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Immunobiology
of hair follicles
Immunology is a broad branch of biomedical science that covers
study of all aspects of the immune system in all organisms. Through
research, we now have a thorough insight of the skin as a complex
and active immunologic organ. Scientists have identified several
distinct cell types in skin that actively participate in generating,
regulating, and perpetuating immune responses.
For over a century, biologists have been working hard to understand
the structure and function of the hair follicle and the factors
that control the growth and development of hair. Recent progress
in hair research, including advances made through molecular and
genetic approaches, brings to light the intriguing facts of hair
follicle biology, and may eventually lead to the development of
more effective treatments for hair growth disorders like alopecia
areata.
The hair follicle is also attracting interest as a useful model
system for studying a range of biological processes, including
tissue development, epithelial cell differentiation, apoptosis
(programmed cell death), and tumor formation. The immunology of
the hair follicle, its relationship with the 'skin immune system'
and its role in hair diseases remain biologically intriguing and
clinically important. Understanding how hair loss might be prevented
by inhibiting abnormal immune cell responses could lead to treatments
not just for hair loss but also other important autoimmune diseases
as well.
It is the research into the mechanism of androgen action in hair
follicles and the pathogenesis of autoimmune disease of hair follicles
that has given several observations that suggest that the immune
system could be involved with hair growth and cycling.
-
Hair follicles provide numerous ports of entry into the body
for micro-organisms.
- The outward movement of the new hair
shaft and displacement of the old club hair could be an avenue
by which microorganisms
can enter the more proximal hair follicle.
- Hair growth is affected by substances
with immunomodulatory characteristics, for example, cytokines,
hormones, neuro-peptides, and some
drugs.
- Hair follicle regression during the catagen stage is associated
with dramatic alterations in the peri-follicular populations
of both macrophages and mast cells.
- There is evidence that some autoimmune diseases
damage the hair follicle.
On the other hand, there is a lack of MHC class I expression
and Langerhans' cells and T cells in the proximal anagen hair
bulb, suggesting this may be an immune privileged site. Gaining
a better understanding of the immune privilege of the hair follicle
may provide insights into the regulation and pathogenesis of immune-mediated
diseases of the skin.
The hair follicle acts as a sensory organ and immunologic watchdog
for the skin. Its complex immunologic profile of Langerhans cells,
mast cells, lymphocytes and macrophages in the connective tissue,
carry out surveillance for the immune system. Hairs detect mechanical
stimuli above the surface of the skin, and the slightest bend
in a hair activates neuroreceptors in the follicle, relaying important
sensory information to the nervous system. The role of the Langerhans'
cells at the opening of the follicle is to provide the immune
system with enough information to prevent pathogens from invading
the body through the skin. Langerhans' cells are present in large
numbers in the infundibulum, but there are very few below the
level of the sebaceous gland and almost none in the hair bulb.
However, an important observation has been documented that they
appear in the hair bulb during catagen, graying and in alopecia
areata. The localization of Langerhan’s cells in the upper
hair follicle suggests that they operate there as the key components
of the ‘sentinel receptor pathway.’
Alopecia areata is associated with the abnormal expression of
class I and II MHC antigens and Langerhans' cells in hair bulbs.
This abnormal presence could be responsible for the induction
and elicitation of autoimmune responses to self antigens in hair
bulbs. Almost all the cells in the body express a protein called
the Major Histocompatibility Complex (MHC) protein. The function
of MHC is to present antigens to T-cells, and the T-cell receptors
plug onto the MHC molecule and try to bind with the presented
antigen. MHC come in two major varieties: MHC class I and MHC
class II. MHC class I is present on almost all nucleated cells,
MHC class II is present only on a population of cells known as
antigen presenting cells (APC). These include:
- Macrophages, which are large cells with round nuclei that
can put out long pseudopodia to surround antigen.
- B-cells lymphocytes,
which are like the body's military intelligence system, seeking
out their targets and sending defenses to
lock onto them.
- Dendritic cells, which can be phagocytic under certain circumstances
and, along with macrophages and B cells help stimulate T
cell activation.
The presence of class I MHC antigens, which are necessary for
interaction with cytotoxic T cells, may facilitate damage to hair
bulb cells by the T cells. The expression of class II MHC antigens,
which are induced by immune injury, suggests that epithelial cells
in affected hair bulbs are injured.
