Your immune system is usually something you’re grateful for; it helps you fight infections, deal with cuts and bruises, and generally defend your body against all the bugs and grubs that are constantly trying to make you sick. However, in rare cases, the immune system turns on itself – instead of attacking bacteria and viruses, it starts to attack YOU. There are several diseases in which this phenomenon, known as autoimmunity, is observed – here Lauren Howson describes recent work by the Cerundolo lab in the MRC Human Immunology Unit at the WIMM that sheds some light on one such disease, known as Autoimmune Addison’s Disease.
You probably haven’t heard of Autoimmune Addison’s disease. Although not well known, for the 6000 people in the UK who have it, research into this disease is vital as it can be life threatening. Autoimmune Addison’s disease is caused when the body’s immune system attacks the adrenal cortex, a part of a gland just above the kidney (shown in red in the image below) that’s responsible for releasing steroid hormones when a person is under stress. Without production of these hormones the body cannot manage stress. This causes weakness, fatigue and can be fatal during times of illness.
Current treatment for the disease involves taking tablets several times a day which replace the hormones that are no longer being produced. In an emergency, such as a car accident, when your body would normally produce extra stress hormones to physically cope, those with Addison’s disease could go into adrenal crisis. In adrenal crisis a person can show symptoms such as fainting, vomiting or even end up in a coma. So, the question is: why does the immune system turn on your own body and attack the adrenal cortex?
When the immune system attacks, it produces its own proteins called antibodies that target a specific invading pathogen – or in the case of autoimmune diseases, a specific part of the body. Twenty years ago the protein targeted by the immune system in Autoimmune Addison’s disease was discovered to be 21-hydroxylase (21-OH). Antibodies that recognize 21-OH are found in 90% of autoimmune Addison disease cases and can therefore be used to diagnose this disease. But the production of these antibodies doesn’t explain what destroys the adrenal tissue as 21-OH is actually found inside cells, where antibodies cannot get in. So what part of the immune system is responsible for destroying the tissue? This is the question the Cerundolo group of the MRC Human Immunology Unit at the WIMM set out to answer.
Besides antibodies, the immune system can attack by arming immune cells and licensing them to kill cells, as in the case of cancer cells or cells infected with a virus. But when the wrong licence is given, these cells, known as T cells, can attack your own tissue. It was thought that this might be how Addison’s disease may be caused and the Cerundolo group designed experiments to find out if this was happening. The results of this study showed that not only was the appropriately named cytotoxic (cell-toxic) T cells of the immune system able to recognise and kill cells with the 21-OH protein, but also found that these cells that killed the tissue are still in the blood, and responsive, 20 years after destruction of the adrenal tissue.
The findings of this study were published recently in the Journal of Immunology and have implications not only in understanding what causes Autoimmune Addison’s disease but also suggest that 21-OH, or a very similar protein, may be still licensing the cytotoxic T cells responsible for the disease to be capable of targeting the adrenal cortex years after the tissue has been destroyed. These results greatly improve our understanding of this serious disease and the work could also have wider implications by identifying a possible therapeutic target for the development of preventative treatments for Addison’s disease.
Post edited by Bryony Graham and Vincenzo Cerundolo.