Search PubMed⌕ Search

Biomedical subjects

Terry J Smith

Publications and source records attributed to Terry J Smith.

42 records · Page 3Linked to original sources
PubMed2002

Igs from patients with Graves' disease induce the expression of T cell chemoattractants in their fibroblasts.

Thyroid-associated ophthalmopathy and dermopathy are connective tissue manifestations of Graves' disease (GD). Tissue remodeling is a prominent feature of both and is apparently driven by recruited T cells. In this study, we report that IgG isolated from patients with GD (GD-IgG) up-regulates T lymphocyte chemoattractant activity in GD-derived fibroblasts from orbit, thyroid, and several regions of skin. This chemoattractant activity, absent in fibroblasts from donors without known thyroid disease, is partially susceptible to neutralization by anti-IL-16 and anti-RANTES Abs. IL-16 is a CD4(+)-specific chemoattractant and RANTES is a C-C-type chemokine. IL-16 and RANTES protein levels, as determined by specific ELISAs, are substantially increased by GD-IgG in GD fibroblasts. Addition of the macrolide, rapamycin, to fibroblast culture medium blocked the up-regulation by GD-IgG of IL-16, implicating the FRAP/mTOR/p70(s6k) pathway in the induction of IL-16 expression. These findings suggest a specific mechanism for activation of fibroblasts in GD resulting in the recruitment of T cells. They may provide insight into a missing link between the glandular and extrathyroidal manifestations of GD.

Caspase 3↗
PubMed2002

Fibroblast subsets in the human orbit: Thy-1+ and Thy-1- subpopulations exhibit distinct phenotypes.

An emerging concept is that fibroblasts are not homogeneous, but rather consist of subsets, capable of producing regulatory mediators that control regional inflammatory responses. Fibroblasts are key effector cells in Graves' ophthalmopathy, responsible for the connective tissue remodeling, and are a rich source of inflammatory mediators. The purpose of this research was to characterize subsets of the fibroblasts in the human orbit. The strategy used was to define fibroblast subpopulations based on surface expression of the Thy-1 antigen. Fibroblast strains derived from human orbital connective tissue exhibit heterogeneous Thy-1 expression. We show, for the first time, separation of orbital fibroblasts into functionally distinct Thy-1+ and Thy-1- subsets using magnetic beading techniques. Both subsets produced the pro-inflammatory cytokine interleukin-6 (IL-6) after stimulation with IL-1beta or the CD40 pathway, whereas Thy-1+ fibroblasts produced higher levels of prostaglandin endoperoxide H synthase-2 (PGHS-2) and prostaglandin E2 (PGE(2)). Thy-1- fibroblasts produced more IL-8 than Thy-1+ fibroblasts, and when treated with interferon-gamma (IFN-gamma) up-regulated MHC class II expression more robustly. Furthermore, CD40 was expressed in a bimodal distribution within each fibroblast subset. These observations suggest that fibroblast subsets in the human orbit play distinct roles in the regulation of immune and inflammatory responses crucial in the initiation and development of thyroid-associated ophthalmopathy.

CD40 Antigens↗
PubMed2002

Orbital fibroblasts exhibit a novel pattern of responses to proinflammatory cytokines: potential basis for the pathogenesis of thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) represents a process confined to the orbit where the connective tissue becomes inflamed and accumulates the glycosaminoglycan, hyaluronan. Ultimately, the orbital tissues become extensively remodeled. Evidence points to the recruitment and activation of T cells as critical elements initiating and driving the pathogenesis of TAO. The phenotype of orbital fibroblasts appears to be distinct from that of other types of fibroblasts. These cells exhibit particularly robust responses to a number of T-cell-derived cytokines. Notable among these are the inductions of key inflammatory genes and their products. We hypothesize that exaggerated cellular responses represent the basis for the involvement of the orbit in Graves' disease.

Cytokines↗
PubMed2002

Orbital fibroblast heterogeneity may determine the clinical presentation of thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy, a process in which the orbital tissues become inflamed and are remodeled, occurs with a variable presentation. In some patients, eye muscle enlargement predominates. In others, the connective/adipose tissue enlargement appears the more significant problem. Orbital fibroblasts exhibit heterogeneous phenotypes in culture. Here we report that fibroblasts derived from the connective/adipose tissue depot are distinct from those investing the extraocular muscles. Connective tissue fibroblasts represent a bimodal population of cells with regard to the surface display of the glycoprotein, Thy-1. Perimysial fibroblasts in contrast express Thy-1 uniformly. In that regard, they resemble those from the skin. When subjected to a newly defined set of culture conditions, adipocyte differentiation occurs in up to 43% of the cells. All adipocytes examined failed to display Thy-1. Fibroblasts derived from perimysium and dermis uniformly do not differentiate into adipocytes when incubated under identical culture conditions. Both Thy-1(+) and Thy-1(-) connective tissue fibroblasts express the adipogenic trigger, peroxisome proliferator activator gamma, suggesting that differences in the potential for differentiation may reside with phenotypic attributes downstream from this receptor/adipogenic transcription factor. These observations enhance our understanding of orbital adipogenesis and define previously unrecognized differences between fibroblasts from the extraocular muscle and connective tissue.

Adipocytes↗
PubMedDate not supplied

The putative role of fibroblasts in the pathogenesis of Graves' disease: evidence for the involvement of the insulin-like growth factor-1 receptor in fibroblast activation.

Graves' disease when fully expressed affects the thyroid gland and connective tissues of the orbit and pretibium. While the glandular disease is relatively well-characterized, the pathogenesis of the orbital and dermal components remains enigmatic. In the following article, we review some of the evidence suggesting that fibroblast activation in Graves' disease might play an integral role in the tissue remodeling associated with ophthalmopathy. The thyrotropin receptor (TSHR) is expressed at low levels in several connective tissue depots and by their derivative fibroblasts, including those from the orbit. Little direct evidence currently links extra-thyroidal TSHR expression with Graves' disease. Very recent observations now implicate the insulin-like growth factor-1 receptor (IGF-1R) as a fibroblast activating antigen. When immunoglobulins from patients with the disease, with or without clinical ophthalmopathy, bind IGF-1R on the surface of fibroblasts, the receptor becomes activated and upregulates the expression of two T lymphocyte chemoattractants, IL-16 and RANTES. Thus, IGF-1R may represent a second self-antigen with a pathogenic role in extra-thyroidal Graves' disease.

Animals↗