Autoreactive IgE in Bullous Pemphigoid
Bullous pemphigoid (BP) is an autoimmune blistering disease
characterized, in part, by the presence of IgG AAb directed against the
hemidesmosomal proteins BP180 (BP antigen 2 / type XVII collagen) and
BP230 (BP antigen 1). Autoantibodies can be found in the bloodstream,
affected tissues, and blister fluid. IgE autoreactivity in BP was first
suggested by Provost et al. in 1974112. The study
utilized immunofluorescence (IF) to discover that patients with BP can
exhibit IgE autoreactivity against the skin basement membrane zone
(BMZ), but the specific autoantigens were unknown at that
time112.
IgE AAb are held to contribute to the pathogenesis of BP by activating
skin mast cells and basophils, similar to CSU and AD. In addition, their
effects on FcεRI-expressing eosinophils accumulated in skin lesions seem
to be central in the pathophysiology of BP113 (Figure
4).
It was not until 1996 that BP230 was identified as the first IgE
autoallergen in BP using a recombinant 55-kDA protein (rBP55) obtained
from its cDNA sequence114. Two years later, BP180 was
also identified as an IgE autoallergen in BP after being
cloned115. With the rise and development of
technologies, such as enzyme-linked immunosorbent assay (ELISA) and
multi-allergen microarray (ISAC™ sIgE 112, Phadia), levels of IgE AAb
against BP180 and BP230 were reported by multiple independent research
groups at variable rates (Table 3). Anti-BP180 IgE positivity in BP
patients varied from 0% to 89% in 18 studies, and anti-BP230 IgE
varied from 22% to 76% in 7 studies112,114-135. This
heterogeneity in prevalence of anti-BP180/BP230 IgE in patients with BP
may be due to different patient populations and different detection
methods (ELISA, IF or protein microarray). The co-occurrence of IgG and
IgE AAb in the same patients, competing for the same antigen and
epitope, could also influence detection levels.
Currently, there is a lack of recombinant anti-BP180/230 IgE as positive
control and bona fide standard available for research purposes.
Six studies have evaluated anti-BP180 IgE and anti-BP230 IgE in the same
cohort of BP patients115,121,122,130,131,133.
Additionally, only one study has assessed IgE AAb against the
intracellular domain of BP180123, while 17 studies
have assessed IgE autoantibodies targeting the ectodomain (NC16A) of
BP180115,118-122,124,126-131. This highlights the need
for the development of standardized assays and research on autoallergen
epitope mapping. These efforts are crucial for gaining a comprehensive
understanding of the involvement of IgE AAb in BP pathogenesis.
The increased expression of cell-bound and soluble IgE receptors
including sFcεRI and sCD23 suggests that the regulation of IgE
production and the role of IgE AAb in the pathophysiology of BP are
complex113. The studies conducted so far report no
consistent relationship between IgE AAb levels and BP disease activity
(Table 3), although the majority of studies reported a positive
correlation with more severe clinical manifestations of BP. There is
insufficient evidence to support higher IgE autoantibody levels being
associated with specific clinical phenotypes of BP136.
This lack of consistency also extends to the association between IgE AAb
levels and total IgE levels, as well as the presence of IgG AAb against
the same target. Therefore, future studies should comprehensively
evaluate both IgE and IgG AAb levels, as well as changes in total IgE
and BP activity during the course of disease, to further elucidate the
role of IgE in BP pathogenesis and the potential of targeting IgE for
therapeutic purposes (see below).