Alopecia Areata 1

Description

Alopecia areata is a genetically determined, immune-mediated disorder of the hair follicle with an estimated lifetime risk of approximately 2%, making it one of the most common human autoimmune diseases. It shows a spectrum of severity that ranges from patchy localized hair loss on the scalp to the complete absence of hair everywhere on the body (Gilhar and Kalish, 2006).

Clinical Features

Alopecia areata is characterized by patchy hair loss on the scalp, which can eventually involve the entire scalp (alopecia totalis) or the entire body (alopecia universalis) (Martinez-Mir et al., 2007). The onset of the disease can be sudden, its progression is unpredictable, and it can be recurrent throughout life. Alopecia areata is viewed as a tissue-specific autoimmune disease of the hair follicle (Martinez-Mir et al., 2007). The hair follicle is an immune-privileged site, with low levels of major histocompatibility complex (MHC) expression. It is thought that alopecia areata represents a breakdown in immune privilege with the subsequent destruction of the hair follicle by T lymphocytes. Reports of overnight whitening of the hair are thought to represent the abrupt onset of alopecia areata, since it preferentially targets pigmented hairs, leaving only white hairs behind (Goldenhersh, 1992; Barlag and Ruzicka, 1995). Alopecia areata has a deeply disturbing psychologic impact on affected individuals.

Lubowe (1959) described a family with affected mother and affected daughter and son. Evidence suggested an autoimmune mechanism in this disorder. See autoimmune diseases (109100). Stankler (1979) observed onset in brother and sister at age 2, with regular and periodic synchronous exacerbation thereafter. One incidence of exacerbation was after mumps. In a white American family, Hordinsky et al. (1984) found alopecia universalis in 2 brothers and alopecia areata in the son of one of them.

Martinez-Mir et al. (2007) suggested that alopecia areata fits the paradigm of a complex or multifactorial genetic trait based on several lines of evidence: its prevalence in the population of approximately 2%; concordance in twins of 55% (Jackow et al., 1998); a Gaussian distribution of severity; a 10-fold increased risk for first-degree relatives of affected individuals; and the aggregation of affected individuals in families with no clear mendelian pattern of inheritance.

Population Genetics

Among first-degree relatives of 348 severely affected patients, van der Steen et al. (1992) found that one of the parents was affected in 7%. Among the sibs, 3% had developed alopecia areata (AA), while AA was present in 2% of the children. Taking into account the age of the children, they estimated that the lifetime risk approached 6%. They concluded that the degree of involvement observed in the probands did not influence the frequency and type of AA present in their first-degree relatives.

Alopecia areata occurs in approximately 0.1% of the general population (Safavi, 1992), but in approximately 9% of patients with Down syndrome (Brown et al., 1977).

Diagnosis

Paller et al. (2003) noted that a form of alopecia universalis (AU), which leads to total hair loss from the whole body, is the most severe form of alopecia areata, and that the onset in infancy of complete alopecia in patients with alopecia with papular lesions (APL; 209500) may lead to their being misdiagnosed as having the AU form of alopecia areata. The differentiation of AU and APL is of extreme importance, because many patients with AU will respond to available therapies, whereas patients with APL will fail to respond to any treatment modality over several years, leading to the diagnosis of APL. APL is caused by mutation in the human 'hairless' gene (HR; 602302). Paller et al. (2003) suggested that APL may be more common than previously thought and that infants with presumed AU from small nonconsanguineous families may warrant testing for HR mutations before embarking on therapeutic modalities that will fail in APL. A congenital form of alopecia universalis (ALUNC; 203655) is also caused by mutation in the HR gene.

Mapping

Linkage to Chromosome 18

In an effort to define a genetic basis of alopecia areata, Martinez-Mir et al. (2007) performed a genomewide search for linkage to 20 families with 102 affected and 118 unaffected individuals from the United States and Israel. The analysis revealed evidence of at least 4 susceptibility loci on chromosome 6, 10, 16, and 18 using several different statistical approaches. Fine-mapping analysis with additional families yielded a maximum multipoint lod score of 3.93 on chromosome 18 at marker D18S967 (AA1), a 2-point affected sib pair (ASP) lod score of 3.11 on chromosome 16 (AA2; 610753), several ASP lod scores greater than 2.00 on chromosome 6q, and a haplotype-based relative risk lod of 2.00 on chromosome 6p, in the major histocompatibility complex locus.

