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Role of insulin-like growth factor-1 (IGF-1) pathway in the pathogenesis of Graves’ orbitopathy

https://doi.org/10.1016/j.beem.2011.10.002Get rights and content

The etiology of Graves’ orbitopathy (GO) remains enigmatic and thus controversy surrounds its pathogenesis. The role of the thyroid stimulating hormone receptor (TSHR) and activating antibodies directed against it in the hyperthyroidism of Graves’ disease (GD) is firmly established. Less well elucidated is what part the TSHR pathway might play in the development of GO. Also uncertain is the participation of other cell surface receptors in the disease. Elevated levels of insulin-like growth factor-1 receptor (IGF-1R) have been found in orbital fibroblasts as well as B and T cells from patients with GD. These abnormal patterns of IGF-1R display are also found in rheumatoid arthritis and carry functional consequences. In addition, activating IgGs capable of displacing IGF-1 from IGF-1R have also been detected in patients with these diseases. IGF-1R forms a complex with TSHR which is necessary for at least some of the non-canonical signaling observed following TSHR activation. Functional TSHR and IGF-1R have also been found on fibrocytes, CD34+ bone marrow-derived cells from the monocyte lineage. Levels of TSHR on fibrocytes greatly exceed those found on orbital fibroblasts. When ligated by TSH or M22, a TSHR-activating monoclonal antibody, fibrocytes produce extremely high levels of several cytokines and chemokines. Moreover, fibrocytes infiltrate both the orbit and thyroid in GD. In sum, based on current evidence, IGF-1R and TSHR can be thought of as “partners in crime”. Involvement of the former probably transcends disease boundaries, while TSHR may not.

Introduction

The pathogenesis of Graves’ orbitopathy (GO), also known as thyroid associated ophthalmopathy, remains clouded in uncertainty. It is unclear whether the same genetic susceptibility factors implicated In Graves’ disease (GD), namely CD40, thyroglobulin, HLA-DR, CTLA-4, and thyroid stimulating hormone receptor (TSHR) are identical to those contributing to GO.1 Moreover, the environmental factors provoking either GD or GO have yet to be identified. The contribution of tobacco use to disease severity has certainly received substantial attention and smoking cessation remains one of the most important behavior modifications we can suggest to our patients.2 Absence of complete preclinical rodent models of GD has hampered efforts to identify the critical constellation of events underlying GO.3 Encouraging news reporting the successful generation of a mouse model replete with many of the infiltrative manifestations that occur in human GD were later found to be incorrect.4, 5 Thus, most of the insights into the pathogenesis of GO derive from measurements made of serum factors and observations from cell culture-based studies. Unfortunately, the vast majority of opportunities to access orbital tissues occur very late in the disease process when surgical rehabilitation is typically undertaken. Our inability to distinguish primary disease events from secondary tissue reactivity in the orbit has too frequently prevented progress toward specific and targeted therapies. This brief review attempts to outline our current knowledge about the potential roles of IGF-1 receptor (IGF-1R) and the spontaneously generated activating antibodies against it in the pathogenesis of GO. These will be referred to as GD-IgG. More importantly perhaps is our goal of drawing attention to what remains unknown about GO and to provide a realistic perspective about what might provide answers as research continues (Fig. 1).

Section snippets

Orbital fibroblasts exhibit a unique set of phenotypic attributes

The unique characteristics exhibited by orbital fibroblasts, including their particularly robust responses to cytokines,6 may underlie clinically aggressive GO. These cells express high levels of inflammatory mediators such as prostaglandins,7, 8, 9, 10 lipoxygenase products,11 and chemokines.12 They display surface receptors for cytokines and produce a diverse array of both Th1 and Th2 cytokines.13, 14 Orbital fibroblasts express multiple enzymes involved in the biosynthesis of the

The strong case for involvement of TSH receptor and its activating antibodies in GO

Glaring deficits in understanding GO have led to considerable debate concerning the potential role of TSHR in this component of GD. While its participation in the hyperthyroidism associated with GD is well established, whether the stimulatory antibodies directed against TSHR, often referred to as thyroid-stimulating antibodies (TSI or TSAb), help initiate or sustain orbital tissue remodeling in GO has not been resolved. Many circumstantial pieces of evidence suggest that TSHR and TSAb may be

IGF-1R represents a multifaceted conduit to signaling involved in mammalian cell regulation from early development

IGF-1, IGF-1R, and IGF-1 binding proteins play many roles in developing and maintaining mammalian tissues.29 Although they are incompletely characterized, multiple aspects of the IGF-I pathway appear to diverge from normal in individuals with autoimmune disease.30 Increasing awareness of these alterations has provoked us to query whether modifying IGF-1 signaling could alter disease course, severity, and activity. Such an impact on the disease might constitute effective therapy. Biological

Where do we stand regarding IGF-1R-targeting antibodies in GD?

Debate has arisen concerning the existence and importance of antibodies targeting IGF-1R in GO. Confirmatory reports have yet to appear demonstrating the effects of GD-IgG on T cell chemoattractant synthesis and hyaluronan production. The findings of van Zeijl et al.67 utilizing fibroblasts exposed to an adipocyte differentiation medium may be in agreement with those of Smith and Hoa,63 but further studies will be necessary.

Efforts have been made to detect the anti-IGF-1R antibodies using

Concluding comments: a potential way forward-testing the hypothesis

Evidence has been advanced that IGF-1R might play a role in autoimmunity.37 This possibility appears consonant with the established impact that both IGF-1 and IGF-1R exert on multiple components of the mammalian immune system. We have suggested that antibodies generated in GD can bind to the receptor and initiate signaling that culminates in the production of chemoattractants and hyaluronan. These effects are disease-selective in that only fibroblasts from individuals with GD respond. But the

Conflict of interest

None of the authors report any conflict of interest.

Acknowledgments

This work was supported in part by National Institutes of Health grants EY008976, EY011708, DK063121, EY016339, EY021197, EY007003, RR00425, AR053858, an unrestricted grant from Research to Prevent Blindness, a Research to Prevent Blindness Career Development Award, the Bell Charitable Foundation, and an unrestricted grant from the Novo Nordisk Foundation.

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