**3. Pathogenesis**

Alopecia areata is an organ-specific T cell mediated autoimmune disease targeting hair follicles. Peribulbar lymphocytic infiltration impairing the normal hair cycle is considered to be the main pathophysiologic mechanism responsible for the disease process. Normal hair cycle is disrupted in alopecia areata; dystrophic changes of anagen follicles along with rapid progression of hair follicles from anagen to catagen and telogen phases are observed. In alopecia areata, perifollicular inflammatory infiltrate spares the bulge region of the follicle where follicular epithelial stem cells reside. Thus, in contrast to cicatricial alopecias, the inflammation does not interfere with the hair follicle integrity [6].

The complex pathophysiology of alopecia areata involves an autoimmune basis. Association of alopecia areata with other autoimmune diseases such as thyroiditis and vitiligo is reported. Presence of lymphocytes around hair follicles and the good response of patients to immunosuppressive treatment also support autoimmune etiology [2].

Etiopathogenetic theories are based upon the loss of immune-privileged status of hair follicles leading to an immune response against follicular antigens. In fact, normal proximal epithelium of anagen hair follicles have a very low expression of MHC class I antigens and no MHC class II antigen expression, along with a potent expression of immunosuppressive cytokines, such as TGF-β1 and α-melanocyte–stimulating hormone (α-MSH) [6]. According to the recent evidence, mechanism leading to hair loss involves the following steps: firstly, hair follicles must enter an anagen phase without the immune privilege described above, making those vulnerable to immune reactions. Subsequently, perifollicular CD8+ T cell infiltration of the anagen hair bulb epithelium ensues, along with a significant increase in interferon-gamma (IFN-γ) and various other cytokines. This milieu further damages the immune-privileged status of hair follicles, autoreactive CD8+ T lymphocytes, and IFN-γ and causes hair follicle dystrophy and premature catagen induction, leading to clinical hair loss [7]. Patients with alopecia areata have also been found to have an increased frequency of hair follicle-specific autoantibodies [2].

Genetic basis is implicated in disease pathogenesis. Many patients report a family history of alopecia areata with a frequency ranging from 10% to 42% of cases [8]. Studies show a higher concordance rate among monozygotic twins compared to dizygotic twins also supporting the role of genetics [9]. HLA-DRB1\*1104 and DQB1\*03 loci that have a role in regulating immunity is associated with susceptibility to alopecia areata [2].

Genome-wide association studies can recognize specific individual genes, which may represent an increased susceptibility to alopecia areata. Petukhova et al. surveyed the entire genome and identified 139 single nucleotide polymorphisms associated with alopecia areata. The study showed that genomic regions containing the CTLA4, IL2/IL21, IL-2RA and Eos genes regulating proliferation of inflammatory cells to be susceptibility loci for alopecia areata. Ligands for the NKG2D receptor were also found to be implicated in disease pathogenesis [10]. Mouse models for alopecia areata gave valuable information regarding the role of CD8+ NKG2D+ T lymphocytes in pathogenesis. Transfer of these cytotoxic cells from mice with alopecia areata induced alopecia areata in healthy mice; on the other hand, NKG2D+ T cell-depleted lymph node cells transferred from the diseased mice to the healthy mice did not cause any disease. Interferon produced by NKG2D+ T cell is thought to contribute to the loss of immune-privileged status of hair follicles [11].
