Elsevier

Journal of Autoimmunity

Volume 98, March 2019, Pages 74-85
Journal of Autoimmunity

Alopecia areata: A multifactorial autoimmune condition

https://doi.org/10.1016/j.jaut.2018.12.001Get rights and content

Highlights

  • Alopecia areata is a polygenic and multifactorial autoimmune disease characterised by non-scarring hair loss.

  • Autoreactive CD8+, CD4+, NK cells and pDCs infiltrate around the hair follicles during the growth (anagen) phase.

  • Increased cytokine activity results in disruption of the hair follicle immune privilege and termination of the anagen phase.

Abstract

Alopecia areata is an autoimmune disease that results in non-scarring hair loss, and it is clinically characterised by small patches of baldness on the scalp and/or around the body. It can later progress to total loss of scalp hair (Alopecia totalis) and/or total loss of all body hair (Alopecia universalis). The rapid rate of hair loss and disfiguration caused by the condition causes anxiety on patients and increases the risks of developing psychological and psychiatric complications. Hair loss in alopecia areata is caused by lymphocytic infiltrations around the hair follicles and IFN-γ. IgG antibodies against the hair follicle cells are also found in alopecia areata sufferers. In addition, the disease coexists with other autoimmune disorders and can come secondary to infections or inflammation. However, despite the growing knowledge about alopecia areata, the aetiology and pathophysiology of disease are not well defined. In this review we discuss various genetic and environmental factors that cause autoimmunity and describe the immune mechanisms that lead to hair loss in alopecia areata patients.

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.

References (153)

  • B.W. Colombe et al.

    The genetic basis of alopecia areata: HLA associations with patchy alopecia areata versus alopecia totalis and alopecia universalis

    J. Invest. Dermatol. Symp. Proc.

    (1999)
  • M.K. Hordinsky

    Overview of alopecia areata

    J. Invest. Dermatol. Symp. Proc.

    (2013)
  • J.P. Sundberg et al.

    Major locus on mouse chromosome 17 and minor locus on chromosome 9 are linked with alopecia areata in C3H/HeJ mice

    J. Invest. Dermatol.

    (2003)
  • A. Arousse et al.

    A novel AIRE gene mutation in a patient with autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy revealed by alopecia areata

    JAAD Case Rep.

    (2018)
  • S.Y. Chu et al.

    Comorbidity profiles among patients with alopecia areata: the importance of onset age, a nationwide population-based study

    J. Am. Acad. Dermatol.

    (2011)
  • M. Noack et al.

    Th17 and regulatory T cell balance in autoimmune and inflammatory diseases

    Autoimmun. Rev.

    (2014)
  • R. Paus et al.

    Immunology of the hair follicle: a short journey into terra incognita

    J. Invest. Dermatol. Symp. Proc.

    (1999)
  • R. Paus et al.

    Hair follicle immune privilege revisited: the key to alopecia areata management

    J. Invest. Dermatol. Symp. Proc.

    (2018)
  • T. Ito et al.

    Collapse and restoration of MHC class-I-dependent immune privilege

    Am. J. Pathol.

    (2004)
  • R. Paus et al.

    The hair follicle and immune privilege

    J. Invest. Dermatol. Symp. Proc.

    (2003)
  • G. Kollias et al.

    Role of TNF/TNFR in autoimmunity: specific TNF receptor blockade may be advantageous to anti-TNF treatments

    Cytokine Growth Factor Rev.

    (2002)
  • M. Tauber et al.

    Groupe de Recherche sur Psoriasis de Société Française de, Club Rhumatismes et Inflammation (CRI), Groupe d’études thérapeutiques des affections inflammatoires du tube digestif (GETAID), Alopecia areata occurring during anti-TNF therapy: a national multicenter prospective study

    J. Am. Acad. Dermatol.

    (2014)
  • R. Paus et al.

    A “hairy” privilege

    Trends Immunol.

    (2005)
  • A. Akar et al.

