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).