Figure 2. Histology of the oral mucosal specimen, stained with hematoxylin and eosin.
a. Submucosal split with a sparse infiltrate,
analyzed at magnification ×20.
Autoantibodies, if present, will attach to structures within the
epithelium of the tissue. 6, 14 For MMP affecting only oral mucosa,
a lower incidence on indirect immunofluorescence has been shown. 1
The pathogenesis of MMP involves an autoimmune reaction to
hemidesmosomes in the basement membrane. It is characterized
by deposition of autoantibodies (usually IgG or IgA) and/or
complement at the basement membrane zone, resulting in
subepidermal blistering. 15 The autoantigen:autoantibody pair
differentiates between the types of pemphigoid disorders. 15
The pathogenicity of autoantibodies against specific antigens
has been well studied. 16, 17, 18 Hence, several target antigens have
been identified: bullous pemphigoid antigen (BPAg) 180, BPAg
230, epiligrin (laminin 5 or 332), both subunits of α6β4 integrin,
type VII collagen, laminin 311, and BPAg2. 1, 5, 6, 7, 17, 19
BPAg 180 and laminin 5 (332) are the most common
proteins targeted by the autoantibodies. 20 BPAg 180 is a
transmembrane hemidesmosomal protein consisting of 15
collagenous subdomains in the extracellular portion. 18 These
are located between a non-collagenous membrane-adjacent
domain referred to as NC16A and a carboxyl terminal domain
referred to as NC1. BPAg 180 plays an integral role in maintaining
adhesion of the epidermal-stromal region in the basement
membrane zone. Laminin 5 (332) plays a role in maintaining
epithelial cell anchorage to the underlying connective tissue. 18
It binds to α6β4 integrin, which has a vital role in hemidesmosome
formation. The subunit α6 is usually targeted in oral MMP, while
β4 is targeted in ocular MMP. 21 Autoantibodies to laminin 5
(332) can bind to three different subunits: α3, β3, and γ2. 18
Bernard et al 20 retrospectively evaluated the prevalence of
anti-laminin 5 (332) antibodies in patients with MMP using
an enzyme-linked immunosorbent assay.
b. Ulcer (denuded mucosa) with a sparse infiltrate and
rare eosinophils, analyzed at magnification ×10.
They found that 20 percent of patients were positive for
anti-laminin 332. 20 Other studies have shown a higher prevalence
(as high as 75 percent) and a correlation between higher titers
of anti-laminin 5/332 antibodies and disease severity. 18
When BPAg 180 is the target antigen, murine studies have shown
that subepidermal blisters occur because of an inflammatory
response. 22 The interaction between the autoantibody and
basement membrane protein triggers a complement-mediated
inflammatory response, resulting in a separation of the epithelial
layer from the connective tissue. The inflammatory cascade
leads to unrestrained activity of neutrophil elastase, which
weakens the basal keratinocyte adhesion at the basement
membrane zone. 15 Fibroblasts are also activated, and these
are responsible for scar formation. 6
While there is no specific trigger for MMP, medications have
been implicated, such as clonidine, furosemide, methyldopa,
and D-penicillamine. 1, 6 There is also a possible genetic association
between MMP and major histocompatibility complex (HLA)
class II DQB1*0301, DRB1*04, and DRB1*11. 5, 6, 23, 24 Interestingly,
oral and ocular MMP are associated with the HLA class II
DQB1*0301, which has been shown to have binding sites at
BPAg 180, BPAg 230, and both subunits of α6β4 integrin. 24
There is no cure for MMP. Symptoms are managed with topical,
intralesional, or systemic immunomodulating agents that alleviate
symptoms and control ulcer and scar formation. 6 Once a patient
is diagnosed with MMP, dermatology and ophthalmology
referrals are necessary to evaluate for mucosal involvement in
those regions. Otolaryngology and urology referrals may also
be considered. 6 Patients with oral involvement only have a
more benign course of the disease. 1, 5
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