Fibroblast activation plays an important role in initiating the inflammatory response. Phenotypic attributes of fibroblasts from specific anatomic regions are thought to underlie the peculiar pattern of manifestations associated with certain diseases. Other fibroblast characteristics appear global, such as the expression of chemoattractants including IL-16, a CD4-specific ligand and RANTES, a C-C chemokine. We have found that fibroblasts from patients with the Graves' disease (GD), when treated with their IgGs (GD-IgG), become activated and express high levels of IL-16 and RANTES and in so doing provoke the migration of T cells. Control fibroblasts from donors without autoimmune disease fail to respond to these IgGs. GD-IgGs, which are rare in control sera, appear to be binding to the insulin-like growth factor-1 receptor (IGF-1R) displayed on fibroblasts. We hypothesize that IGF-1R represents an important activational self-antigen. Its ligation with GD-IgG up-regulates chemoattractant expression in fibroblasts. Further, we hypothesize that the IGF-1R display by disease-derived cultures in some way differs from that on control fibroblasts. These inductions could underlie T cell infiltration in GD. We now propose the following studies to test our central hypothesis.
Specific aims : (1) To define the mechanisms involved in the up-regulation by anti-IGF-1R Abs (i.e. GD-IgG) of IL-16 and RANTES expression in GD- fibroblasts by assessing transcriptional and translational regulation and cell signaling through IGF-1R. (2) To determine whether fibroblasts from patients with GD express functionally different IGF-1R from control fibroblasts, we will perform IGF-1 binding studies, northern and western blot analysis of IGF-1R alpha and beta subunit levels and examine IGF-1R tyrosine phosphorylation. (3) To determine whether serum and tissue levels of IL-16 and RANTES are higher in GD by performing ELISA, in situ hybridization and immunohistochemical studies. (4) To determine whether GD-IgG induces chemoattractant expression in vivo in xenotransplanted human orbital tissue from patients with GD in SCID mice. We believe that important insights into disease pathogenesis and identification of novel therapeutic targets will emerge from these studies. ? ?
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