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Hair follicle antigens in alopecia areata
Alopecia areata is a common non-scarring form of hair loss disorder.
Resulting from selective, reversible damage to the hair follicle
as it enters the growth phase called anagen, alopecia areata initially
appears as patchy areas of complete hair loss (on scalp and other
parts
of the body). If left unattended, aloepcia areata progresses to
complete loss of all body hair. Recently it has been brought to
light that
other
than human beings, alopecia areata affects other nonhuman mammals
like dogs, horses, inbred mice and rats as well.
Research studies in alopecia areata have indicated the involvement
of an immune-mediated pathology but the causes and origins of
alopecia areata
is
not yet fully understood.
This assumption of right identification of the target auto-antigen
is based on the finding since alopecia areata like all other autoimmune
diseases (with both T and B cell components) produces autoantibodies
and autoreactive T cells to hair follicles, will also share target
autoantigens/epitopes. The following discussion briefs on those
progressions that have been made in the identification of hair
follicle antigens targeted by antibodies and lymphocytes in alopecia
areata.
Antibodies, hair follicles and human alopecia areata
An analysis of the studies undertaken, indicate that the cases
of failing to establish any relationship outreach the number of
studies that successfully established a connection.
Actually, given that the hair
follicle is the central target tissue in alopecia areata,
it is generally expected that it will show evidences of specific
immune responses. Studies conducted by Tobin and others (between
1994-97) provided the first proof of the presence of antibodies
(specifically directed at hair
follicle) in alopecia areata. Comparative observation of
normal individuals and AA patients by Tobin and others presented
the following two interesting facts about alopecia areata:
- Low titer IgM anti-hair
follicle antibodies were detected in the
normal individuals by using highly sensitive immunoblot assays.
- In
contrast, simple Low-sensitivity Indirect Immunofluorescence
Test of the biopsy samples of the alopecia areata affected people
was enough to detect the presence of high titer IgG anti-hair
follicle antibodies
in addition to the low titer IgM.
This switching of the Immunoglobulin isotype from the low titer
IgM (representing the natural auto-antibody pool) to the high
titer IgG is a pathological consequence and embodies the maturing
of the antibody response to hair
follicle antigens. Thus, the above observation
establishes the immune system’s ability to induce an immune
response to hair
follicle proteins expressed on or in normal hair
follicle. This provides
the evidentiary support to the autoimmune origin of alopecia areata.
The targeted hair follicle regions
Alopecia areata antibodies target hair follicles without reacting
much with the adjacent epidermis or dermis. In contrast, control
sera
are
known to react (athough weakly) with the hair follicle epithelium,
the epidermis and the epithelium of other skin adnexa.
The alopecia areata antibodies are aimed at multiple structures
within the anagen hair follicle (and to multiple antigens therein).
The most common
hair follicle structures targeted in human alopecia areata are
all keratinocyte-derived structures, namely supra-Auber’s
matrix (the cells that make the hair fiber cortex)/ pre-cortex,
followed by the outer root sheath and the inner root
sheath. Since most
of the target points are located in or near the multiplying and
differentiating
sections
of the
anagen
hair follicle, it may be that antibody reactions are more likely
to halt hair differentiation and growth. In the case of sera,
the
IgG
antibody
associations
to hair follicle components puts forth a unique pattern of reactivity – with
reactivity becoming evident only with the onset of cortex differentiation
or in response to keratinocytes that will later form the inner
root sheath.
In the last few years numerous investigations using the aging
C3H/HeJ mouse model for alopecia areata, the DEBR model, dogs
and horses with alopecia areata have been undertaken in order
to ascertain the antibody reactivity
to hair
follicle-specific
targets. All these studies have gone on to show that similar hair
follicle components
are targeted by IgG antibodies irrespective of the species and
include the supra-Auber’s matrix/ precortex, outer root
sheath, and inner root sheath. These findings speak strongly in
favor of the assertion that
autoantigens
in alopecia areata primarily include keratinocyte differentiation-associated
proteins.
The hair follicle antigen targets
The lack of information and the non-identification of the hair
follicle autoantigen triggering the alopecia areata condition
has long been a major drawback in the better understanding of
alopecia
areata . The Immunoblotting studies undertaken in human, canine,
equine and murine models
of late (using alopecia areata associated antibodies to identify
hair follicle antigen targets) have been of immense help.
An immunoblot analysis (involving the binding of antibodies to
specific epitopes of electrophoretically separated subspecies
of antigens) undertaken by Tobin and Bystryn offers an interesting
case study in this respect. The study established that one of
the more common bands of immunoreactive protein expressed in human
hair
follicle extracts separates at 44/46 kDa (a hairspecific keratin
expressed in the pre-cortical zone of anagen hair follicles) in
SDS-PAGE.
