Rare autoimmune disease not so rare after all
Very few people are diagnosed with the autoimmune disease APECED. New research, however, suggests that it is more common than originally thought. Simple tests can now detect whether people have this inheritable form of autoimmunity, which has implications for diagnosis and follow-up.
The immune system is designed to protect us against bacteria, viruses and foreign tissues. During development, immune cells that recognize the body’s own tissues are deleted from the immunological repertoire to provide tolerance. In the disease autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) this process is defective due to mutations in the autoimmune regulator (AIRE) gene.
“APECED was previously considered an ultra-rare disease with an estimated prevalence in most countries of about 1 per 100,000. A recent study published in Immunity suggests that a milder form of APECED is much more common,” explains Eystein Husebye, Professor at University of Bergen and head, K.G. Jebsen Center for Autoimmune Diseases.
Milder than the classical form
The AIRE gene promotes expression of tissue specific proteins in the thymus and displays these to T cells under maturation. T cells that react to these self peptides normally undergo apoptosis, but in APECED these cells escape into the blood, where they give rise to autoimmune disease in various organs, including the adrenal cortex, parathyroid glands and ovaries.
“Until recently, APECED was considered to be an autosomal recessive disease. This means that both copies of the AIRE gene have to mutate to cause illness. Recently we discovered that mutations in certain critical positions of the gene give rise to disease even in those with only one mutated copy of the gene.”
The mechanism is called a dominant negative effect, in which the mutated protein inhibits the function of the healthy wild-type one.
“Fortunately, the disease is often milder than the classical form of APECED, and many people are not classified as having APECED; instead they are thought to have common forms of organ-specific autoimmunity.”
The tip of the iceberg
People with the dominant form of APECED often develop vitiligo, a disease of the pigment-forming melanocytes in the skin that leaves white spots. Many also lack vitamin B12 secondary to chronic autoimmune inflammation of the gastric mucosa. Since inheritance is dominant, the trait can be transmitted from one generation to the next and aggregate in families.
“All variants contributing to the dominant negative effect except one are located in a specific domain of the AIRE protein called the plant homeodomain 1. Examining the frequencies of these variants in public databases revealed that about 1 in 1000 people has such a variant.”
Since autoimmune diseases often run in families, AIRE gene mutations might be a much more common cause of organ-specific autoimmune disease than previously thought.
“In some families, not all gene carriers have the disease. We therefore suspect that genetic and environmental factors likely play a role in determining the phenotype and how the disease presents and develops further.”
Today, people with APECED are mostly given replacement therapy for hormone deficiencies: corticosteroids for adrenal insufficiency and potent vitamin D preparations for hypoparathyroidism. The new knowledge on the monogenic causes of the disease is important in order to develop diagnostic tools and personalized therapy and follow-up.
“I believe it is important to identify these monogenic forms, since carriers run a considerable risk of developing autoimmune disease.”
People with Classical APECED almost always display autoantibodies against type 1 interferons, which can be used as an effective screening tool. However, not everyone with the dominant form has such autoantibodies.
“When we learn more about the dominant forms we can develop more reliable ways to diagnose APECED. This knowledge will enable us to follow the patient and family members more closely and to diagnose and treat potentially fatal manifestations earlier. Thus, there is hope that targeted immunotherapy or gene therapy that corrects the immunological tolerance defect can be developed for these patients.”
“Dominant mutations in the autoimmune regulator AIRE are associated with common organ-specific autoimmune diseases” was published in Immunity with a front-cover illustration and an accompanying editorial. In 2014, the Novo Nordisk Foundation awarded a grant to Eystein Husebye for the project The Mosaic of Autoimmunity Revealed by the Kaleidoscope of Autoimmune Polyendocrine Syndromes.