Associations Pending Confirmation

Valsecchi et al. (1985) found 6 cases in 3 generations and showed that all affected persons had the same haplotype, HLA-Aw32,B18. In 2 Israeli families, Zlotogorski et al. (1990) could find no linkage to HLA.

Galbraith and Pandey (1989) suggested an association between the gene encoding the Km1 allotype of the immunoglobulin kappa light chain determinant (see 147200) and a chromosome 2 gene encoding susceptibility to alopecia areata, based on a significantly higher frequency of this allotype in patients with the disorder than in a reference population of 105 healthy subjects. Within the patient population, an association between the absence of detectable serum antibody and the Km1 allotype was observed.

Galbraith and Pandey (1995) studied 2 polymorphic systems of tumor necrosis factor alpha (TNFA; 191160) in 50 patients with alopecia areata. The first biallelic TNFA polymorphism was detected in humans by Wilson et al. (1992); this involved a single-base change from G to A at position -308 in the promoter region of the gene. The less common allele, A at -308 (called T2), shows an increased frequency in patients with IDDM, but this depends on the concurrent increase in HLADR3 with which T2 is associated. A second TNFA polymorphism, described by D'Alfonso and Richiardi (1994), also involves a G-to-A transition at position -238 of the gene. In alopecia areata, Galbraith and Pandey (1995) found that the distribution of T1/T2 phenotypes differed between patients with the patchy form of the disease and patients with totalis/universalis disease. There was no significant difference in the distribution of the phenotypes for the second system. The results suggested genetic heterogeneity between the 2 forms of alopecia areata and suggested that the TNFA gene is a closely linked locus within the major histocompatibility complex on chromosome 6 where this gene maps and may play a role in the pathogenesis of the patchy form of the disease.

The MX1 gene product (147150) is strongly expressed in lesional anagen hair bulbs from patients with alopecia areata but not in normal follicles. To study the possible involvement of MX1 in the pathogenesis of alopecia areata, Tazi-Ahnini et al. (2000) defined the MX1 exon/intron organization and screened the exons and introns by conformation-sensitive gel electrophoresis for polymorphic markers. They found 4 single-nucleotide polymorphisms (SNPs) in intron 6. These polymorphisms were concentrated within 147 bp and showed strong linkage disequilibrium. In a case-control association study for the MX1(+9959) polymorphism in 165 alopecia areata patients and in 510 controls, they found a significant association of the intron 6 marker with the disorder. The association was stronger for patchy alopecia areata (mild disease) and early age at onset.

Petukhova et al. (2010) undertook a genomewide association study in a sample of 1,054 cases and 3,278 controls and identified 139 SNPs that were significantly associated with alopecia areata (p = 2.5 x 10(-7) or less). These associations were in genomic regions containing several genes controlling the activation and proliferation of regulatory T cells: cytotoxic T lymphocyte-associated antigen-4 (CTLA4; 123890), represented by rs1024161, P value 3.55 x 10(-13); odds ratio 1.44, 95% confidence interval 1.3-1.59; IL2/IL21 (147680/605384); IL2 receptor A (IL2RA; 147730); EOS (606239); and the HLA region. Petukhova et al. (2010) also found association evidence for regions containing genes expressed in the hair follicle itself (PRDX5, 606583 and STX17, 604204). A region of strong association resides within the ULBP gene cluster on chromosome 6q25.1, encoding ligands of the natural killer cell receptor NKG2D (611817) that had not theretofore been implicated in an autoimmune disease. By probing the role of ULBP3 (605699) in disease pathogenesis, Petukhova et al. (2010) also showed that its expression in lesional scalp from patients with alopecia areata is markedly upregulated in the hair follicle dermal sheath during active disease. Petukhova et al. (2010) concluded that their study provided evidence for the involvement of both innate and acquired immunity in the pathogenesis of alopecia areata, and helped define the genetic underpinnings of this disorder, placing it within the context of shared pathways among autoimmune diseases, and implicating a novel disease mechanism, the upregulation of ULBP ligands, in triggering autoimmunity.

Animal Model

The C3H/HeJ mouse is an inbred laboratory strain that spontaneously develops an adult-onset disease that resembles adult-onset alopecia areata in humans. Sundberg et al. (2004) identified 4 genetic susceptibility loci on mouse chromosomes 8, 9, 15, and 17, wherein the chromosome 17 locus corresponds to HLA orthologs.