AUTOIMMUNE BULLOUS DISEASES
Epidemiology and Immunogenetics of Autoimmune
Bullous Diseases
David Dasher1 and Luis A. Diaz1
1
Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
Correspondence: Luis A. Diaz, E-mail: luis_diaz@med.unc.edu
doi:10.1038/skinbio.2008.7
Most cases of autoimmune diseases
occur sporadically, without evidence
of geographic or familial clustering.
However, numerous exceptions to this
tendency have been uncovered that
may offer insight into potential triggers
to the autoimmune response. Schmidt
(1926) described the coincidence
of idiopathic hypothyroidism and
Addison’s disease in two patients, a
coincidence that has since been reported in over 100 patients now recognized
as
having
Schmidt’s
syndrome (autoimmune polyendocrine
syndrome, type 2). This observation
prompted others to seek out potential
genetic and/or environmental factors
that may predispose one individual to
develop multiple autoimmune diseases. Multiple additional diseases of
presumed autoimmune pathogenic
etiology have since been shown to
occur with increased frequency both
within individual patients and among
members of the same family.
Lilly et al. (1964) demonstrated a
genetic linkage between the murine
major transplantation (H-2) antigen
complex and viral leukemogenesis ,
stimulating other investigators to contemplate the role of histocompatibility
antigens in human disease. Given this
initial observation, early work predictably focused on HLA associations with
hematologic malignancy. However,
Grumet et al. (1971) observed an
increased frequency of histocompatibility antigens HL-A8 and W15 (LND)
in a group of 40 unrelated patients with
systemic lupus erythematosus , marking
the first observed HLA association with
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an autoimmune disease. Increased frequencies of certain genetically determined MHC antigens, especially HLA
class II antigens, have since been
observed in several autoimmune bullous disorders, including dermatitis
herpetiformis, pemphigus vulgaris
(PV), and endemic pemphigus foliaceus
(PF) (also known as fogo selvagem (FS)).
Additionally, the epidemiologic features of dermatitis herpetiformis, PV,
and FS are unique and have provided
investigators a valuable tool for eliciting potential pathogenetic mechanisms
of autoimmunity. This section emphasizes these features in these diseases.
Katz et al. (1972) noted an increased
prevalence of the same histocompatibility antigen associated with glutensensitive enteropathy (HL-A8) among
patients with dermatitis herpetiformis,
providing a genetic basis for the association between these two diseases. A
year later, Fry et al. (1973) reported
improvement in both the cutaneous
and gastrointestinal manifestations of
dermatitis herpetiformis in patients on a
gluten-free diet, marking the first instance where controlling exposure to
an environmental trigger was shown to
block the development of the clinical
manifestations of an autoimmune disease.
Despite an apparent lack of geographic or familial clustering of cases,
the immunogenetics of PV are unique.
Eller and Kest (1941) were the first to
report increased percentages of PV
among individuals of Jewish descent.
Krain et al. (1973) noted increased
frequency of HLA-A10 among nonre-
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lated Jewish patients with PV when
compared with Jewish controls as well
as non-Jewish patients and controls.
The same year, Katz et al. (1973)
reported an increased frequency of
HLA-A13 among PV patients. In more
recent years, extensive reports have
documented the strong association of
PV with HLA class II alleles HLA
DRB1*0402 and HLADQ*0503, with
over 95% of PV patients exhibiting one
or both alleles (Sinha et al., 1988;
Szafer et al., 1988). Recently, Brazilian
investigators have described an endemic form of PV in endemic areas of FS
(Rocha-Alvarez et al., 2007), suggesting that rare individuals exposed to
environmental desmoglein cross-reactive antigen(s) may develop FS or
endemic PV.
Fogo selvagem is a fascinating model of a human organ-specific autoimmune disease mediated by pathogenic
IgG autoantibodies where the immune
response is linked to an environmental
etiology. Unique epidemiological features of FS include geographic and
temporal clustering of cases, increased
incidence among young adults and
children, increased frequency of familial cases, and an association with
certain distinct HLA alleles such as
the DRB1*0102, 0404, 1402, or 1406
(RR:14; Moraes et al., 1997). HansFilho
et
al.
(1996)
reported an approximately 3% prevalence of disease in the Amerindian
reservation of Limao Verde, located
in the state of Mato Grosso do Sul,
Brazil. Intriguing subsequent seroepidemiological
observations
from
E31
Limao Verde, including the clinical and
serological conversion from normal-todisease state in several individuals,
suggest that the immune response in
FS patients likely arises from recurrent
and persistent antigenic exposure to an
as yet unknown environmental crossreactive antigen(s) harbored in endemic areas (Warren et al., 2000). Efforts
to uncover the specific environmental
trigger(s) are ongoing. Future studies
will be aimed at better understanding
of the interplay of genetic, environmental, and immunologic factors in the
pathogenesis of this disease.
CONFLICT OF INTEREST
The authors state no conflict of interest.
TO CITE THIS ARTICLE
Dasher D, Diaz LA (2008) Epidemiology and
immunogenetics of autoimmune bullous diseases.
J Invest Dermatol 128: E31–E32
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