Midway evaluation - Kine Edvardsen
Autoimmunity and viral immunity in autoimmune Addison’s disease
Autoimmune Addison’s disease (AAD) also known as primary adrenocortical failure is an organ-specific disease situated in the adrenal gland. It is caused by a specific immune response against the cells in the adrenal cortex producing vital steroid hormones and the current treatment option is lifelong hormone replacement therapy. The dominant antigen among these patients is steroid cytochrome P450 21-hydroxylase (21OH), a protein exclusively expressed in the adrenal cortex and recognized by autoreactive T cells. There are known genetic predisposing factors, but we do not know what causes the disease. It’s believed to be a multifactorial process where endogenous and environmental factors also are involved.
The aim for this project is to elucidate the pathogenic mechanisms of immune-mediated destruction of the adrenal cortex in AAD. Focusing on how 21OH, the T cells and the adrenocortical cells themselves could be involved.
Viral infections and interferons are believed to be a precipitating event in autoimmune disease development. Chemokines like the interferon-induced CXCL10 are known to be elevated in sera for various autoimmune diseases, including Addison’s. We have data showing the same for both CXCL10 and CXCL9, another interferon-induced chemokine. When stimulating PBMC from these same patients with type I and II interferons however, we observe a significantly reduced production of those chemokines compared to healthy controls. These data suggests that the elevated chemokines in the sera are produced in the adrenal cortex, probably as a result of local interferon production.
Though majority of patients have 21OH autoantibodies, studies of the cellular immunity to 21OH and its autoantibodies are in an early phase. Cytotoxic CD8+ T cells are believed to be the main contributor to adrenal cell destruction, but CD4+ helper T cells could also be responsible. We have located peptide epitopes of 21OH restricted for the different T cell types in patients, which give a similar response in mice immunized with 21OH. This suggests that these epitopes are naturally processed and presented from full length protein.
To conclude, 21OH-specific T cells are present in patients with Addison’s disease and are likely to play a role in the pathogenesis. The adrenal cortex itself probably plays a major role in invoking the 21OH-specific T cells, possibly after local precipitating events involving the production of interferons.