Inducing Graves’ ophthalmopathy

Abstract

The majority of patients with Graves’ disease (GD) have some degree of ocular involvement and this requires surgical or medical intervention in about 5% of cases. There are autoimmune and inflammatory processes operating in Graves’ ophthalmopathy (GO), which together induce glycosaminoglycan production, edema and adipogenesis resulting in an increase in the volume of the orbital contents. GO is a heterogeneous disorder, i.e.: 1) whilst usually associated with hyperthyroidism it may occur in euthyroid (and even hypothyroid) patients; 2) expansion of orbital tissues may be due to ‘big-fat’ or ‘big muscles’. The heterogeneity is further exemplified by the spectrum of protocols which have succeeded in inducing aspects of the disease both in animal models and in humans including: 1) Production of severe hypothyroidism in guinea pigs by thyroidectomy and administration of pituitary extract (TSH); 2) Induction of T cells autoreactive to the thyrotropin receptor (TSHR) in mice; 3) Depletion of regulatory T cells in humans susceptible to autoimmunity; 4) Modulation of adipose tissue metabolism in mice and men. In addition, identical induction protocols result in different pathological features depending on the environment, e.g. TSHR primed T cells produce thyroiditis and ocular pathology in BALBc mice in Brussels but thyroid stimulating antibodies accompanied by elevated thyroxine in these animals (from the same supplier) in Cardiff. Thus, experiences in the induction of GO have confirmed the polygenic, multifactorial nature of the disorder and highlight the importance of careful disease classification to promote further progress in understanding.