Mechanism of autoimmun adrenal destruction
Autoimmune diseases is a large and heterogeneous group of about 100 diseases that may affect almost any tissue or organ. Autoimmune Addison’s disease, or primary adrenal insufficiency, was among the first diseases recognized as autoimmune during the 1950s, approximately 100 years after initially described by the British physician Thomas Addison. However, we still don’t know why certain people develop this disease, or what the underlying mechanisms are. We strongly believe that if we can succesfully answer these questions, we might be able to offer better treatment and possibly also a cure to Addison’s disease in the future.
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We know that the immune system of patients with Addison's disease attacks the hormone-producing cells of the adrenal cortex and that the adrenal cortex is invaded by T and B lymphocytes (Figure 1)
Figure 1. Histology section from the adrenal cortex of a patient with autoimmune Addison’s disease. Notice the extensive infiltration of T lymphocytes (pink color) and B lymphocytes (brown color). Apparently, normal endocrine tissue is also present to the left of the massive lymphocytic infiltrations.
Still, we lack knowledge about why this attack is occuring. What initiates it? How are the adrenocortical cells destroyed?
As for most autoimmune disease, Addison’s disease is presumed to be caused by a combination of genetic and environmental factors. The genetic ones are by far the best described, with most genetic risk factors described to date being active in T and B lymphocytes (Figure 2).
Figure 2. Genetic factors associated with increased susceptibility to develop autoimmune Addison’s disease. Most genes associated with autoimmune Addison’s disease are involved in the interplay between T lymphocytes and other immune cells (including B lymphocytes). Among other things, these genes affect how the T lymphocytes recognize and respond to antigens.
To what target in the adrenal cortex are these lymphocytes reacting? We know that almost all patients with autoimmune Addison’s disease have antibodies directed against an enzyme almost exclusively expressed in the adrenal cortex. This enzyme is called 21-hydroxylase and plays a key role in the synthesis of vital steroid hormones like cortisol and aldosterone. However, the patients also have T lymphocytes recognizing this enzyme (Figure 3).
It is suspected that a subgroup of T lymphocytes, the so-called cytotoxic T lymphocytes, that actually kills and destroys the hormone producing cells of the adrenal cortex in a highly selective manner. For a decade, we have studied these T lymphocytes in order to detect, isolate and characterize them.
In order to describe the detailed events when the cytotoxic T cells recognize adrenocortical cells, we are currently developing methods to study the interplay between these cell types. With the use of the patients own stem cells (harvested from urine or skin), we want to grow «adrenal-like» steroid-producing cells that closely resemble the cells of the adrenal cortex. These cells will be used to design cell culture model systems along with T cells from the patients’ own blood.
If successful in establishing such model systems we willnot only gain increased insight to the mechanisms leading to autoimmune Addison’s disease, but also be granted the opportunity to test out new treatments and drugs that are targeted to halt or possibly even reverse the disease.
Perhaps can this increased insight to autoimmune Addison’s disease be valuable for the understanding of other autoimmune diseases as well?
Figure 3: Detection of 21-hydroxylase specific T cells in peripheral blood using flow cytometry. In a blood sample straight from the arm of the patients we area ble to detect small populations of 21-hydroxylase specific T cells (lower right) among millions of other blood cells (upper left).
