Pathogenesis of autoimmune Addison’s disease and polyendocrine syndromes – identifying pathologies and pathways for future treatment

Autoimmune adrenal insufficiency (Addison disease) leads to the destruction of the adrenal cortex and lack of the essential hormones cortisol and aldosterone. It affects individuals in their most productive years with a majority of women. Addison disease is deadly if left untreated, but with hormone replacement therapy, most patients can live productive lives. However, we have currently now treatment able to stop the autoimmune process and prevent development of adrenal insufficiency. Two thirds of patients also have other organ-specific autoimmune disorders such as autoimmune thyroid disease, type 1 diabetes and early menopause seen in ten percent of women. As such Addison disease is an interesting model disease to study the mechanisms of autoimmunity. The main aim is to utilize the unique national Addison registry with patient data and blood samples, various model system and immunological and genetic studies to learn in detail what the disease mechanisms are. We will perform a detailed mapping of the immune system and genetics of affected persons and a corresponding mouse model. The project also includes a clinical study where patients at risk for autoimmune Addison’s disease will be followed prospectively with regards to development of adrenal failure, in order to identify triggering events and factors important for progress of the immunological destruction of the adrenal cortex. With this information in hand, we are confident that we will be able to provide improved risk estimates and offer future treatment aimed at stopping the disease before the whole adrenal is destroyed and perhaps even reverse adrenal insufficiency and related diseases.

Autoimmune diseases affect several hundred millions of patients worldwide. Collectively, they are among the leading causes of morbidity, chronic illness and death. Among these, autoimmune Addison's disease (AAD) is a unique model disease as patients develop autoreactivity towards one specific target (21-hydroxylase), and most patients manifests an autoimmune polyendocrine syndrome (APS) with familial clustering. Many aspects of the pathogenesis of AAD are unknown due to insufficiently sized patient cohorts, unavailability of tissues, and nonexistence of a relevant mouse model. As a world-leading capacity in the field, we are now in the position to overcome these limitations by access to the world's largest registries and biobanks on AAD. Our recently published and first ever genome-wide association study of AAD and APS type 2 identified several novel genetic associations, among them coding variants in the autoimmune regulator (AIRE) gene, hitherto only implicated in the monogenic autoimmune disease APS type 1. However, the overall impact of of AIREon central immune tolerance in autoimmune endocrine disorders, and why AIRE seems to be specifically related to AAD, is yet to be determined. To fill these knowledge gaps, we will elucidate the functional impacts of genetic variants associated with AAD (in particular AIRE-variants), and develop novel mouse models. We will perform extensive single cell characterisations of the immune cell landscape in both adrenals and peripheral blood, and study the natural course of AAD development by following 21-hydroxylse-positive individuals from normal adrenal function to overt AAD by a range of techniques. The results will provide new insights beyond the state of the art into the fundamental questions on how AAD and organ-specific autoimmune diseases arise, deliver improved and personalized diagnostic and prognostic tests, and lay the foundations for targeted treatment and prevention of AAD and APS in the future.