IMMUNE REGULATORY PLASMACYTOID DENDRITIC CELLS SE- LECTIVELY ACCUMULATE IN PERITHYROIDAL LYMPH NODES OF PATIENTS WITH GRAVES DISEASE: IMPLICATIONS FOR THE UN- DERSTANDING OF AUTOIMMUNITY

Endocrine orbitopathy(EO) is the most common extrathyroidal manifestation of Graves disease (GD) but the involvement of the underlying immunological dysregulations remains largely unknown. The major source for IFNα-production, plasmacytoid dendritic cells (PDC) are fundamentally involved in the integration of TH1 and TH2 immune responses but also implicated in the pathogenesis of autoimmune diseases such as lupus. Aim: To establish whether PDC may play a role in GD autoimmune reaction and in the pathogenesis of EO. Material and methods:In a series of six sequential patients with GD as well as six further patients with multinodular goiter, cervical lymph nodes (LN) were sampled and preserved in the setting of thyroid resection. In parallel, peripheral blood samples were collected. The frequency of PDC from the peripheral blood and lymph nodes were determined. Mononuclear cells (MC) were enriched from lymph nodes and peripheral blood using Fiquoll-hypaque density gradient centrifugation. Mononuclear cells were stained using BDCA-2-PE and CD123-FITC monoclonal antibodies and their frequency subsequently analyzed using fluorescence activated cell sorting (FACS). Dead cells were excluded from analysis by appropriate gating strategies and propidium iodide (PI) staining. Results:In all patients with GD (with or without EO), PDC frequency was significantly increased in perithyroidal LN as compared to LN of patient not suffering form autoimmune diseases, e. g. patients with multinodular goiter (p < 0.01). The number of PDC infiltrating lymph nodes (LN-PDC) was also higher when compared to peripheral blood PDC (pB-PDC) of patients with multinodular goiter (p < 0.05). Finally, LN-PDC counts in perithyroidal lymph nodes of patients with GD were substantially increased when compared to pB-PDC of the same patients (p < 0.01) indicating a migration and accumulation of PDC in the draining LN. Conclusions: We found evidence that PDC selectively accumulate in perithyoidal LN of patients with GD, but not other thyroid diseases such as multinodular goiter. Based on their central importance in the pathogenesis of autoimmune processes such as in lupus erythematoides, we suggest that the migration and accumulation of PDC in an anatomical joining point between the thyroid gland and orbita may be of critical importance for the initiation and maintenance of a chronic autoimmune stimulation. This implies a so far unknown role for PDC in GD and as putative cellular targets for new therapeutic approaches.