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Evidence
of an autoimmune etiology for alopecia areata
Alopecia areata is a disorder of unclear etiology that is a common
problem in primary care practice. The disease typically presents
as patchy areas of hairlessness on various regions of the body,
especially the scalp. Although the exact pathophysiology of alopecia
areata has not been established, it has been evident for a while
that dystrophic hair follicles in alopecia areata are caused by
a leukocytic infiltrate composed mainly of activated T lymphocytes,
with a preponderance of CD4 cells and Langerhan’s cells.
It was Van Scott’s documentation in 1958 that formally raised
the hypothesis by Rothman that alopecia areata is actually an
autoimmune disorder. Until recently, evidence in support of an
autoimmune mechanism of alopecia areata was largely circumstantial.
In the last few years, compelling direct and indirect evidence
that supports an autoimmune etiology for alopecia areata has been
collected.
What
is an autoimmune disorder
Put simply, autoimmune disorders are conditions caused by an
immune response against the body's own tissues. The immune system
is the body's defense against infectious organisms, and there
are various kinds of immune cells such as lymphocytes, monocytes,
macrophages and other cells, all of which have different roles
to play in fighting off infection. For example, B-lymphocytes
are like the body's military intelligence system, seeking out
their targets and sending defenses to lock onto them; T lymphocytes
are like soldiers, destroying the invaders that the intelligence
system has identified.
Through a series of steps called the immune response, the immune
system attacks organisms and substances that invade our systems
and cause disease. Under normal circumstances, the body’s
immune system is capable of distinguishing "self" from "non-self" tissue.
Every human being’s self cells are coded with a unique "serial
number", called the HLA (human leukocyte antigen), that lets
the immune system know the particular cell is a self cell. This
serial number is a unique group of proteins called (self) antigens.
Antigens are found on almost every cell in the body and are determined
by a particular segment of our DNA (deoxyribonucleic acid). In
autoimmune diseases, a foreign antigen mimics a group of self-proteins,
and then when the immune system intensifies an attacking response
against these foreign invaders, it inadvertently attacks and destroys
self-tissues.
Before a disease can be accepted as autoimmune, certain basic
conditions need to be met. These basic assumptions are:
- Presence of one or more unique antigens in the affected organ.
- An
autoimmune response (either antibody or T-cell response) to
the antigens.
- An autoimmune response specifically associated
with the disease.
- The autoimmune response producing rather than
following the disease process
- The disease being able to be passively
transferred by the autoantibody or T cells.
- The disease shows
a response to immunosuppression therapies.
Circumstantial
evidence for alopecia areata being an autoimmune disease
The cause of alopecia areata is not known but studies show that
there appears to be a destructive response, mainly from lymphocytes
and macrophages, to certain antigens in the hair follicle. So
far, the suspect antigens that should be present in the hair follicles
of alopecia areata patients have not been identified and the mechanism
by which hair loss is induced is not fully understood. Alopecia
areata is associated with several non-specific abnormalities and
numerous requirements for ascribing autoimmune status to alopecia
areata now appear to be in place. These include:
- The presence of a peri and intrafollicular mononuclear
infiltrate with activated CD4 and CD8 T lymphocytes, which implicates
a cell-mediated autoimmune mechanism as the underlying pathogenic
etiology
- An increased expression of class I and II MHC antigens
and of Langerhans' cells in hair bulbs
- Deposits of immune reactants
around hair follicles
- Effective therapies for alopecia areata
have an immunosuppressive effect on immune cells in skin.
In most autoimmune diseases, autoantibodies can play an active
role in disease pathogenesis. Autoantibodies are produced by B
cells of the immune system, and are small pieces of protein, which
can recognize antigens. Autoantibodies recognize self antigens
and they can occasionally have very destructive activity. In all
forms of autoimmune disease, an elevated production of antibodies
reactive with the target tissues is usually evident and can be
organ specific. Studies on autoantibodies in alopecia areata have
been many and the results conflicting. Many researchers conclude
that the presence of autoantibodies to various organs is significantly
elevated in alopecia areata sufferers, while others are of the
opinion that there is no increased incidence of autoantibodies.
