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Hair Loss News Archives
July 2010
New Study Implicates Autoimmune Mechanisms in Alopecia Areata
Hair loss disease has risk loci in common with many other autoimmune diseases.
July 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), and IKZF4 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."