Abstract
Bullous pemphigoid (BP) is an autoimmune blistering disease which carries a significant mortality and morbidity. While historically BP has been characterized as an IgG driven disease mediated by anti-BP180 and BP230 IgG autoantibodies, developments in recent years have further elucidated the role of eosinophils and IgE autoantibodies. In fact, eosinophil infiltration and eosinophilic spongiosis are prominent features in BP. Several observations support a pathogenic role of eosinophils in BP: IL-5, eotaxin, and eosinophil-colony stimulating factor are present in blister fluid; eosinophils line the dermo-epidermal junction (DEJ) in the presence of BP serum, metalloprotease-9 is released by eosinophils at the site of blisters; eosinophil degranulation proteins are found on the affected basement membrane zone as well as in serum corresponding with clinical disease; eosinophil extracellular DNA traps directed against the basement membrane zone are present, IL-5 activated eosinophils cause separation of the DEJ in the presence of BP serum; and eosinophils are the necessary cell required to drive anti-BP180 IgE mediated skin blistering. Still, it is likely that eosinophils contribute to the pathogenesis of BP in numerous other ways that have yet to be explored based on the known biology of eosinophils. We herein will review the role of eosinophils in BP and provide a framework for understanding eosinophil pathogenic mechanisms in mucocutaneous disease.
Highlights
TO BULLOUS PEMPHIGOIDClinical Presentation of Bullous PemphigoidBullous pemphigoid (BP) is the most common autoimmune blistering disease with an estimated annual incidence between 2 and 22 new cases per million people [1,2,3,4,5,6,7,8]
We have demonstrated that major basic protein (MBP) has a concentration dependent cytotoxic effect on cultured keratinocytes [96]
While we demonstrated a cytotoxic effect of degranulation proteins on keratinocytes at physiologic doses seen in BP [96], it is unclear the extent of damage in vivo as necrosis is not a histologic feature of BP
Summary
Eosinophils are effector cells found in various organs including the skin. Their impact on biological processes is likely mediated primarily by their cytoplasmic granules. Eotaxin and MCP-4 are two chemokines that play a significant role in the selective recruitment of Th2 effector cells, and eosinophils to the inflammatory site of BP, both of which are present at elevated levels in tissue and blister fluid [79, 122, 192]. Autoantibodies to BP180 mediate the release of IL-8 from human keratinocytes in a dose and time dependent manner [42, 195] This cytokine is known to be elevated in sera and blister of BP patients with significantly higher levels of IL-8 in blister fluid as compared to serum [42, 194, 196]. Epidermal expression of eotaxin appears to be a consistent feature among all eosinophilic dermatoses [193]
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