Foreword

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Derek LeRoith, MD, PhD Consulting Editor

This issue of Endocrinology and Metabolism Clinics focuses on clinical and molecular advances in autoimmune endocrine conditions.

In the opening article, Talal Chatila describes the role of the thymus-derived natural regulatory T lymphocytes, which are important for immunological tolerance. Recent studies have determined the lineage markers and differentiation pathways of natural regulatory T lymphocytes and that mutations in FOXP3, the key transcriptional regulator in these cells, leads to autoimmune diseases, such as neonatal type 1 diabetes and other endocrinopathies. Modulation of these regulatory T lymphocytes may prove to be useful in treating certain food allergies and autoimmune diseases.

Noriko Shikama, Gretel Nusspaumer, and Georg Holländer discuss the mechanisms involved in the autoimmune polyendocrinopathy syndrome type 1. Mutations in the gene encoding the autoimmune regulator protein (AIRE) prevents the thymus from expressing many nonthymic self-antigens that would normally cause deletion of developing T lymphocytes. Thus, these auto-reactive T lymphocytes are exported and can induce the autoimmune process. The result is a syndrome consisting of mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical insufficiency. The authors also describe in detail the AIRE gene; its structure, function, and regulation; and its role in the thymus.

Autoimmune thyroid disease, including Graves' and autoimmune hypothyroidism, as well as autoimmune type 1 diabetes (TID), are genetic disorders that share common loci, but also have their own specific genetic loci. Simon Pearce and Tony Merriman describe the relationship of the human leukocyte antigen alleles, encoded within the major histocompatibility complex (MHC), as an example of a shared susceptibility locus. Other examples include the lymphoid tyrosine phosphatase, cytotoxic T-lymphocyte antigen-4, CD25, and the interferon-induced helicase-1 gene locus. Meanwhile, loci specific for autoimmune thyroid disease include those for the thyrotropin receptor, Fc receptor–like S, and CD40 genes. For type 1 diabetes, the insulin gene is an excellent example. The authors conclude that in type 1 diabetes, while numerous non-MHC loci have been found, they each probably only contribute a small percentage towards the genetic susceptibility to the disease.

Frank Waldron-Lynch and Kevan Herold in their article describe the exciting new developments in type 1 diabetes that relate to the immunopathogenesis of this classic autoimmune disorder and that have led to immunomodulatory therapeutic trials. Following preclinical trials that were quite successful, human trials followed using insulin, Diapep277, and GAD65 as antigen therapy. Meanwhile, non–antigen-specific immunomodulation was tried using nicotinamide, immunosuppressive therapies, and anti-CD20 and anti-CD3 monoclonal antibodies. While these therapies are yet to be useful, they have paved the way for future attempts at “curing” type 1 diabetes.

In the article by Rauf Latif, Syed Morshed, Mone Zaidi, and Terry Davies, we are introduced to some new concepts regarding the thyrotropin receptor. While the thyrotropin receptor is known to control thyroid maturation and function, it has also been shown to be expressed in extrathyroidal tissue, including adipocytes and bone cells. In adipocytes, the thyrotropin receptor may stimulate human orbital fibroblasts to differentiate and further stimulate adipogenesis. Thyrotropin may inhibit osteoclastogenesis and activate osteoblastogenesis and may therefore be antiresorptive and anabolic in bone. Recently identified human thyrotropin receptor monoclonal antibodies have also revealed additional detail about the structure–function correlates of the receptor.

In their article, Selçuk Dağdelen, Yi-chi Kong, and Paul Banga point out the need for experimental animal models of hyperthyroid Graves' disease. Such models would help us better understand the underlying pathophysiology of hyperthyroid Graves' disease and point the way to better therapies, given that there are variations in the disease presentation and that the disorder often recurs. The authors describe the earlier animal models, including the Shimojo model that induced anti–thyrotropin receptor antibodies, models developed by DNA injection using the thyrotropin receptor gene, models developed by the adenovirus method, and, more recently, models developed by passive transfer of thyrotropin receptor monoclonal antibodies with thyroid stimulating antibody activity. While the road has been long and steep, the more recent models are showing promise in enabling investigators to study the mechanisms involved in the autoimmunity and the presentations, including, for example, Graves' ophthalmopathy.

Two articles deal with management of Graves' hyperthyroidism and thyroid-associated orbitopathy. Laszlo Hegedüs discusses the standard management of hyperthyroidism, including antithyroid medication, radioactive ablation therapy, and surgery, and the pros and cons of each. The novel use of monoclonal antibody therapy in Graves' disease is also described. Jane Dickinson and Petros Perros discuss the perennially difficult clinical problem of orbitopathy, its diverse presentation, and when and how to treat. These two articles are important clinical therapeutic components of this issue.

Adrenal insufficiency has a number of causes, but a common cause in westernized countries is autoimmune adrenalitis. While Addison's disease is often associated with type 1 diabetes and thyroid disease, it may also be associated with gonadal failure secondary to this autoimmune process that affects many endocrine glands. As discussed by Eystein Husebye and Kristian Løvås, some autoantibodies, such as 21-hydroxylase, are useful in the diagnosis of autoimmune Addison's disease. In the case of ovarian failure, antibodies to side-chain cleavage enzyme and 17-hydoxylase may also be useful. Recently interest has increased about the role of vitamin D deficiency and autoimmune disorders and whether replacement therapy may reduce the burden of these disorders.

Treating adrenal insufficiency and avoiding adrenal crises can be quite challenging. These days patients also have legitimate expectations for a good quality of life and a full sense of well-being. Nicole Reisch and Wiebke Arlt discuss the use of glucorticoid therapy and the considerations for the use of mineralocorticoid therapy. They also suggest that dehydroepiandrosterone replacement may in fact be quite useful to increase the energy level and libido in women with adrenal insufficiency.

Autoimmune polyglandular syndromes are very diverse, with many varieties of both major components and minor manifestations. Catherine Owen and Tim Cheetham describe in detail the various syndromes, their manifestations, the diagnostic criteria, and the prognosis. In addition, they appropriately stress that early detection, correct diagnosis, and early intervention can preclude many of the complications that occur with these syndromes.

Autoimmune hypoparathyroidism may be an isolated disorder or a component of the autoimmune polyglandular syndromes. Edward Brown discusses the calcium-sensing receptor (which his group discovered) and its role in controlling whole-body calcium homeostasis. Soon after the calcium-sensing receptor was characterized, autoantibodies to this important receptor were discovered in cases of hypoparathyroidism. These antibodies may activate or inhibit the receptor. Activation of the receptor causes hypoparathyroidism, whereas inhibitory antibodies result in hyperparathyroidism. Mutations of the calcium-sensing receptor are associated with familial hypocalciuric hypercalcemia.

This timely issue on autoimmune endocrine disorders brings to the reader the latest in our understanding of the pathogenesis of the diseases, the complexity of their presentations, and the management of each condition. I believe it will be extremely informative to the endocrinologist and wish to thank Professor Pearce and the authors for their marvelous contributions.