (RTE).
Methods
Flow cytometric analysis was performed on PBL from 58 patients with Graves’ disease or Hashimoto’s thyroiditis, and compared with 48 matched controls. Testing was performed for CD4+CD45RA+, CD4+CD31+ and CD4/CD8 double-positive cells, which are all markers of RTEs. In addition cells were examined for the presence of T cell receptor excision circles (TRECs), a molecular marker of RTEs.
Results
Significantly higher numbers of PBL were RTEs in the patients than in controls. TRECs were also increased in patients older than 35 compared to age-matched controls. Examination of telomere length as a marker of proliferative history indicated that these increases were not due to expansion in the periphery. TREC levels in paired samples of PBL and ITL showed there were more RTEs in the thyroid during the first two and half years of disease, indicating that these cells seem to be going to the thyroid. Further analysis of Foxp3 expression showed that the TREs in the ITL were not natural regulatory T cells. Conclusions: These results indicate that the thyroid contains a surprising excess of RTEs in autoimmune thyroid disease. The functional role of these cells is so far unknown but the data suggest that it would be worth exploring the role of central tolerance far more in these conditions.
Commentary
This study has examined a large number of patients and established that both naïve T cells (expressing CD45RA) and recent thymic emigrants (RTEs, expressing CD31 and CD4, CD8 double positive) are increased in PBL and ITL. Since telomeres were not shortened in the patients with thyroid disease, this indicates that the expansion of naïve T cells is unlikely to be due to expansion or lower conversion rate to CD45R0 memory cells. Although present results could be explained by a lower death rate of cells in patients with thyroid disease, the fact that RTE populations are also expanded suggests that all 3 subsets analyzed by flow cytometry are increased secondary to higher thymic output, and the results using TRECs again support this idea. Moreover, in early disease the authors have shown that RTEs are present in higher levels in the ITL than in PBL. This is surprising since it would be expected that the chronic inflammation would lead to expansion of T cells that have accumulated there, and these would dilute out the RTEs. This change may well explain the results with late stage disease but one would not have predicted the footprint of RTE invasion to persist so long. The authors have also excluded that expansion is simply due to T regulatory cells which are known to accumulate in the thyroid, in an attempt, teleologically speaking, to suppress the disease process.
It is a long way in immunology from phenotype to function, and many thyroid studies have been plagued by failure to address this fact. The authors are very careful to stress that present findings are a start in pointing to a possible new direction in understanding thyroid autoimmunity. We certainly know how important central tolerance is in the aetiology of autoimmune polyglandular syndrome type 1 in which multiple autoimmune disorders occur because of a failure to delete self-reactive T cells within the thymus. Such patients develop autoimmune thyroid diseases but with a lower frequency than other components such as Addison’s disease and hypoparathyroidism. Nonetheless this increase in thyroid autoimmunity prevalence, which can also be seen in adults with APS 1, also points to a role for central tolerance in averting thyroid autoimmunity.
If there is a continued imposition of central tolerance on the T cell repertoire, then we can envisage that these results show that thyroid-autoreactive T cells are escaping form the thymus in patients with thyroid disease and accumulating in the thyroid. It is possible that environmental triggers could be responsible for influencing such thymic egress and this could also have a genetic component. The beneficial effects of thymectomy in myasthenia gravis are well-known. Could further research in this area make the thymus a possible future target for therapeutic intervention in serious cases of thyroid disease?
Summary and commentary prepared by Anthony Weetman (Related to Chapter 7 of TDM)
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