ARTICLE
Alopecia areata (AA) has been proposed to be an autoimmune disease based
on several indirect observations in humans and animal models of the disease
[1]. Genetic influence has been clearly demonstrated in most other autoimmune
diseases and one would expect that AA is no exception. AA is clearly a
complex disease, it does not segregate according to the rules of Mendelian
inheritance [2-5]. As with other autoimmune diseases, AA most likely has
a polygenic character where susceptibility is dictated by several major
genes and the phenotype may be modified by numerous minor genes. Here
we review the characteristics of polygenic disease theory as applied to
AA and identify methods to define AA susceptibility and severity modifying
genes.
AA as a polygenic trait
Genetically influenced diseases may be classified as monogenic, oligogenic,
or polygenic traits [6]. Classic monogenic diseases involve a single gene
locus. The phenotype results from the activity of one or two alleles.
Genes involved in monogenic disease inheritance have effects large enough
to be measured by segregation analysis of the affected population and
Mendelian inheritance patterns are representative of monogenic diseases.
A disease phenotype that involves interaction between a limited number
of major genes is sometimes termed oligogenic. The effects of the genes
may be incompletely penetrant and while segregation analysis may be possible,
it is unreliable. Polygenic disease traits may be continuously variable
characters that depend on the additive action of several major susceptibility
genes. Minor severity modifying genes may further modulate the polygenic
disease phenotype. Polygenic disease involves numerous minor genes, each
with a potential contribution to the phenotype, but the effects of each
individual gene are so small as to be unmeasurable by segregation analysis.
For polygenic diseases the effects of individual genes on the phenotype
must be identified by allelic association (linkage disequilibrium) [6].
Polygenic disease theory postulates the existence of a thres- hold level
of genetic susceptibility below which a phenotype is not expressed in
a normal population. If the total sum of minor and major susceptibility
genes, severity modifying genes, and resistance genes breaches the threshold
level the AA phenotype may develop [7]. Above the threshold level, with
augmentive gene influence, the phenotype may be expressed with increasing
severity as a continuous trait (Fig.
1). This is consistent with the AA phenotype where some genetically
related individuals express AA while others do not and individuals may
have AA limited to a single patch or the disease may be more severe with
multiple patches through to complete body hair loss. Severe forms of AA
may reflect the presence of a greater total number of, or the presence
of more powerful, severity modifying genes working synergistically.
The threshold line between non-expression and expression of AA may shift
under the influence of exogenous factors. The threshold for onset of AA
may be different at different ages, or for individuals living in different
environmental conditions. While the threshold levels within separate sub-populations
may be different, the threshold level for onset of AA may also change
over time for the same sub-population and even within the same individual
as exogenous influences on disease change. Consequently, genetically susceptible
individuals may not initially develop AA, but with time and changes to
their environment, they become susceptible to onset of the AA phenotype.
Equally, changes to the environment may raise the threshold level for
disease expression and a patient with AA may enter remission. The threshold
theory of polygenic disease susceptibility is one of several models that
may be relevant to AA, but it is the most suitable model to use in preliminary
investigations.
Rodent models
Isolated examples of AA have been identified in several species. However,
the limited characterization or availability of these examples restricts
their usefulness in any genetic research for AA [8]. Two rodent models
have been developed and characterized for use in AA research, the Dundee
experimental bald rat (DEBR) and the C3H/HeJ mouse [9, 10]. Both models
are inbred strains. Despite their inbred nature, rodents may have a wide
variety of hair loss presentations from isolated patches, or diffuse AA,
to near universal hair loss. AA in both rodent models has been shown to
be an autosomal polygenic trait with partial phenotype penetrance by analysis
of breeding programs.
The DEBR, originally a hybrid between BDIX and Wistar rats, has been
intercrossed for over 35 generations. Two separate inbred DEBR sub-strains
exist, one black hooded and the other brown, but with similar AA phenotype
properties. Hair loss is associated with a primarily CD4+ and
CD8+ lymphocyte cell infiltrate of anagen stage hair follicles
and production of hair follicle specific antibodies [11, 12]. Spontaneous
expression of AA develops in 42% of individuals with onset from 7 months
of age in both males and females. Hair loss typically first develops in
symmetrical bald patches on the flanks. Multiple patches may develop to
affect the head, dorsal and ventral skin with approximately 15% of affected
individuals reaching a near universal hair loss state. DEBR have been
cross bred with PVG/OlaHsd rats yielding 21% affected F1 offspring (Oliver,
personal communication) suggesting PVG/OlaHsd rats contain few AA susceptibility
genes. PVG/OlaHsd rats may be one of several strains suitable for use
in an intercross or backcross breeding strategy to identify AA susceptibility
and severity modifying genes by linkage disequilibrium.
