title: Dysregulation of TNF/TNFR superfamily members: a systemic link between intra- and extrathyroidal manifestations in Graves' disease.
abstract: 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.
authors.affiliation: Division of Endocrinology, Department of Medicine, University of Duisburg-Essen, Essen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Quadbeck
authors.forename: M
authors.initials: M
authors.lastname: Stucke
authors.forename: A K
authors.initials: AK
authors.lastname: Eckstein
authors.forename: D J
authors.initials: DJ
authors.lastname: Heise
authors.forename: K
authors.initials: K
authors.lastname: Mann
authors.forename: R K
authors.initials: RK
authors.lastname: Gieseler
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D019013:CD40 Antigens / Q000378:metabolism; D016022:Case-Control Studies; D003713:Dendritic Cells / Q000502:physiology; D005260:Female; D006111:Graves Disease / Q000378:metabolism*; D049970:Graves Ophthalmopathy / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D019013:CD40 Antigens; D018124:Receptors, Tumor Necrosis Factor; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha