Patrice E. Fort, PhD, MS
Inflammation is increasingly recognized as a major player in the pathophysiological mechanisms of diabetic retinopathy. Through our discovery approaches performed on ocular tissues from human donors with and without diabetes and/or retinopathy, several inflammatory regulators have been identified and are currently under investigation.
Additionally, alpha-crystallins have been associated with inflammation in multiple sclerosis and other neuro-inflammatory associated diseases, but the potential interaction in diabetic retinopathy has not been explored. We are exploring the role of alpha-crystallins in the regulation of the retinal inflammatory response using cell culture methods as well as animal models of neuro-infllammatory diseases.
Alon Kahana, MD, PhD
Thyroid Eye Disease
Thyroid disorders are among the most common endocrine disorders, affecting 20 million Americans, 30 million Europeans, and millions more throughout the developing world, particularly in areas of low iodine intake.[1-3] In areas with adequate iodine dietary intake, thyroid disorders are usually related to auto-immunity, ranging from Graves disease (hyperthyroid autoimmune disease) to Hashimoto’s (hypothyroid autoimmune disease), with associated thyroid autoantibodies.
With wide spread availability of thyroid hormone-containing medications – both synthetic and natural – the endocrinologic derangement can essentially be cured. In hypothyroid states, patients are supplemented with thyroid hormone, and in the hyperthyroid state, the inflamed thyroid gland can be ablated surgically (thyroidectomy) or via radioactive iodine (RAI) administration, followed by thyroid hormone supplementation to achieve a euthyroid endocrine status. If thyroid gland ablation is not desired, a euthyroid state can still be achieved in many cases by inhibiting the activity of thyroperoxidase using either methimazole or propylthiouracil. Either way, management of the endocrine disorder is usually straight forward and generally successful.
A key sequela of autoimmune thyroid conditions is the development of thyroid eye disease (TED), also known as Graves orbitopathy, thyroid associated ophthalmopathy, and other similar terms that pertain to the same disorder. Importantly, while the treatment of dysthyroid endocrine disorders is usually straight forward, the treatment of TED is anything but, and long after the endocrine disorder has been treated and stabilized, patients continue to wrestle with the after effects of TED, namely the disfigurement, discomfort, social isolation, diplopia, dry eyes and sometimes even loss of vision. The transformative goal of this project is to cure TED and prevent its occurrence in the first place.
TED is considered an inflammatory orbitopathy characterized by a multitude of ophthalmic signs and symptoms. These include eyelid retraction (most common), conjunctival chemosis, eyelid edema, ocular surface disease (unstable tear film and exposure keratopathy), exophthalmos, restrictive strabismus with diplopia, orbital compartment syndrome, compressive or stretch optic neuropathy, chronic pain, facial deformity, and vision loss that includes the possibility of blindness and loss of the eye from corneal perforation. Thyroid associated periorbitopathy refers to changes that occur to the periocular skin and subcutaneous tissues. And TED is commonly associated with a more systemic dermopathy, most commonly manifesting as pretibial myxedema.
TED is associated with a hyperthyroid state in 90% of cases but it can also occur in hypothyroid and euthyroid patients. Risk factors include smoking, fluctuating T3 levels, post-ablative hypothyroidism, high levels of thyroid stimulating immunoglobulin, radioactive iodine treatment (particularly in the absence of post-treatment steroids), and associated dermopathy (pretibial myxedema). The pathogenesis of TED is thought to involve antigenic mimicry, with autoantibodies against the TSH receptor and associated IGF receptor attacking orbital tissues. This would, in turn, lead to activation of orbital fibroblasts and release of proinflammatory cytokines, with a subsequent cycle of infiltration, fibrosis and transdifferentiation into myofibroblasts and adipocytes. However, antigenic mimicry fails to explain the reason for the selective involvement of orbital tissues and skin, since most tissues in the body express TSH and IGF1 receptors. Furthermore, efforts to trigger the orbitopathy immunologically with administration of autoantibodies have been only marginally successful.
To explain these discrepancies, we hypothesize that the orbit and skin share a unique physiologic trait that predisposes them to pro-fibrotic inflammation in response to a dysthyroid condition. We further hypothesize that TED is driven by a local trigger that is distinctly separate from the inflammatory process that propagates the disease, i.e. a “Trigger-Propagation” hypothesis. We are currently pursuing novel approaches to test our hypothesis and identify the triggers for de novo cytokine release in orbital tissues of patients with autoimmune thyroid dysfunction.