Alopecia areata is a systemic hair loss disorder, which affects roughly around 4.7 million people in the United States alone. [NAAF]. It is characterized as an autoimmune disease that leads to either localized or complete hair loss. The disease is independent of race, gender or age specifications, and hence affected people represent a diverse group. The effects of the disease may either be permanent or reversible depending on the nature and extent of damage to the hair follicles. It is believed that both genetic as well as environmental factors have an influence in the onset of the condition. However, the pathology of the disease is yet to be ascertained concretely. Though there is no physical distress accompanying the disease the psychological devastation suffered by the affected person is debilitating. Let us have a brief overview of the different types of alopecia before we discuss in detail the possible pathophysiology and the treatment options for the disease. Alopecia (Different Types)

Alopecia is a disease triggered by the immune response of the body, which attacks and alters the normal development cycle of the hair follicles. Normally each hair follicle is in any one of the following three stages of life cycle namely anagen (growth phase), catagen (regression phase) and telogen (resting phase). Alopecia areata refers to the significant hair loss observed due to the immune response against the hair follicles in the anagen stage, resulting in severe reduction or complete stoppage of the hair growth phase. When the hair loss is observed throughout the body it is called as alopecia universalis. When complete hair loss is confined to the head, the condition is referred to as Alopecia totalis while hair loss that is localized and observed as patchy bald regions is known as Alopecia areata. [Ralph Paus]

Hair Follicles (Complex Morphognesis)

It is important to understand that the morphogenesis of a hair follicle is a quite complex process involving multiple genes and growth responsive factors. The complex interaction that starts with the first triggering signal from the dermis to the epithelium is followed by placode formation, which is controlled by fibroblast growth factor (FGH), ( catenin and WNT genes among other growth factors. Recent research has emphasized the important role of ( catenin in stem cell differentiation. [Huelsken, J ] The development of dermal papilla in itself is controlled by growth factors like PDGF -- A and SSH. So there are complex interactions of genes, receptors and growth factors at every level of the hair follicle formation and its life cycle. [George Cotsarelis]

Androgenic Alopecia

Androgenic alopecia is an important and most commonly observed type of the disease, which as the name suggests is triggered by the levels of the male sex hormone androgen. It is really a puzzling mystery that the very androgens, which stimulate hair growth in certain parts of the body, contribute to hair loss in some regions. This is a genetically inherited disease, which involves the miniaturization of hair follicles in certain regions of the scalp resulting in a particularly regionalized bald formation in men and women. There is a gradual shortening of the anagen phase of the hair follicles resulting in a condition called telogen effivium. (Profuse shedding of the hair shaft) Androgenic alopecia is considered as a potentially reversible condition as the hair follicles are still maintained though the growth phase is severely limited. The condition is incident in both women and men with different patterns of hair loss. While in men the hair loss is visible in the frontal regions in women it is predominant in the vertex. The androgen dihydrotestosterone (DHT) is thought to be responsible for the shrinkage of the hair follicles leading to baldy patches. It is to be noted that such structural changes in hair follicles even under normal circulation levels of androgen are manifest only in genetically predisposed individuals. [Roberts Janet] To have a better understanding of the anomaly it is essential to have a brief outlook into the changes that happen at the Molecular level.

Molecular Pathology of AGA

Research into the pathophysiology of AGA though still inconclusive, has offered enough insight and has identified the important role of androgens in the progressive miniaturization of the hair follicles leading to baldness. Testosterone and its metabolite dihydrotestosterone (DHT) in particular have been directly related as causative factors. The presence of the enzyme 5[Alpha]-reductase is essential for the catalytic reduction of testosterone into the more potent form of DHT. Chromosome 2p has the gene necessary for encoding 5[Alpha]-reductase. Extensive studies conducted on people suffering from AGA have revealed an excess of 5[Alpha]-reductase,...

