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Matthew R. Edmunds, Omar M. Durrani, Kristien Boelaert, Jayne A. Franklyn, S J. Curnow; Decreased CD4+ and CD8+ Effector Memory T Lymphocyte Populations in Thyroid-Associated Ophthalmopathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1011.
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Relative proportions of peripheral blood T lymphocyte memory subsets have previously been shown to vary in a number of inflammatory and autoimmune conditions, such as rheumatoid arthritis, primary biliary cirrhosis and myasthenia gravis. The aim of this study was to definitively characterize CD4+ and CD8+ T cell memory populations in patients with Graves’ disease (GD) with manifestations of Thyroid-Associated Ophthalmopathy (TAO), an inflammatory condition of the orbit associated with autoimmune thyroid disease (GD+TAO+), those with GD without such manifestations (GD+TAO-), and healthy controls.
Multicolour flow cytometry was used to analyse CD4, CD8, CD45RO and CCR7 expression and IFN-γ and IL-17 production by PMA- and ionomycin-stimulated peripheral blood mononuclear cells from 28 GD+TAO+ subjects, 11 GD+TAO- subjects and 20 age- and sex-matched healthy controls. Memory populations were sub-divided into naïve (CD45RO- CCR7+), central memory (CD45RO+ CCR7+), effector memory (CD45RO+ CCR7-) and effector memory RA (CD45RO- CCR7-). Statistical analysis was undertaken with Mann-Whitney U test.
For TAO+ subjects there were significant increases in naïve CD4+ (67% vs 56%, p=0.002) and CD8+ (69% vs 39%, p=0.004) T cells with corresponding reductions in central memory CD4+ (12% vs 21%, p=0.001), effector memory CD4+ (11% vs 15%, p=0.02) and effector memory CD8+ (10% vs 20%, p=0.01) T cells, as compared with controls. In addition, there was lower production of IFN-γ (4.4% vs 11%, p=0.001 for CD4+ and 5% vs 12%, p<0.009 for CD8+) and IL-17 (0.36% vs 0.82%, p=0.01 for CD4+, although non-significant for CD8+). TAO- subjects also demonstrated an increased proportion of naïve CD8+ (although not CD4+) T cells (67% vs 39%, p=0.001) with reduced IFN-γ by CD4+ (6.3% vs 11%, p=0.01) and CD8+ T cells (11% vs 13%, p=0.04), as compared with controls. There were no significant differences between TAO+ and TAO- subjects in any of the parameters. The expression of early (CD69) and late (CD71 and CD154) T cell activation markers were unchanged between the three groups
This study demonstrates reduced cytokine-producing effector memory CD4+ and CD8+ T cells in TAO+ and TAO- GD subjects. Skewing of memory T cell populations may represent dysregulated lymphocyte homeostasis, with preferential generation or survival of naïve T cells, increased sequestration of effector memory T cells in inflamed tissues, or an effect of thionamide or immunosuppressant drugs. Future experiments will aim to clarify the immunopathogenic significance of this observation.
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