Midway evaluation - Alexander Hellesen

ABSTRACT

Immuno-endocrine interactions in autoimmune Addison’s disease

Autoimmune Addison’s disease (AAD) is caused by a selective immune response directed against the adrenal cortex, resulting in loss of hormone-producing cells and a life-long requirement for steroid hormone replacement therapy. Recent data suggest that T cells may play an important role in this immune response, yet the pathogenic events leading to adrenocortical destruction remains ill defined. Most patients with AAD have circulating autoantibodies against 21-hydroxylase (21OH), an enzyme exclusively expressed in the adrenal cortex, but the pathological significance of these autoantibodies is unknown. Also, little is known about environmental factors and the role played by adrenocortical cells themselves.

In the present project, we aim to elucidate pathogenic mechanisms of immune-mediated destruction of the adrenal cortex in AAD focusing on autoantibodies, T cells, and adrenocortical cells as possible contributors to their own destruction.

Using the well-characterized adrenocortical carcinoma cell line H295R, we have showed that adrenocortical cells are able to recognize virus-like structures and produce signal substances that attract immune cells 1. Viral infections are typically accompanied by the production of interferons by host cells that act to eliminate the infection. Such interferons have been implicated in various autoimmune diseases, and may serve to initiate or perpetuate an autoimmune reaction. We have demonstrated specific effects of interferons on immunologically relevant parameters in H295R adrenocortical cells that could contribute to the development of AAD (Manuscript to be submitted November 2013).

The possible involvement of 21OH autoantibodies in the pathogenesis of AAD is currently being investigated. Preliminary data suggest that these antibodies may have an augmenting effect on the T cell response to 21OH. Similar effects have been reported for related autoimmune endocrine disorders like type 1 diabetes. The project is scheduled for completion by the end of 2014.

1. Bratland, E., Hellesen, A. & Husebye, E.S. Induction of CXCL10 chemokine in adrenocortical cells by stimulation through toll-like receptor 3. Mol Cell Endocrinol 365, 75-83 (2013).