C3H/HeJ mice have existed as a unique inbred strain at the Jackson Laboratory
since 1947, but onset of the AA phenotype was first observed in several
individuals of a C3H/HeJ mouse colony in 1993. The mouse breeding pattern
permitted tracing the genetic history of the affected mice to a single
breeding pair at generation F198 [10], suggesting a genetic modification
of the strain in one parent. The frequency of spontaneous AA expression
in aged mice, up to 18 months old, increased to approximately 20% in 3-4
generations for over 300 mice evaluated [10]. Both males and females are
affected with initially ventral hair loss typically developing in females
from 6 months and in males from 10 months of age. Hair loss may progress
to the dorsal surface and reach near universal loss in 10% of affected
individuals. Histopathology shows all affected anagen stage hair follicles
to be affected by non-scarring focal inflammation of primarily CD4+
and CD8+ lymphocytes and hair follicle specific autoantibodies
are present at a high titer [13, 14].
Recent studies have demonstrated that all adult C3H/HeJ mice are susceptible
to AA. Grafting skin from spontaneous AA affected mice to normal haired
C3H/HeJ mice consistently promotes onset of AA 8-10 weeks after grafting
[15]. Skin grafts from AA affected mice to the histocompatible C3H/OuJ
inbred strain promotes AA onset with a similar phenotype and pathology,
but in only 40% of graft recipients [15]. Crosses between C3H/HeJ mice
with AA and mice from the closely related C3HeB/FeJ strain with no history
of age associated alopecia, yielded F1 and subsequent generation mice
with an AA expression frequency of 10-12% [10]. The AA induction technique
suggests that while inbred C3H/HeJ mice may all be genetically susceptible,
the AA phenotype must be activated. It is possible that the environment
provides a trigger for initial disease onset. The apparent reduced susceptibility
of the C3H/OuJ and C3HeB/FeJ strains to AA suggest that these strains
carry fewer AA susceptibility genes as compared to the C3H/HeJ strain.
The segregation pattern of phenotypes suggests that AA in laboratory mice
is under the control of one or more dominant gene alleles.
A preliminary backcross study between C3H/HeJ mice and C57BL6/J mice
suggested a tentative locus for susceptibility on mouse chromosome 6 (37
cM, 1 recombinant/24 alleles with D6MIT230 is 4.2 cM, p = 3.10-
6, 95% confidence interval of the distance is 0.1-21.1 cM) [16].
Within this region are numerous immunoglobulin genes, a gene for cytokine
TGFalpha, as well as genes for the lymphocyte surface markers CD8 and
Ly36. The mouse locus corresponds to human chromosome region 2p13. Thus,
this region may be worthy of close attention within a genome wide screen.
C3H/HeJ mice cross bred with C57/BL6J mice yield 7% of affected F1 generation
mice (10% affected females, 2% affected males) and intercross studies
with C57BL6/J mice are in progress with up to 13 candidate gene loci under
investigation supporting the hypothesis that AA is a polygenic disease
(Sundberg, personal communication).
Other inbred and congenic rodent strains have recently been identified
with AA-like lesions and may also provide information about genetic susceptibility
to AA [17]. The location of AA susceptibility genes in the rodent genomes
may predict the location of homologous genes in the human genome by the
use of comparative maps for mice and humans [18, 19]. Different rodent
models may contain common key dominant susceptibility genes, but different
minor genetic susceptibility or severity modifying genes that may be associated
with different phenotype characteristics or involve different interaction
with environmental triggers.
Human epidemiology
There is a higher incidence of AA in genetically related individuals.
This suggests that at least some people are genetically predisposed to
develop AA. The triggers for the onset of AA may be environmental, but
the resistance of the AA lesion to treatment, its persistence and regression,
and its extent over the body may be influenced by the presence and interaction
of multiple genes.
