Human Eosinophils Express the High Affinity IgE Receptor, FcεRI, in Bullous Pemphigoid

Abstract

Bullous pemphigoid (BP) is an autoimmune blistering disease mediated by autoantibodies targeting BP180 (type XVII collagen). Patient sera and tissues typically have IgG and IgE autoantibodies and elevated eosinophil numbers. Although the pathogenicity of the IgE autoantibodies is established in BP, their contribution to the disease process is not well understood. Our aims were two-fold: 1) To establish the clinical relationships between total and BP180-specific IgE, eosinophilia and other markers of disease activity; and 2) To determine if eosinophils from BP patients express the high affinity IgE receptor, FcεRI, as a potential mechanism of action for IgE in BP. Our analysis of 48 untreated BP patients revealed a correlation between BP180 IgG and both BP180 IgE and peripheral eosinophil count. Additionally, we established a correlation between total IgE concentration and both BP180 IgE levels and eosinophil count. When only sera from patients (n = 16) with total IgE≥400 IU/ml were analyzed, BP180 IgG levels correlated with disease severity, BP230 IgG, total circulating IgE and BP180 IgE. Finally, peripheral eosinophil count correlated more strongly with levels of BP180 IgE then with BP180 IgG. Next, eosinophil FcεRI expression was investigated in the blood and skin using several methods. Peripheral eosinophils from BP patients expressed mRNA for all three chains (α, β and γ) of the FcεRI. Surface expression of the FcεRIα was confirmed on both peripheral and tissue eosinophils from most BP patients by immunostaining. Furthermore, using a proximity ligation assay, interaction of the α- and β-chains of the FcεRI was observed in some biopsy specimens, suggesting tissue expression of the trimeric receptor form in some patients. These studies provide clinical support for the relevance of IgE in BP disease and provide one mechanism of action of these antibodies, via binding to the FcεRI on eosinophils.

Mechanisms of Disease: Pemphigus and Bullous Pemphigoid

“…Histological studies have positioned mast cell activation upstream of that of eosinophils by showing that the latter are attracted to the site of mast cell degranulation (144). Like mast cells and basophils, eosinophils were recently shown to express the high-affinity IgE receptor FcεRI, which provides an explanation of how eosinophils may be activated in BP—namely by binding anti-BP180 IgE that is crosslinked by BP180 or its degradation products (143, 145). …”

IgE-mediated mechanisms in bullous pemphigoid and other autoimmune bullous diseases

“…[76] In this line, Messingham et al recently identified FcεRI on peripheral blood and skin eosinophils. [77] Tanaka et al found FcεRI expression in 70% of the eosinophils in lesional BP skin. [76] Binding of anti-BP180 NC16A IgE on these eosinophils might result in eosinophil degranulation or may trigger mast cell degranulation, which has been suggested to be in a piecemeal degranulation pattern [78,79] and therefore might contribute to blister development.…”

Eosinophil localization to the basement membrane zone is autoantibody‐ and complement‐dependent in a human cryosection model of bullous pemphigoid

“…The early phase of lesion development, including urticaria, eosinophil infiltration and spontaneous blistering, were only observed in models utilizing IgE autoantibodies from patient sera or monocolonal IgE antibodies specific for BP180 . Interestingly, circulating eosinophil numbers correlate with levels of both NC16A‐specific IgG and IgE in BP sera , but it is unknown if these autoantibodies directly influence lesional eosinophils.…”