Dysregulation of TNF/TNFR superfamily members: a systemic link between intra- and extrathyroidal manifestations in Graves' disease.

Graves' disease (GD) coincides with the occurrence of disease-associated intrathyroidal dendritic cells (DC) and intraorbital inflammatory macrophages (Mphi). Physiologically, tumour necrosis factor-alpha (TNF-alpha) strongly affects the differentiation of DC and Mphi from monocytic precursors; we thus hypothesized that dysregulation of the TNF/TNFR superfamilies may provide a systemic pathogenic link in GD. In patients without eye symptoms, percentages of TNF-alpha-stimulated blood monocytes were highly significantly (P < 0.001) elevated, corresponding to both intrathyroidal DC maturation as well as increases in mature blood DC (MHC-II(hi)/CD40+/RFD1(hi)) and B cells (CD20(hi)/CD40+). GD patients also displaying eye symptoms revealed a striking reduction in blood monocytes, yet significantly (P < 0.05) increased CD40(hi) and TNF-alpha(hi) leucocytes. These findings suggest for GD that excess TNF-alpha induces monocytes to differentiate into hyperactivated thyroidal DC that, once emigrated, initiate systemic humoral autoimmunity associated with CD40/TNF-alpha upregulation. Such overexpression may instigate differentiation of periorbital inflammatory Mphi from CD14(hi)/CD16+ monocytes as a likely precursor subset. These results indicate that dysregulation of TNF/TNFR superfamily members provides a systemic pathogenic link in GD in that hyperactivated circulating monocytic precursors give rise to locally restricted, disease-associated DC and Mphi. Monocytes, therefore, may serve as a suitable target to therapeutically address the common precursor of key promoters of GD.