Several studies suggest that AA has a genetic basis [2, 3]. AA with
similar times of onset or similar hair loss patterns has been reported
in monozygotic twins [20-26]. Families with several generations of AA
affected individuals also suggest AA may be a genetically determined disease
[3, 5, 27-31].
Epidemiological studies provide basic evidence for AA susceptibility
genes. Numerous studies suggest AA may be more frequently expressed in
genetically related individuals. Typically, 10 to 20% of patients with
AA indicate at least one other affected family member (Table
I). In contrast, the lifetime risk of AA expression in the general
population has been suggested to be 1.7% [32]. Familial incidence may
be significantly higher than reported in epidemiological studies as the
marked psycho-social consequences of hair loss inhibits some individuals
from seeking diagnosis. In addition, some may not be aware of their hair
loss if it is limited or develops in an area not immediately visible to
the individual.
A strong association has been observed between AA and trisomy 21 (Down's
syndrome). From 1,000 patients and 1,000 control subjects, Du Vivier and
Munro observed 60 cases of trisomy 21 individuals with AA versus
1 control [33]. Carter and Jegasothy identified 19 cases of AA in 214
trisomy 21 affected patients and the statistical relationship is further
supported in other studies [34, 35]. The genetic mutation for autoimmune
polyendocrinopathy syndrome type 1 (AIRE, autoimmune regulator gene) [36]
is also associated with a 29 to 37% prevalence of AA [37]. These studies
suggest that candidate gene loci for AA susceptibility may be present
on human chromosome 21.
Associations of AA with other autoimmune diseases have also been reported.
Between 7% and 27% of AA affected patients may also have a thyroid disease,
including goiter presence, myxedema and Hashimoto's thyroiditis [4, 38-40].
Co-expression of vitiligo and AA has also been reported at between 4%
and 9% [41, 42]. However, the statistical significance of these disease
associations when compared to appropriate control populations has been
disputed elsewhere [43-45]. Numerous case reports detail concordant presence
of AA with other autoimmune diseases, such as diabetes and myasthenia
gravis, although the statistical significance is unknown [8].
HLA genes
Human leukocyte antigen (HLA) genes on human chromosome 6 code for the
major histocompatibility complex (MHC) proteins that are important in
presentation of antigens and self recognition by immune cells. MHC class
I antigens comprise the HLA-B, HLA-C and HLA-A loci in this order. MHC
class II is coded by genes in the HLA-D region that is subdivided into
gene clusters HLA-DP, HLA-DQ, and HLA-DR [46]. MHC class I antigens are
expressed on almost all nucleated cells. CD8+ lymphocytes have
the capacity to recognize cellular antigens presented in association with
MHC class I via their T cell receptors. In contrast, MHC class
II antigens are normally expressed on antigen presenting cells (APCs),
such as macrophages and Langerhans' cells, and expression may be induced
on other nucleated cells during inflammatory processes such as AA [47,
48]. CD4+ lymphocytes may recognize antigen plus MHC class
II complexes on APCs. Different MHC proteins may have superior presenting
properties for particular antigens compared to other MHC complexes and
consequently some antigen plus MHC complexes will be more effective in
their activation of lymphocytes than others. In part, this may determine
the ability of lymphocytes to respond to the hair follicle antigen(s)
targeted in AA and may define how potent an immune response against a
particular antigen will be.
Genetic research into other autoimmune diseases has shown HLA encoding
alleles to segregate with specific disease phenotypes. However, inconsistent
results have been found with analysis of HLA class I haplotypes of the
A and B series and AA. Some studies report statistically significant associations,
but other studies found no HLA class I association [49, 50]. HLA-A2, B40
and Aw32, B18 have each been reported as associated with AA [30, 31].
Associations between HLA-B12 in Finnish patients, HLA-B18 in Israelis,
B13 and B27 in Russians have also been suggested [51-53].
