Chemokines are a group of peptides of low molecular weight that induce the chemotaxis of different leukocyte subtypes. The major function of chemokines is the recruitment of leukocytes to inflammation sites, but they also play a role in tumoral growth, angiogenesis, and organ sclerosis. In the last few years, experimental evidence accumulated supporting the concept that interferon-γ (IFN-γ) inducible chemokines (CXCL9, CXCL10, and CXCL11) and their receptor, CXCR3, play an important role in the initial stage of autoimmune disorders involving endocrine glands. The fact that, after IFN-γ stimulation, endocrine epithelial cells secrete CXCL10, which in turn recruits type 1 T helper lymphocytes expressing CXCR3 and secreting IFN-γ, thus perpetuating autoimmune inflammation, strongly supports the concept that chemokines play an important role in endocrine autoimmunity. This article reviews the recent literature including basic science, animal models, and clinical studies, regarding the role of these chemokines...

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Role of chemokines in endocrine autoimmune diseases.

Hyperthyroidism in Graves’ disease is due to the binding of stimulatory autoantibodies to the TSH receptor (TSHr) on thyroid follicular cells. The stimulation of this G proteincoupled receptor by autoantibodies leads to excessive and uncontrolled production of thyroid hormone. Our understanding of Graves’ disease has increased remarkably after the cloning in 1989 of TSHr (1–3). This achievement led to insights regarding TSHr biology, including the unique two-subunit structure of this receptor that may render it especially prone to autoimmune attack (4). In contrast, the pathophysiology of Graves’ ophthalmopathy (GO) and thyroid-associated pretibial dermopathy (PTD) is less well understood. However, studies by several groups have begun to unravel the many complex factors contributing to development of these ocular and dermal manifestations of Graves’ disease. The progression of GO and PTD from initiation to subclinical disease to fully developed ocular and dermal manifestations appears not to be a linear process. It seems rather to be a positive feedback cycle composed of mechanical, immunological, and cellular processes (Fig. 1). In this review each of the major components of this disease cycle will be examined with an eye toward understanding the limitations of current therapy and identifying targets for future therapy. Mechanical contributions to GO pathogenesis Many of the clinical symptoms and signs of GO can be explained on a mechanical basis by the increase in volume of intraorbital tissues characteristic of the disease (5). Although most individuals with GO have evidence of both extraocular muscle and orbital adipose tissue enlargement, some exhibit a predominance of either muscle or fat expansion (6). Individuals younger than 40 yr of age are considerably more likely to exhibit orbital fat expansion in the absence of muscle enlargement, whereas patients over 70 yr are more prone to severe, fusiform muscle enlargement without significant changes in orbital adipose tissue volume (7). Proptosis, the forward displacement of the globe, stems from this increase in orbital tissue volume within the unyielding confines of the bony orbit. Extraocular muscle dysfunction is caused, early in the disease, by swelling of the muscle bodies. Enlargement of the muscles at the apex of the orbit may lead to compressive optic neuropathy and visual loss. In later stages the extraocular muscles may become fibrotic and atrophic as a result of chronic inflammation and compression of the muscle fibers. Chemosis and periorbital edema appear to be caused primarily by decreased venous and lymphatic drainage from the orbit secondary to compression of these channels. Similarly, patients with severe PTD have compromise of low pressure lymphatics in the lower extremities (8), which probably contributes to the dependent edema seen in this condition. Histological examination of orbital adipose and extraoc

Clinical review 157: Pathophysiology of Graves' ophthalmopathy: the cycle of disease.

Thyroid peroxidase autoantibodies in euthyroid subjects

Thyroid eye disease (TED) is an inflammatory condition of the orbit closely associated with Graves' disease. During the course of TED, fibrosis can develop around the extraocular muscles, and excess extracellular matrix and fat accumulates in the periorbital space. This dramatic remodeling results in protrusion of the eye, also known as exophthalmos. Current treatments are sometimes effective in alleviating the symptoms of the disease, but there remains a demand for treatments that prevent or reverse the pathological alterations of orbital tissues. Such treatments may become available as a result of research aimed at understanding the mechanism by which Graves' disease leads to specific remodeling of orbital tissues. Recent findings have uncovered the importance of intercellular communication between autoreactive T cells and orbital fibroblasts. When orbital fibroblasts are activated, possibly by Graves' disease-related autoantibodies, they release T cell chemoattractants, initiating an interaction in which these cells activate each other. These interactions ultimately result in fibroblasts expressing extracellular matrix molecules, proliferating and differentiating into myofibroblasts or lipofibroblasts. Although the mechanisms underlying these processes are not completely understood, several currently available therapeutic strategies might interrupt the signaling between B and T cells and fibroblasts, thereby treating the clinical manifestations of TED.

Immune mechanisms in thyroid eye disease.

Autoantibodies to thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) are of immunoglobulin G (IgG) class and have high affinities for their respective autoantigens. Both autoantibodies are markers of thyroid autoimmunity and they can be measured by a variety of assays. From the clinical perspective, TgAb are less prevalent than TPOAb and less useful than TPOAb for prediction of thyroid dysfunction. Moreover, TgAb interfere with Tg measurements to monitor metastases in thyroid cancer. However, increasing evidence suggests that these TgAb provide a surrogate for Tg. In terms of disease pathogenesis, Tg has been suggested to play a role in Graves' ophthalmopathy. Pending further studies, TgAb epitopes could distinguish between individuals who are euthyroid or who have clinical disease. A final, intriguing reason for measuring and characterizing TgAb is the interest these autoantibodies have rekindled in their autoantigen. It is conceivable that Tg polymorphisms, combined with the explosive mix of iodine, TP...

Why measure thyroglobulin autoantibodies rather than thyroid peroxidase autoantibodies

Molecular cloning and characterization of human thyroid peroxidase autoantibodies of lambda light chain type

Isolation and characterization of a monoclonal human thyroidperoxidase autoantibody of lambda light chain type

IgA class thyroid peroxidase and thyroglobulin autoantibodies in Graves' disease: association with the male sex.

Amplification by polymerase chain reaction of immunoglobulin heavy and light chain genes from orbital tissue of patients with Graves' ophthalmopathy.

Several lines of evidence indicate that Graves’ ophthalmopathy (GO) is an autoimmune disorder.1 Humoral and cell-mediated immune reactions have been implicated in the pathogenesis of GO, but the precise mechanisms responsible for the orbital damage remains to be elucidated. The autoimmune and inflammatory nature of GO has led to consider therapeutic approaches aimed at suppressing the immune response or at abating the inflammatory process. In this regard, immunosuppressive therapy is widely employed in patients with moderate to severe GO. Glucocorticoids, orbital radiotherapy, or a combination of both, are the most frequently used immunosuppressive therapies, but other treatments like cyclosporine, azathioprine, intravenous immunoglobulins, and plasma exchange, have also been used (Table 1).

Mark F. Prummel

Papers

Molecular cloning and characterization of human thyroid peroxidase autoantibodies of lambda light chain type

Isolation and characterization of a monoclonal human thyroidperoxidase autoantibody of lambda light chain type

IgA class thyroid peroxidase and thyroglobulin autoantibodies in Graves' disease: association with the male sex.

Amplification by polymerase chain reaction of immunoglobulin heavy and light chain genes from orbital tissue of patients with Graves' ophthalmopathy.

Immunosuppressive management of Graves’ ophthalmopathy