Tobin and Bystryn successfully isolated an antibody from a human
alopecia areata immunoblot and used it to react with freshly frozen
hair-bearing sections of human scalp. They detected antibody reactivity
(in
the form of binding of specific antibodies to respective antigenic
bands) in the anagen hair bulbs. Lynch and others had earlier
detected a similar pattern of reactivity (localized in the anagen
hair bulb) with AE13 monoclonal antibody. A more significant discovery
in alopecia areata has been the observation that IgG, which immuno-precipitated
the hair-specific keratin 46 kDa was present only in alopecia
areata sera. On the other hand, the AE1 reactive soft keratins
were equally
precipitated by both alopecia areata sera and control sera.
Another target autoantigen is the inner root sheath-rich protein
trichohyalin (a member of the intermediate filament-associated
protein family).
Immunoblot tests conducted in all four animal species have confirmed
that high-titer IgG present in the alopecia areata sera binds
strongly to inner root sheathand reacts with a 200/220 kDa doublet.
Thus, both canine
and
equine
alopecia areata sera (but not control sera) has been shown to
immunoprecipitate proteins from a hair
follicle protein extract that reacts
with a monoclonal
antitrichohyalin antibody, AE15.
Additional studies undertaken to prove and evaluate the degree
of cross-reactivity of serum IgG in various alopecia areata -affected
species, involved murine and human sera. An investigation carried
out by
Tobin et al showed that C3H/HeJ serum IgG reactivity with hair
follicle-specific
proteins in human hair
follicle extracts shared similar molecular weights
to those detected when human AA serum was reacted against murine
hair
follicle extracts. These findings have substantiated the view
that alopecia areata targets similar hair
follicle components and antigens
in all species
affected
by this disorder.
Though much development has not been done with anti-hair follicle
antibodies, it needs mentioning that the production of anti-hair
follicle antibodies
further causes the alopecia areata condition to deteriorate. The
contribution of anti-hair follicle antibody reactivity to the
correct identification
of the target antigens has perhaps been the best finding as far
as
alopecia areata research on hair follicle antibodies is concerned.
Immune response in alopecia areata and cellular targets
Classic bulbitis in alopecia areata points to an early anagen
hair bulb location/expression of antigen as the most likely immune
response target. Scientists have identified three different types
of cells as the prime target cells – cortical keratinocytes, melanocytes
and endothelial cells. Alopecia areata’s propensity for
targeting hair bulb cells during the mitotic activities associated
with anagen stages III/IV of hair growth corresponds to both the
beginning
of differentiation of cortical keratinocytes and the functional
activation of melanocytes.
- Keratinocytes. There is ample clinical, histological,
immunohistochemical and electron microscopic (EM) evidence to
indicate that precortical
keratinocytes are damaged in alopecia areata. Changes in keratinocytes
such as cytoplasmic swelling and vacuolization, frank cellular
necrosis and increased apoptosis have all been identified in transmission
electron microscopy studies.The strong reactivity shown by sera
from alopecia areata patients to hair follicle-specific hard
acidic keratins (44-46 kDa) indicates
the hair follicle keratinocyte-involvement
in the development of alopecia areata. This involvement is further
strengthened by the heightened reactivity shown by alopecia areata
sera to trichohyalin in the hair follicle inner root sheath. That
keratinocytes are a target in alopecia areata is further proved
by the location of antigens in the supra-Auber’s
region of the anagen hair bulb – the region of active keratinocyte
differentiation into the hair cortex and the inner root sheath.
Not surprisingly then, in acute forms
of alopecia areata the hair strands become comparatively weak
and taper to take the shapes of ‘exclamation marks’.
- Melanocytes. The fact that melanocytes are
targets of autoimmune responses is supported by alopecia areata’s
association with several clinical pigmentary anomalies. It has
been observed that while melanocyte containing
hair follicles are attacked in alopecia areata, depigmented white/gray
hairs are most often spared. Scientists have attributed this
unique penchant (of alopecia areata) for pigmented hair follicles to
the fact that bulbar melanocytes are the first cells in the
hair bulb to be attacked by infiltrating
immune cells. That hair bulb melanocytes are indeed damaged in
alopecia areata, is evidenced by the presence of melanophages
around the involved hair bulb and within the cortical matrix.
Further proof that corroborates
the view that melanocytes are specific targets of alopecia areata
is theat re-growing hairs are most often
depigmented. Transmission electron microscopy studies have indicated
a lowering of both melanocyte activity and melanocyte number
at a stage when hair follicles enter a successful anagen phase after an alopecia areata attack.
However, while the links between alopecia areata and pigmentation faults have been
firmly established, there has been no evidence of the involvement
of epidermal melanocytes. Research on alopecia areata rather points
to the cytoplasmic origin of hair follicle antigens being the
target in humans with alopecia areata. Although some
melanocyte cultures have indicated the presence of alopecia areata
hair follicle antigens on the cell surface, these antigens are
noticeably different in nature from those present in epidermal melanocytes.
Studies concentrating on hair follicle antigens – especially
self-antigens in keratinocytes and/or melanocytes – have
substantially broadened our understanding of alopecia areata.
Given the unique antigenic properties of keratinocytes and melanocytes
in hair follicles, the selective targeting of hair follicles in alopecia areata seems
fully justified. These interpretations have established that alopecia
areata is most pronounced in phases when both the cortical keratinocytes and
the melanocytes are active.
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