The death of adrenocortical cells in autoimmune Addison's disease: Homicide or suicide?

In the project "The death of adrenocortical cells in autoimmune Addison's disease - homocide or suicide" we have studied the molecular and cellular mechanisms (pathogenesis) behind the development of Addison's disease (primary adrenal insufficiency). Addison's disease is a classic autoimmune disease where the immune system for unknown reasons attacks and kills the hormone-producing cells in the adrenal cortex. This means that the adrenal cortex is no longer able to produce the essential steroid hormones cortisol and aldosterone. The disease is therefore fatal if not diagnosed in time, and patients must be treated for life with the supply of hormones. We know very little about why Addison's disease occurs, but this is important to find out in order to improve treatment and quality of life in patients. One of the project's main objectives has been to develop an animal model for the disease. In collaboration with leading European groups at the universities of Oxford and Basel, we have now developed a mouse model for Addison's disease which reflects many of the characteristics of the disease in humans. Disease in mice can also be treated by adding steroid hormones to the drinking water. Publications describing this mouse model is under preparation. One of the project's main hypotheses was that adrenocortical cells greatly affect the way Addison's disease develops and how inflammation of the adrenal cortex is maintained. Traditionally it has been assumed that autoimmune disorders such as Addison's disease is primarily caused by cells of the immune system that for some reason attack and kill the body's own organs and cells. We believe that the cells of the adrenal cortex itself plays an important role in this process by recruiting and activating cells of the immune system. We have now demonstrated this process experimentally through three different publications (Bratland et al Mol Cell Endocrinol 2013 Hellesen et al Clin Exp Immunol 2014 Edvardsen et al J Interferon Cytokine Res 2015), with two additional publications under preparation. We have also, together with a large network of European colleagues, surveyed in detail how white blood cells (lymphocytes) in patients with Addison's disease recognize proteins in the adrenal cortex and kill adrenocortical cells. This is a significant breakthrough in research on the mechanisms of Addison's disease, and the findings were published in the prestigious Journal of Immunology in 2014. A follow-up work that will put these findings in the context of better diagnosis and possible new treatment for Addison's disease is under preparation.

Autoimmune Addisons disease (AAD) is an immunological and endocrine disease resulting from the immune systems destruction of hormone producing cells in the adrenal cortex. Diagnosis is frequently first established after a life-threatening adrenal crisis h as occurred, often resulting in untimely fatalities. The disease is more common in women than in men, and also affects children. AAD very frequently concurs with other autoimmune diseases, such as type 1 diabetes mellitus, autoimmune thyroid disease and/o r premature ovarian failure, but still very little is known about its pathogenesis. Based on national and European networks of patient registries and biobanks and a translational approach, the project aims to unravel the pathogenesis of AAD, ultimately to improve diagnosis and treatment as well as offer strategies for disease prevention. The cellular and molecular mechanisms of autoimmunity directed at the adrenal cortex will be unravelled both in humans with ADD and in a novel mouse model for this disord er. Together, these efforts will increase our still incomplete understanding of pathogenic pathways operational in AAD and pave the way for new therapies of this debilitating disorder. As a model disease for organ-specific autoimmunity the results of the project will not only lead to the development of novel diagnostic and therapeutic interventions for Addison patients, but also increase our understanding of the pathogenesis of autoimmune diseases in general. Such knowledge may ultimately lead to entirel y new strategies for prevention, diagnosis and treatment of common autoimmune disorders.