DHT affects the hair follicles by binding with the dermal papilla cells creating androgen receptor complexes. Androgen receptors act as transcription factors and are directly involved in the synthesis of the protein substances that affect the hair follicles. Genetic mutation of these Androgen receptors makes a person vulnerable for changes in the regulatory factors and thus the onset of AGA. [M. Fiuraskova et.al]
Immunology of Alopecia Areata

There is enough evidence to indicate that alopecia areata is an autoimmune disease. Scalp biopsies of persons affected by Alopecia Areata have a clear preponderance of autoreactive cells. It is identified that at the base of the hair follicle there is an unusual concentration of (up to 90%) T. lymphocytes. The higher CD4 count and the CD4 to CD8 ratio of 2-4:1 is specific to AA patients. This T cell infiltrate in the hair follicles is a common feature for all Alopecia patients regardless of the severity of the condition. Further Langerhans cells (antigen transporters) have also been implicated in triggering the immune response as they are observed in the bulb and matrix regions of the affected tissues. [Medical College of Georgia]

Tazini et.al studied the possible role of AIRE (auto immune regulator gene) in Alopecia areata. 202 patients were observed for the study and their genotypes were compared with 175 control subjects. Upon screening for the AIRE coding sequences the researchers noted 20 different variations, the positions of two of which (at G961G and T1029C) resulted in changes in the amino acid composition. While there was no considerable difference in the frequency of the polymorphic form T1029C in both the patient and the control groups, there was a significant increase in the frequency of the G961G allele in the patient group. While the frequency of this allelic form was .08 in the control group it was 0.13 in the alopecia areata (mild, patchy hair loss) group and was the highest at 0 .20 with the patients suffering from Alopecia universalis. Thus the allele AIRE G961G is considered to be a huge risk factor for Alopecia universalis. Researchers presume that changes in the AIRE -DNA binding as a result of the polymorphic changes in the AIRE gene maybe the cause for the onset of Alopecia. [Tazini et.al] The AIRE gene mutation is also known to be the causative factor in many different clinical conditions including thyroid problems, insulin regulation, ectodermal dystrophies, etc.

Microcirculation in scalp Tissues

Though there is much attention directed towards the immunological etiology of alopecia areata research findings also prompt us to believe that other factors may also be responsible for the disease. Research into the scalp tissue of AA patients indicates that defective microcirculation in the scalp tissues may be a causative factor. Rossi et.al (1997) observed the correlation between subcutaneous microcirculation and hair loss. Hair follicles are nourished by sensory neurons that surround the bulge area. It is well-known that subcutaneous nerves are rich in neuropeptides such as calcitonin gene-related peptide (CGRP), SP and VIP (vasoactive intestinal polypeptide). For the study the researchers observed 10 patients (17 to 45) with AA and performed scalp biopsies to assess levels of the neuropeptides CGRP, SP and VIP using radioimmunoassay (RIA). Five control subjects (25 to 55) were also chosen and the experimental results compared. [Rossi et.al]

Blood flow levels were monitored in the AA patients by introducing two probes in the alopecic scalp regions. Similar probes were also introduced in the shaved scalp of control subjects and the blood flow monitored continuously using an attached computer. The radioimmunoreactivity readings for the neuropeptides for the patients when compared with the control group, showed a marked difference in the levels of CGRP and SP neuropeptides, while there was not much difference in the levels of VIP. The Tissue levels of CGRP-LI and SP-LI in the control group was 4.68 ± 0.55, 0.215 ± 0.015 pmol g-1, while the same in the Patient group was 1.04 ± 0.31 and 0.132 ± 0.011 pmol g-1 showing the significant difference in the neuropeptide levels. The scalp micro vessels respond to the neuropeptides in the sensory neurons that replenish them. The results from the study clearly indicate reduced sensory innervation in AA patients. As neuropeptides are involved in multiple roles such as growth modulators, immunomodulators and neurotransmitters their deprivation might have a negative growth impact. The increased sensitivity to intradermal CGRP injections among the patient group further proves the deficiency related hypersensitivity. Thus it is inferred that reduced microcirculation in the affected tissues…