Over the last three years, our Laboratory has been systematically defining pathogenetic mechanisms that are operative in the autoimmune cutaneous disease pemphigus. The animal model we have developed, employing passive transfer of human autoantibodies in neonatal mice, has allowed us to define these mechanisms in vivo. It is our intention to extend these studies to define the role of plasminogen activator in the production of Lesions in vivo, to examine the potential importance of other proteinase inhibitors of various specificities to inhibit acantholysis, and to examine the possible therapeutic effect of drugs that interfere with cell surface-cytoskeleton interactions and internalization. A long-term goal is to expand the current model and attempt to produce disease in these animals by immunization with antigen. This would allow us to examine many more aspects of this complex autoimmune disease such as immune regulation by idiotypic and anti-idiotypic networks. Bullous pemphigoid (BP) is another cutaneous blistering disease in which autoantibodies are present. We have recently shown that antibodies from BP patients bind specifically in the area of the cytoplasmic attachment plaque of the epidermal basal cell hemidesmosome. We propose a series of studies to define if there are distinct populations of autoantibodies that bind to intracellular and/or extracellular BP antigens, if the different populations of antibodies are complement fixing, and if extracellular antigen is present in skin only from certain areas of the body. Once these questions are answered, we will examine the pathogenicity of these defined autoantibodies in vivo in mice and in the rabbit cornea. It is also possible that factors that permeabilize the basal cell membrane such as trauma and UV light are necessary to initiate cutaneous lesions, and these autoantibodies can then bind the cytoplasmic antigen, activate complement and propagate the lesion. This series of studies will help us understand the pathophysiology of this complex blistering disease in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Modified Research Career Development Award (K04)
Project #
5K04AR001686-03
Application #
3071307
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1987-01-01
Project End
1991-12-31
Budget Start
1989-01-01
Budget End
1989-12-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Fullerton, S H; Woodley, D T; Smoller, B R et al. (1992) Paraneoplastic pemphigus with autoantibody deposition in bronchial epithelium after autologous bone marrow transplantation. JAMA 267:1500-2
Oursler, J R; Labib, R S; Ariss-Abdo, L et al. (1992) Human autoantibodies against desmoplakins in paraneoplastic pemphigus. J Clin Invest 89:1775-82
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Robledo, M A; Kim, S C; Korman, N J et al. (1990) Studies of the relationship of the 230-kD and 180-kD bullous pemphigoid antigens. J Invest Dermatol 94:793-7
Anhalt, G J (1990) Pemphigoid. Bullous and cicatricial. Dermatol Clin 8:701-16
Yokel, B K; Hood, A F; Anhalt, G J (1989) Induction of acantholysis in organ explant culture by penicillamine and captopril. Arch Dermatol 125:1367-70

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