Immunoglobulins from Patients with Graves’ Disease Induce Hyaluronan Synthesis in Their Orbital Fibroblasts through the Self-Antigen, Insulin-Like Growth Factor-I Receptor

Abstract

A distinctive histopathological feature associated with thyroid-associated ophthalmopathy is the disordered accumulation of the glycosaminoglycan, hyaluronan, in orbital connective tissues. This often occurs in the context of dramatic inflammation and tissue remodeling. Orbital fibroblasts exhibit a novel phenotype including exaggerated responses to cytokines. Here, we report for the first time the ability of IgG isolated from the sera of patients with Graves' disease (GD-IgG) to provoke in orbital fibroblasts the synthesis of hyaluronan. The effect of GD-IgG can be reproduced by IGF-I, appears to be mediated through the IGF-I receptor, and is abolished with glucocorticoid treatment. TSH failed to influence the synthesis of hyaluronan. In contrast to the effects in GD fibroblasts, cultures derived from donors without known thyroid disease fail to respond to GD-IgG or IGF-I. The observation that hyaluronan production is induced by GD-IgG in fibroblasts suggests that the IGF-I receptor and its activating antibodies may represent a key pathway through which important pathogenic events in thyroid-associated ophthalmopathy are mediated.

Aberrant Expression of the Insulin-Like Growth Factor-1 Receptor by T Cells from Patients with Graves’ Disease May Carry Functional Consequences for Disease Pathogenesis

“…Treatment of these IGF-1R ϩ fibroblasts with either IGF-1 or GD-IgG results in the synthesis of two powerful T cell chemoattractants, IL-16 and RANTES (38,39) as well as the generation of hyaluronan (33). In this study, we report a similarly expanded population of IGF-1R ϩ T cells.…”

“…In addition, orbital fibroblasts from patients with GD synthesize increased levels of hyaluronan when treated with GD-IgG, an action mediated by IGF-1R (33). Autoantibodies directed against IGF-1R can be detected in almost all patients with GD but in few individuals without the disease (32)(33)(34). We now report increased proportions of IGF-1R ϩ T cells from patients with GD.…”

“…When treated with IGF-1 or with IgG derived from these patients (GD-IgG), GD fibroblasts, but not those from control donors, synthesize high levels of IL-16 and RANTES, two powerful T cell chemoattractants (32). In addition, orbital fibroblasts from patients with GD synthesize increased levels of hyaluronan when treated with GD-IgG, an action mediated by IGF-1R (33). Autoantibodies directed against IGF-1R can be detected in almost all patients with GD but in few individuals without the disease (32)(33)(34).…”

Monoclonal Pathogenic Antibodies to the Thyroid-Stimulating Hormone Receptor in Graves’ Disease with Potent Thyroid-Stimulating Activity but Differential Blocking Activity Activate Multiple Signaling Pathways

“…Another group of anti-TSHR (blocking) Abs (TSBAbs) may act as antagonists of TSH binding to the receptor, a role that may occasionally lead to hypothyroidism (3). One recent model indicates potential cross-reactivity of anti-TSHR Abs with IGF-1R, resulting in the T cell-mediated induction of extracellular matrix components and leading to the manifestation of thyroid-associated ophthalmopathy and pretibial myxoedema (2,4,5). Neutral class Abs to the TSHR that have neither agonist nor antagonist activity have also been described, although their role in disease remains to be clarified.…”

The rationale for B lymphocyte depletion in Graves’ disease. Monoclonal anti-CD20 antibody therapy as a novel treatment option

“…It is possible that temporary disruption of unbalanced B cell homeostasis, depletion of memory B cells and depletion of precursors of the autoantibody-producing plasma cells could have a beneficial, or even curative, effect in GD. The pathogenesis of the extrathyroidal manifestations of GD, in particular TAO, is murkier than thyroidal GD and may be more T cell dominated; antibodies are, however, involved in the pathogenesis (41,42). Apart from the potential effect of RTX on the function of the B cell as an APC and on autoantibody production, we have hypothesized that B cell depletion may have a beneficial effect, directly or through the influence on T cells, on disturbed fibroblast function in TAO (Table 1).…”