Unraveling the significance of IgE autoantibodies in organ-specific autoimmunity: lessons learned from bullous pemphigoi
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IMMUNOLOGY AT THE UNIVERSITY OF IOWA
Unraveling the significance of IgE autoantibodies in organ-specific autoimmunity: lessons learned from bullous pemphigoid K. A. N. Messingham • H. M. Holahan • J. A. Fairley
Ó Springer Science+Business Media New York 2014 J. A. Fairley
Abstract Bullous pemphigoid (BP), a cutaneous autoimmune blistering disease, has provided a useful model to elucidate a role for IgE in autoimmunity. IgE antibodies specific for the BP180 autoantigen are detected in sera and biopsy samples from the majority of BP patients. In BP biopsies, both IgE and BP180 antigen localize to the surface of mast cells, and incubation of circulating basophils from these patients with BP180 protein triggered degranulation. The in vivo pathogenicity of BP180-specific IgE was confirmed in mouse models, where injection of purified BP IgE into human skin grafted onto nu/nu mice replicated the early phase of lesion development, including mast cell degranulation, eosinophil infiltration and development of urticarial plaques. In addition, IgE antibodies from patient sera bind to BP180 on basal keratinocytes, resulting in internalization of BP180, production of inflammatory cytokines, IL-6 and IL-8, and a decrease in the number of hemidesmosomes at the basement membrane zone. These findings have led to therapeutic trials of the anti-IgE monoclonal antibody omalizumab in BP, resulting in substantial improvement in the patients’ disease. Overall, the work in BP provides the first evidence for a pathogenic role for IgE in autoimmunity. Keywords
IgE Autoantibody Bullous Pemphigoid BP180 Type XVII collagen
Introduction IgE is best known for its role in parasitic immunity and type I hypersensitivity responses, including asthma, allergy, some types of chronic urticaria and atopic dermatitis [1, 2]. Recently, a role for IgE in the regulation of immunity and development of autoimmune disease has been proposed [3]. IgE autoantibodies were reported several decades ago [4, 5] and, since then, have been documented in an ever-increasing number of autoimmune diseases. IgE autoantibodies are present in anti-SSA-positive women who experience fetal loss, in patients with K. A. N. Messingham H. M. Holahan J. A. Fairley (&) Department of Dermatology, University of Iowa College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA e-mail: [email protected] J. A. Fairley Department of Dermatology, VA Medical Center, Iowa City, IA, USA
Graves’ disease, targeting thyroid peroxidase in Hashimoto’s thyroiditis, and targeting myelin peptides in patients with multiple sclerosis [6–9]. Furthermore, IgE-targeting dsDNA has been linked with disease activity and the presence of nephritis in lupus patients [10]. Despite these observations, relatively little is known about the pathogenicity of IgE in these diseases. In contrast, we and others have established a critical role for IgE autoantibodies in the pathogenesis of bullous pemphigoid (BP), an autoimmune blistering disease affecting the skin. BP predominantly affects patien
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