July 2, 2010 — Alopecia areata (AA), a hair-loss disease often considered similar to psoriasis because of the inflammation and T-cell involvement, shares many genetic associations with a broad spectrum of autoimmune diseases, according to a study appearing in the July 1 issue of Nature.
Hair loss in AA results from "collapse of immune privilege" in hair follicles, such that a person's own immune system attacks and destroys cells of their hair follicles. Interestingly, AA attacks pigmented hairs more actively than nonpigmented hairs. Thus, selective loss of pigmented hair, causing people to become "gray overnight," could actually result from acute AA onset during intense stress or grief.
The genome-wide association study (GWAS) involved international researchers, led by a group at Columbia University Medical Center, New York City. Genotypic analysis of 1054 patients with AA and 3278 control individuals found more than 100 single nucleotide polymorphisms (SNPs) associated with AA at a GWAS-significant level (P ≤ 5 × 10−7). The majority of these SNPs were concentrated in 8 regions, most containing 1 or 2 genes with recognized immune function.
"Finding the initial genes underlying [AA] is a big step forward, but the nature of the genes is even more exciting," observed senior author Angela M. Christiano, PhD, professor, Dermatology and Genetics & Development, and director of the Center for Human Genetics, Columbia University Medical Center, in a Columbia University news release.
Six of the loci contained, respectively, CTLA4, IL-2/IL-21, the HLA region, ULBP genes, IL-2RA (CD25), andIKZF4 and ERBB3; 1 locus was within STX17, and 1 lay near PRDX5. The strongest association (P = 1.38 × 10−35) was found for HLA gene DQA2. Outside of the HLA region, the strongest association was for ULBP6 (P = 4.49 × 10−19) and ULBP3 (P = 4.43 × 10−17). Both ULBP3 and ULBP6 are NKG2D-activating ligands.
The ULBP3 protein (referred to as NKG2D ligand 3) is present at low levels in normal hair follicles, but the study found it was highly expressed in the "dermal sheath as well as the dermal papilla" of 2 patients in the early stages of AA. Immunohistochemical analysis found significantly more cells positive for ULBP3 in 16 additional patients with AA. Upregulation of ULBP3 may be important in initiating the immune response at the onset of AA, or it may be part of an "inflammatory cascade."
ULBP3 produced in hair follicle cells binds to the NKG2D receptor on natural killer (NK) cells, activating these cells. NK cells are a major type of lymphocyte in the innate immune system that are able to destroy other cells. As the study explains: "The autoimmune destruction in AA may be mediated in part by CD8+ NKG2D+ cytotoxic T cells, whose activation may be induced by upregulation of ULBP3 in the dermal sheath of the hair follicle."
ULBP6 and ULBP3 had not previously been associated with autoimmune diseases; STX17 was implicated in premature hair graying, but not autoimmunity. However, most of the other loci were involved in classic autoimmune diseases such as type 1 diabetes and rheumatoid arthritis, and several were associated with celiac disease, multiple sclerosis, systemic lupus erythematosus, Graves' disease, or psoriasis, among others.
The present study suggests that the upregulated ULBP3 in the outermost layer of hair follicles engages NKG2D on the NK cells, initiating an immune response. The NKG2D receptor has already been recognized as important in the development of type 1 diabetes, rheumatoid arthritis, and celiac disease.
"There seems to be a shared mechanism among organs that express NKG2D danger signals as part of the initiating process," said Dr. Christiano. Drugs are already being developed to target those pathways in rheumatoid arthritis, type 1 diabetes, and other diseases where the NKG2D receptor is involved.
"We may soon be able to test these drugs in clinical trials for [AA]," said Dr. Christiano. "Finally, we have the possibility of developing drugs that specifically target the mechanism behind the disease."
The authors of the study have disclosed no relevant financial relationships.
Nature. 2010;466:113-117.
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