Genetic Findings in Alopecia Areata Have Implications for Multiple Autoimmune Diseases
Scientists supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the National Cancer Institute (NCI) have identified genetic variations associated with the development of alopecia areata, a disease in which the body's immune system attacks the hair follicles, causing patchy, widespread or total hair loss.While the finding has the potential to help researchers better understand and develop treatment for the disease, they say it also has implications for the understanding and treatment of other diseases as diverse as rheumatoid arthritis and type 1 diabetes.
The genome-wide association study, the first of its kind for alopecia areata, compared genetic material from 1,054 people with alopecia areata to that of 3,278 people without the disease, looking for genomic regions where people with the disease differed from controls. The genetic material from alopecia areata patients was provided by the NIAMS-sponsored National Alopecia Areata Registry — a network of five centers that is registering, identifying and collecting information and blood samples.
Of the 450,000 or so genetic markers studied, the comparison turned up about 150 that were represented differently in the people with alopecia areata, says Angela M. Christiano, Ph.D., Professor of Dermatology and Genetics and Development at Columbia University Medical Center, who led the study. The variations were clustered in eight different regions — one in the human leukocyte antigen (HLA) region associated with autoimmune diseases, five involved in the immune system and two involving the hair follicle — none of which surprised Dr. Christiano and her colleagues. What did surprise the researchers was that alopecia shared few, if any, genetic similarities with psoriasis and vitiligo, two autoimmune diseases of the skin, which they had suspected would be related to alopecia. Even more surprising was that alopecia shared similarities with three seemingly unrelated autoimmune diseases with completely different targets: rheumatoid arthritis, type 1 diabetes and celiac disease.
One clue to a shared disease mechanism came from a gene called ULBP3, which was upregulated in scalp biopsies of the alopecia areata patients. In the normal hair follicle, ULBP3 is turned off, because usually the hair follicle is invisible to the immune system, says Dr. Christiano. In active lesions from alopecia areata patients, however, the gene was activated in the outermost layer of the hair follicle, called the dermal sheath.
ULBP3 belongs to a class of proteins known as natural killer (NK) cell ligands, which serve to attract immune cells marked by a natural killer cell receptor known as NKG2D, which are then poised to injure the hair follicle. Interestingly, NK ligands are also expressed in the affected organs of humans and animal models of the other three diseases: the joint lining in rheumatoid arthritis, the islet cells of the pancreas in type 1 diabetes and the gut in celiac disease.
This unexpected finding not only identifies potential targets for alopecia areata therapy, but suggests a shared disease mechanism that could help scientists study the immune pathology and develop treatments for all four diseases. Because drugs that target the pathway are in development for these other diseases, Dr. Christiano believes these same drugs might be effective against alopecia areata, the most common among all autoimmune diseases.
Dr. Christiano says the next steps are to gather and compare genetic information from more people with alopecia areata, and investigate shared genetics among all four diseases. Also, knowing the genes involved in the disease, scientists can now begin to develop mouse models to help them better understand its pathology, and also to test new therapies in pre-clinical studies that may pave the way to innovative clinical trials for a disease which has had very limited effective therapies up to now.
