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Identification of an Epitope within Human Integrin ₆ Subunit for the Binding of Autoantibody and Its Role in Basement Membrane Separation in Oral Pemphigoid¹

Khwaja Aftab Rashid^*, Joel N. H. Stern^* and A. Razzaque Ahmed^2,

^* Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115; and Center for Blistering Diseases, Department of Medicine, New England Baptist Hospital, Boston, MA 02120

Oral pemphigoid (OP) is a rare chronic autoimmune disease characterized by blisters and erosive lesions in the oral mucosa. We identified an epitope for the binding of OP autoantibodies within the integrin ₆ subunit, by cloning four overlapping fragments (A, B, C, and D). Immunoperoxidase studies demonstrated that all of the fragments were present in the oral mucosa. Sera of 20 patients with active OP were studied. All sera bound to integrin ₆ in DU145 cell lysate by immunoprecipitation and immunoblot assay. The same sera bound only to fragment A and its subfragment A2 on an immunoblot assay. The specificity of the binding was further characterized by blocking and cross-absorption studies. A 14-aa synthetic peptide A2.1, within fragment A2, bound to all the test sera. The sera in this study bound to only one epitope. Controls were sera samples from 10 healthy volunteers and 40 patients with other variants of mucous membrane pemphigoid and mAb GoH3 and BQ16 to integrin ₆. Control sera did not bind to the full-length integrin ₆ subunit nor any of the cloned fragments. The OP patient sera and immunoaffinity-purified OP sera, rabbit antisera against fragments A and A2, and mAb GoH3 produced basement membrane separation of oral mucosa in organ culture. This study identifies a peptide within the extracellular domain of integrin ₆ molecule, to which Abs in the sera from patients with OP bind, and which may play an important role in the pathogenesis of OP.