    Antioxidant enzymes and lipid peroxidation in the scalp of patients with alopecia areata

    J. Dermatol. Sci.

    (2002)
  • S. Shimoda-Matsubayashi et al.

    Structural dimorphism in the mitochondrial targeting sequence in the human manganese superoxide dismutase gene. A predictive evidence for conformational change to influence mitochondrial transport and a study of allelic association in Parkinson's disease

    Biochem. Biophys. Res. Commun.

    (1996)
  • R. Willemsen et al.

    Increased history of childhood and lifetime traumatic events among adults with alopecia areata

    J. Am. Acad. Dermatol.

    (2009)
  • F. Russiello

    Stress, attachment and skin diseases: a case-control study

    J. Eur. Acad. Dermatol. Venereol.

    (1995)
  • A. Picardi et al.

    Psychosomatic factors in first-onset alopecia areata

    Psychosomatics

    (2003)
  • R. Paus

    Exploring the “brain-skin connection”: leads and lessons from the hair follicle

    Curr. Res. Transl. Med.

    (2016)
  • T. Fujii et al.

    Physiological functions of the cholinergic system in immune cells

    J. Pharmacol. Sci.

    (2017)
  • K. Kawashima et al.

    Critical roles of acetylcholine and the muscarinic and nicotinic acetylcholine receptors in the regulation of immune function

    Life Sci.

    (2012)
  • M.K. Hordinsky et al.

    Relationship between follicular nerve supply and alopecia

    Dermatol. Clin.

    (1996)
  • E.M.J. Peters et al.

    Probing the effects of stress mediators on the human hair follicle: substance P holds central position

    Am. J. Pathol.

    (2007)
  • D. Rigopoulos et al.

    No increased prevalence of Helicobacter pylori in patients with alopecia areata

    J. Am. Acad. Dermatol.

    (2002)
  • S. Yang et al.

    The genetic epidemiology of alopecia areata in China

    Br. J. Dermatol.

    (2004)
  • D.A. Guzmán-sánchez et al.

    A clinical study of alopecia areata in Mexico

    Int. J. Dermatol.

    (2007)
  • A.C. Villasante Fricke et al.

    Epidemiology and burden of alopecia areata: a systematic review

    Clin. Cosmet. Invest. Dermatol.

    (2015)
  • A. Nanda et al.

    Alopecia areata in children: a clinical profile

    Pediatr. Dermatol.

    (2002)
  • E. Tan et al.

    A clinical study of childhood alopecia areata in Singapore

    Pediatr. Dermatol.

    (2002)
  • F.L. Xiao et al.

    The epidemiology of childhood alopecia areata in China: a study of 226 patients

    Pediatr. Dermatol.

    (2006)
  • J. Rocha et al.

    [Alopecia areata: a retrospective study of the paediatric dermatology department (2000-2008)]

    Acta Med. Port.

    (2011)
  • K.J. MacLean et al.

    Alopecia areata: more than skin deep

    Practitioner

    (2013)
  • L. Petukhova et al.

    Genome-wide association study in alopecia areata implicates both innate and adaptive immunity

    Nature

    (2010)
  • C.H. Pratt et al.

    Alopecia areata

    Nat. Rev. Dis. Prim.

    (2017)
  • M. Ghoreishi et al.

    Type 1 interferon signature in the scalp lesions of alopecia areata

    Br. J. Dermatol.

    (2010)
  • L. Xing et al.

    Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition

    Nat. Med.

    (2014)
  • A. Gilhar et al.

    Alopecia areata

    N. Engl. J. Med. Med.

    (2012)
  • J. Abou Rahal et al.

    Plasmacytoid dendritic cells in alopecia areata: missing link?

    J. Eur. Acad. Dermatol. Venereol.

    (2016)
  • C. Thein et al.

    Lesional alopecia areata T lymphocytes downregulate epithelial cell proliferation

    Arch. Dermatol. Res.

    (1997)
  • A. Tanemura et al.

    Alopecia areata: infiltration of Th17 cells in the dermis, particularly around hair follicles

    Dermatology

    (2013)
  • Cited by (0)

    View full text