T cells are a very important component of the hair follicle immune
system. The cell-mediated immune system consists of T-cells, which
are highly-specialized cells in the blood and lymph to fight bacteria,
viruses, fungi, protozoans, etc. within host cells and react against
foreign matter such as organ transplants. The surface of a T-cell
contains thousands of T-Cell Receptors (TCR) but, for any one
T-cell, all the receptors are identical. This means that any one
T-cell is only able to recognize a small group of related antigens-
in other words each T-cell is specific only to those antigens
and is not effective against any others. The receptor rarely binds
with an entire antigen but with a sub-section of it called an
epitope.
T cells are of three types:
-
A killer T cell is a cell with a particular immune specificity
and an endogenously produced receptor for antigen, capable
of specifically killing its target cell after attachment to
the target
cell by this receptor.
- T helper cells (sometimes also known
as effector T cells) are a group of lymphocytes (a type of
white blood cell or leukocyte)
that coordinate the actual immune response of the body. These
cells are very unusual because they have no cytotoxic or phagocytic
activity of their own, and cannot kill infected cells or invading
pathogens. Without other immune cells, these cells would usually
be considered useless against an infection.
- Suppressor T-cells
are involved with suppressing an immune response.
In contrast to animal models, a high density of CD4 cells has
been observed in the infundibular outer root sheath of the human
hair follicle, with a gradual decline of these cells towards the
proximal hair follicle. CD4 cells are also present in the dermis.
A similar distribution of the CD8 T-cells, which kill abnormal
or infected body cells, has been observed. Hair follicle associated
mast cells are very common in the connective tissue sheath or
strategically located very close to the hair follicle. The mast
cells are what control many of the body's allergic reactions.
When the body comes into contact with an allergen, the mast cells
release histamine-containing granules. Macrophages are not found
in the hair follicle epithelium. Like mast cells, they have a
role in antimicrobial /parasitic defense, but may also secrete
multiple immunomodulatory cytokines during hair follicle regression.
The hair follicle immune system differs dramatically from the
skin immune system as the epithelium of proximal anagen hair follicle
lacks classical MHC class 1A antigen. Class I MHC molecules are
necessary in initiating immune responses in which endogenous antigens
are presented to activate CD8 T lymphocytes. For this reason,
hair follicles are pre-supposed as one of the few immunoprivileged
parts of the body; that is, they are protected from the immune
system so the body does not treat them as foreign and attack them.
Protection to hair follicle melanocytes from autoimmune attack
is seen in vitiligo, where hair follicle melanocytes are spared,
while epidermal melanocytes are destroyed. Studies indicate that
MHC class 1A antigen expression is lost from the hair follicle
at a time when melanogenesis (the formation of melanin by living
cells) is activated. This has particular relevance in the study
of alopecia areata, where melanocyte abnormalities have been detected.
Another avenue of intrigue and study is whether hair follicle-associated
immune responsitivity changes as a function of the hair growth
cycle. Experiments carried out on rodent models indicate that,
in mice at least, there is, indeed such a hair growth cycle-associated
alteration in the hair immune system. Identifying the factors
that coordinate the transitions between the three stages of the
hair follicle cycle and figuring out how these factors work are
central problems of hair biology research. Because alopecia areata
involves abnormalities in the cycle rather than total destruction
of the follicle, the condition is thought to be reversible, at
least in theory. It is this fact that gives researchers hope that
understanding the signaling networks that regulate hair follicle
cycling will provide the key to developing new and more effective
treatments alopecia areata.
A comprehensive understanding of the hair follicle immune system
is particularly important in the dissection of the immunopathology
of alopecia areata. Based on its accessibility, dispensability,
and self-renewal capacity as well as its fascinating structure,
the hair follicle has become a model system for investigating
the totally unknown signal transduction events associated with
immunomodulatory drugs with hair growth effects. The sharply reduced
numbers of T cells and Langerhans cells, and the virtual absence
of MHC class I expression all suggest that the anagen proximal
hair follicle constitutes an area of immune privilege within the
hair follicle immune system, whose collapse may be crucial for
the pathogenesis of alopecia areata.
Immunobiology
of hair follicles references
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