Genetic analysis studies in AA have primarily focused on the HLA-D genes
(MHC class II encoding) as the most likely region for genes that regulate
susceptibility, severity of, or resistance to disease [54]. Consistent
associations have been observed between class II haplotypes and AA including
DR4 [54-58], DR5 [55-57], DR6 [58], DR7 [53] and broad antigen DQ3 [2,
59, 60]. More recent research has shown allele DRB1*1104 (DR11) to be
present with significant increased expression in patients with AA [2,
60] and this was confirmed in other studies [59, 61, 62]. Allele DRB1*0401
(DR4) was strongly associated with AA totalis or universalis sub-groups
[60]. DQB1*0301 (DQ7 by serology) was also significantly expressed only
in association with AA totalis and universalis [2, 60, 61]. Other studies
implicate other DQB1 alleles, DQB1*302, DQB1*601, and DQB1*603, in AA
[58]. The current consensus is that AA in humans has a genetic basis,
but is not always in a familial aggregation [2, 3].
It has been suggested that the HLA gene products, the MHC antigens,
could be important for the presentation of an unknown AA antigen. Aberrant
expression of MHC proteins within AA affected hair follicles is frequently
found, but the question of its true significance remains [47, 48]. There
are many more alleles that code for other factors within, and outside
of, the immune system that may be vital in the development of AA.
Non HLA genes
The HLA gene region is likely to be only one of several gene loci involved
in AA, but limited research has been conducted in other areas of the genome.
One investigation has shown an association between AA and allele 2 of
a 5 allele polymorphism for the IL-1rn gene on human chromosome 2 that
codes for the IL-1 receptor antagonist [63]. Results indicated allele
2 was present in 41% of controls versus 44% in individuals with patchy
AA, 66% of those with alopecia totalis and 77% of alopecia universalis
affected individuals [63]. Allele 2 is known to influence IL-1beta production.
Galbraith et al. identified the IL-1beta-1,2 genotype as significantly
increased in frequency for individuals with extensive, but not patchy,
AA further suggesting that the severe form of disease may be associated
with increased IL-1beta production [64].
Genes for immunoglobulin heavy (Gm) and light (Km) chain genotypes on
human Chromosome 14 have also been implicated in AA susceptibility [65,
66] with the suggestion that IL-1beta (IL-1beta-1,2) and light chain (KM-1,3)
genotypes may interact to increase AA susceptibility [64]. TNFalpha gene
polymorphisms, or adjacent genes in the HLA region may also influence
AA susceptibility [67, 68]. Involvement of all these gene loci, as susceptibility
or severity modifying genes, is consistent with an autoimmune pathogenesis
of AA.
Abbreviations
AA Alopecia areata
APC Antigen presenting cell
DEBR Dundee experimental bald rat
HLA Human leukocyte antigen
IL Interleukin
MHC Major histocompatibility complex
TGF Transforming growth factor
TNF Tumour necrosis factor
CONCLUSION
Rodent model research has shown that AA is an immune mediated disease
and strongly suggests that the mechanism is autoimmune in nature [1].
It is probable that AA susceptibility and severity modifying genes will
primarily be involved in the immune system, but other susceptibility genes
may control hair follicle function. From observation in humans and animal
models, AA can be described as a polygenic dominant disease with a variable
spectrum of severity of the phenotype.
While previous research studies have understandably focused on the HLA
region and identification of marker genes segregating with the AA phenotype,
there is a clear need for genome wide analysis to define further candidate
susceptibility, severity modifying, and possibly resistance gene loci.
Human population analysis suggests potential gene loci may be located
on chromosomes 2, 6, 14, and 21 [2, 33, 63, 65]. Careful categorization
of DNA samples based on phenotypic presentation of hair loss in the individual
will be important for defining sub-categories of AA. It might be possible
to define specific alleles with linkage disequilibrium in association
with to particular AA phenotypes such as patchy AA, AA totalis, or AA
universalis.
Both mouse and rat models of AA will play an important role in recognizing
candidate gene loci. Several rodent models have been identified, each
of which may represent separate or overlapping subsets of the AA phenotype.
Different rodent models may reveal susceptibility genes common to different
phenotype subsets and severity modifying genes unique to each phenotype
[69, 70]. Information about the possible location of rodent susceptibility
genes will provide human geneticists with clues as to where they may find
genes involved in AA [18, 19]. When the locations of these genetic factors
are known in man, rodent genetics will continue to be useful in the long
term goal of defining gene-gene and gene-environment interactions and
identifying candidate severity modifying genes.
Acknowledgements
This work was supported in part by an Ernst Schering Research Foundation
fellowship (KJM) and the Deutsche Forschungsgemeinschaft (Ho 1598/8-1,
PF-P).
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