In contrast, Compact disc34+ cells were absent among orbital fibroblasts from control donors uniformly

In contrast, Compact disc34+ cells were absent among orbital fibroblasts from control donors uniformly. which therapeutic agencies might be directed. is not however known. The foundation for the mobile diversity seen in these connective tissues depots has however to be motivated, but may eventually describe the patterns of tissue remodelling observed in both anatomic regions. With regard to the orbit, the potential for Thy-1- fibroblasts to differentiate into adipocytes might help to explain the apparent expansion of fat found in Graves’ disease. Infiltration of fibrocytes into tissues might contribute to apparent fibroblast diversity Fibrocytes represent circulating bone-marrow derived monocyte MG-132 lineage cells MG-132 that present antigen efficiently to lymphocytes, prime naive T cells and can enter sites of tissue injury [10,11]. They are distinct from fibroblasts, T and B lymphocytes, monocytes, epithelial, endothelial and dendritic cells and can differentiate into mature fat cells, osteoblasts and myofibroblasts. Their ultimate fate MG-132 depends, at least in part, upon the signals they receive from their microenvironment and which of the intracellular signalling pathways become activated [12]. In this regard, fibrocytes resemble fibroblasts. Fibrocytes were first described by Bucalla and established rheumatoid arthritis were similar, suggesting that the levels of signalling might prove invariant following disease initiation. In a mouse model of sclerosing cholangitis, designated mice [26]. Fibrocytes from patients with thermal burns and those from normal donors have substantially less capacity for collagen production than do dermal fibroblasts [27]. When conditioned medium from fibrocytes derived from burned individuals was incubated with dermal fibroblasts, they exhibited accelerated proliferation when compared to those incubated in medium from control fibrocytes. These effects could be blocked with TGF- neutralizing antibodies [27]. These same investigators have shown that IFN-2b can reduce scar formation following thermal injury by attenuating fibrocyte activity and reducing their numbers [28]. With regard to the kidney, the participation of bone marrow-derived stem cells remains controversial [29]. Results generated in a number of models of renal injury suggest that these stem cells can localize to specific areas of the kidney and might facilitate tissue regeneration. Thus, their therapeutic potential in several forms of human kidney dysfunction is under evaluation. The outcome of such studies will probably influence the research being conducted in allied disease processes involving other organs and tissues. Graves’ disease as a model of fibrocyte participation in human autoimmunity: basis for orbital fibroblast heterogeneity? Graves’ disease represents an autoimmune process where the thyroid becomes enlarged and overactive [30]. The basis for the over-production of thyroid hormones and gland enlargement in this disease involves the production and activity of autoantibodies targeting the thyrotrophin (aka thyroid-stimulating hormone) receptor (TSHR). In addition, the IGF-1 receptor (IGF-1R) is over-expressed by orbital fibroblasts [31], B [32] and T cells [33,34] in patients with the disease. IGF-1R represents a MG-132 second potentially pathogenic autoantigen that may account for abnormal thyroid enlargement and underlie the trafficking of lymphocytes to affected tissues, including the pretibial skin and orbit. Pritchard in orbital tissue from patients with TAO TMPRSS2 but were absent in those from healthy donors (Fig. 1). They were consistently CD31-, indicating that the putative fibrocytes were unrelated to endothelial cells. Surprisingly, high levels of TSHR were detected on the circulating fibrocyte surface. The levels of this protein appear equivalent to those found on thyroid epithelial cells, where they mediate thyroid hormone production (Fig. 2). Even more surprising was their observation that the receptor is functional. When ligated with bovine thyroid-stimulating hormone (bTSH) or M22, an activating monoclonal antibody generated against TSHR, the production of inflammatory cytokines such as TNF- and IL-6 is up-regulated dramatically (Fig. 3) [50]. When orbital fibroblasts from patients with TAO were subjected to flow cytometric analysis, a subpopulation of cells was found to exhibit the CD34+Col1+ phenotype. In contrast, CD34+ cells were uniformly absent among orbital fibroblasts from control donors. This phenotype was stable in culture over many serial passages. Moreover, it appears that the vast majority of CD34+ orbital fibroblasts are also CD90+ (Thy-1+). MG-132 Open in a separate window Fig. 3 Thyroid-stimulating hormone receptor (TSHR) displayed on fibrocytes generated from peripheral blood mononuclear cells (PBMCs) can function to initiate cytokine production. Cultured cells, in this case from a patient with Graves’ disease, were treated with bovine thyroid-stimulating hormone (bTSH) (5 mU/ml) or interleukin (IL)-1 (10 ng/ml) for 48 h. The medium was subjected to enzyme-linked immunosorbent assays specific for (a) IL-6 or (b) tumour necrosis factor (TNF)-. Data are expressed as the mean standard error of the mean of three replicate culture wells from a representative experiment (* 0001). (Reprinted with permission; Douglas, RS em et al /em . Increased.