Deposition of eosinophil granule proteins precedes blister formation in bullous pemphigoid. Comparison with neutrophil and mast cell granule proteins

Abstract

Eosinophils, neutrophils, and mast cells have all been implicated in the pathogenesis of bullous pemphigoid (BP). To comparatively characterize the involvement of these cells in BP, 10 lesional skin biopsy specimens were identified retrospectively and studied for tissue localization of eosinophil, neutrophil, and mast cell granule proteins. Subsequently, multiple skin biopsies of lesions in various developmental stages were obtained from 3 patients with untreated BP. Involved and uninvolved skin specimens were also obtained from 2 patients. Using indirect immunofluorescence, retrospectively identified lesions showed eosinophils and extracellular granule protein deposition prominently in areas of blistering. Evolving lesions showed eosinophil granule protein deposition in all stages but was most marked in early erythematous and prebullous (urticarial) lesions and was minimal in uninvolved skin. Vascular cell adhesion molecule-1, E-selectin, and P-selectin were detected on vessels and very late activation antigen-4 was detected on mononuclear cells and eosinophils by immunoperoxidase staining of lesions. Eosinophil granule proteins were increased in the peripheral blood, urine, and blister fluid. Blister fluids caused increased eosinophil survival that was inhibited by antibodies to interleukin-5 and interleukin-3. Although neutrophil and mast cell infiltration was observed, extracellular granule protein deposition from these cells was minimal except in two specimens. These results demonstrate that eosinophils infiltrate and deposit granule proteins early in the development of BP lesions, that eosinophil-activating cytokines are present in blister fluid, and that eosinophil-selective adhesion molecules are present. These studies strongly support a role for eosinophils in blister formation in BP.