Alopecia areata, similar to many other autoimmune diseases, is
linked with certain HLA-Class II alleles (An allele is an alternate
form of the gene for a specific trait). Explorations in genetic
research have been made to identify the particular HLA haplotype
(the genetic constitution of an individual chromosome) in alopecia
areata. These have produced inconsistent results in the case of
class I antigens, but increasingly convincing associations are
now being reported with respect to certain class II haplotypes.
The expression of some of the class II haplotypes appears to co-relate
with different types of alopecia areata. There is also evidence
that the severity of alopecia areata may be associated with the
expression of some alleles of the IL-1 receptor antagonist gene,
which also occur in other inflammatory autoimmune disorders including
systemic lupus erythematosus.
Further evidence that alopecia areata is an autoimmune response,
comes from the association of alopecia areata with other autoimmune
diseases. This association can reveal common target antigens.
The relationship of alopecia areata with Vitiligo, a condition
involving loss of pigment in the skin in patches, which may affect
varying areas of the body, is controversial. Some case studies
indicate that it occurs more frequently in alopecia areata patients
compared to the general population. Current data advocates that
vitiligo may result from an intrinsic biochemical defect of the
entire epidermal melanin unit in skin. The incidence of clinically
evident thyroid abnormalities, such as Hashimoto's chronic lymphocyte
thyroiditis, thyrotoxicosis, exophthalmic goiter, and myxedema,
is also controversial, but there is evidence to show that these
diseases of the thyroid gland are also frequently seen in association
with alopecia areata, indicating an association between the two
conditions. There is also increasing evidence of an increase in
the prevalence of diabetes mellitus, especially type I insulin-dependent
diabetes, in relatives of patients with alopecia areata but not
in the patients themselves. These findings suggest a genetic association
between the two diseases, and also indicate that the pre-disposition
for alopecia areata may be protective against the development
of diabetes. This association of alopecia areata with other autoimmune
diseases suggests that alopecia areata itself is an autoimmune
disease.
Indirect
and direct evidence for alopecia areata being an autoimmune
disease
Alopecia areata is regarded as a systemic
disease because there is frequent involvement of organs other
than the hair follicles
including the nails and eyes. Thus, the defect may be extrinsic
to hair follicles. Some of the best direct evidence implicating
circulating immune factors in the pathogenesis of alopecia areata
comes from the transplantation experiments carried out by Gilhar
and colleagues. Gilhar demonstrated that alopecia areata affected
human skin regrew hair when transplanted to severe combined immunodeficiency
mutant mice. After regeneration of hair, in vitro activated lymphocytes
derived from alopecia areata affected human skin directly injected
into the skin grafts induced recurrence of alopecia areata. This
study provides good indirect evidence implicating lymphocytes
in a cell-mediated mechanism of hair loss.
Further, in their most recent experiments, the role of T lymphocytes
in this disorder has been investigated with cell transfer experiments.
Scalp explants from patients were transplanted to severe combined
immunodeficiency (SCID) mice and injected with autologous T lymphocytes
isolated from involved scalp. T lymphocytes, which had been cultured
with hair follicle extracts and antigen presenting cells were
capable of inducing the changes of alopecia areata, including
hair loss and perifollicular infiltrates of T cells, along with
HLA-DR and ICAM-1 expression of the follicular epithelium. Similar
changes were not observed in grafts injected with scalp-derived
T cells that had not been cultured with hair follicle extracts
and antigen presenting cells. These data indicate that alopecia
areata is mediated by T cells, which recognize a follicular autoantigen.
Although great progress has been made in comprehending the part
played by cell-mediated immunity against the follicular target,
the studies are still at an early stage and require deep research
with the latest techniques in cellular and molecular immunology.
A scientific breakthrough in the understanding of the autoimmune
response that drives alopecia areata would certainly provide the
stepping-stone in the development of novel, more targeted therapies.
Evidence of an autoimmune etiology for alopecia areata references
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