Alopecia areata: A multifactorial autoimmune condition
Introduction
Alopecia areata is an autoimmune disease characterised by hair loss due to inflammatory responses that target the hair follicles. Incidence of disease in the USA and UK is about 2%, but the data varies for different populations and in different studies, with global incidence ranging from 0.57% to 3.8% [[1], [2], [3], [4]]. In addition, some paediatric studies report a higher prevalence in children ranging from 10 to 50%, especially for those with a family history of alopecia areata, indicating a genetic basis for disease development [[5], [6], [7], [8]].
The onset and progression of alopecia areata are unpredictable. Spontaneous hair re-growth is estimated to occur in 80% of patients within a year after the first incidence of alopecia, and relapse or progression to alopecia totalis and universalis can occur at any stage [1,2,4,9]. Due to the high percentage of patients that experience recovery, alopecia areata has been described as a short-term transient condition, although, based on genetic studies of sufferers and from mouse models the disease can also have a chronic phase which is more likely to progress to more advanced stages characterised by widespread hair loss [[10], [11], [12]].
Although the exact cause of alopecia areata is poorly understood, genetics and immunity are confirmed as the most important contributors to disease. Infiltrates of T helper (Th) cells, cytolytic T cells, natural killer cells and plasmacytoid dendritic cells surround the lower part of the hair bulb during the anagen, the growth phase, where their autoimmune activities cause the collapse of the hair follicle immune privilege and alopecia (Fig. 1) [[10], [11], [12], [13], [14], [15], [16], [17], [18]]. CD8+ cells recruit early in disease and are thought to be the main cell type that initiates alopecia areata [12,15,16]. Autoreactive Th1, Th17, NK and CD8+ cells produce IFN-γ which disturbs hair follicle functioning and causes disruption of the hair growth cycle, premature hair loss and inhibition of hair growth [11,12,14,15,19]. Type 1 interferons, chemokines (e.g. CXCL10) and cytokines (e.g. IL-12/23, TNF-α), have also been implicated in the maintenance of immune infiltrates and disease manifestation [13,17,20]. Despite the autoimmune perturbations, the hair follicle is not destroyed, so the outcome is hair fall without scarring or permanent loss of tissue [11,12,14].
There are no therapeutics available for the prevention or cure alopecia areata. Various treatment options that target immune cells exist for the disease (Table 1), however the effectiveness varies between individuals and is dependent on the duration and stage of disease at commencement of treatment [[21], [22], [23]]. In addition, most treatments have a high relapse rate after the termination and are followed by negative side effects [21,[23], [24], [25]]. Sudden hair loss and disfiguration puts a psychological and economic burden on alopecia areata sufferers, and increases the risk of poor psychological health, low self-esteem and psychiatric morbidities [4].
Therein, we discuss the link between genetics, the immune response and other external factors which when combined result in alopecia areata pathophysiology. Understanding the cellular and molecular mechanisms underpinning this disease is crucial to the informed development of effective therapeutics for the treatment and cure of alopecia areata.
Section snippets
Inheritance of susceptibility for developing alopecia areata
Alopecia areata is more likely to occur in patients with a family history of disease. Prevalence of disease in adult patients with a family history is estimated to range from 0% to 8.6% [1,2,4], and in children between 10% and 51.6% [[5], [6], [7], [8]]. In addition, the occurrence of the disease in identical twins [[26], [27], [28]], siblings [29] and several generations of the same family [30,31], provides further evidence to support a genetic link. However, due to the frequency of the
Alopecia areata is a polygenic autoimmune disease
Genetic studies in both mouse models and in the human population have shown that alopecia areata is a complex, polygenic condition [[10], [11], [12],32]. Many of the genes which are strongly associated with alopecia areata are also involved in a variety of other autoimmune diseases such as type 1 diabetes mellitus, multiple sclerosis, psoriasis, and inflammatory bowel disease (Table 2) [11,33,34]. Hundreds of single nucleotide polymorphisms (SNPs) have been identified in alopecia areata
Immune responses and cells involved in alopecia areata
Alopecia areata onset and progression is strongly influenced by the immune system. Skin biopsies of affected patients show lymphocytic infiltrates in and around the lower part of the hair follicle in the anagen (hair growth) phase [12,14]. The autoimmune activity at the site of the hair follicle has been linked to the disruption of the hair cycle and hair loss [4,11,12,45] In many cases alopecia areata coexists with other autoimmune diseases, such as thyroid disease, celiac disease, rheumatoid
Other factors involved in initiation and progression of autoimmune alopecia areata
In addition to the genetic predisposition for developing alopecia areata, there are different environmental factors that could initiate autoimmunity and disease. Different studies discussed further in this review indicate that alopecia areata is a multifactorial autoimmune disease with genetic and environmental aetiology (Fig. 3).
Treatments for alopecia areata are focused at targeting the autoimmunity
Genetic and immunological observations suggest a strong cell-mediated response for the onset and progression of disease, therefore representing an attractive target for therapeutics. In fact, some of the most successful therapies that exist for alopecia areata target the immune cells and their activity (Table 1). The mechanism of action for many of these drugs involves inhibition of cytokine signalling (e.g. JAK inhibitors), altering the Th1-type immune responses (e.g. contact sensitizers) and
Conclusion
Alopecia areata is an autoimmune disease with genetic and environmental aetiology. The disease manifests when the immune privilege of the hair follicles is impaired and immune cells infiltrate around the hair bulb during the anagen phase. The autoreactive immune responses lead to the disruption of the hair cycle by prematurely terminating the anagen followed by hair follicle atrophy and dystrophy in persistent disease. However, the hair follicle tissues are not destroyed, so reversing alopecia
Acknowledgement
Author Simakou T. is carrying out research for alopecia areata and has a studentship funded by the University of the West of Scotland and Alopecia UK.
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