This application is a competitive continuation of the grant """"""""Pemphigus and Pemphigoid"""""""" seeking support for studies on the immunopathology of these diseases. Projects accomplished in the previous funding period include the following: In Pemphigus Vulgaris (PV) and Pemphigus Foliaceus (PF), a) we have fully defined the animal models of PV and PF. Using these models we have demonstrated the minimal role of b) plasminogen activator and c) complement activation in the pathogenesis of acantholysis; d) we have demonstrated the pathogenic nature of PF IgG4 autoantibodies and PF Fab' fragments in PF. e) We have characterized proteolytic fragments from human epidermis which react specifically with PF and PV autoantibodies. In Bullous Pemphigoid (BP) we have demonstrated that: f) BP autoantibodies recognize hemidesmosomal antigens. g) the sera of BP patients react with two """"""""major"""""""" BP antigens (240 kD and 180 kD) nad other lower m.w. """"""""minor"""""""" BP antigens; and h) herpes gestationis sera react with the 180 kD BP antigen. i) We have recently identified two cDNA clones from a keratinocyte cDNA library corresponding to the two major BP antigens (180 and 240 kD). Analyses of the cDNA-encoded fusion proteins showed that the 180 and 240 kD BP antigens are indeed distinct hemidesmosomal polypeptides. Sequence analysis has revealed that the 180 kD BP antigen contains a collagen-like domain which is a potential basement membrane binding site. Autoantibody- mediated disruption of such an interaction may be relevant to blister formation in BP patients. The present application includes studies designed to continue and advance the knowledge in immunopathogenesis of PV, PF and BP. This will be accomplished by defining at the molecular level: a) the epitopes recognized by the respective autoantibodies, b) the nature and relationship of the """"""""minor"""""""" and """"""""major"""""""" BP antigens, c) the IgG subclass of the IgG autoantibody systems present int he sera of these patients, d) the mechanisms by which Fab' from PV and PF autoantibodies cause acantholysis by impairing the adhesive function of its antigen), and e) by developing the animal model of BP based on the results of epitope mapping studies. We are confident that we have the expertise and the laboratory facilities to continue our success in advancing our understanding of the immunopathology of these diseases. The data generated will be novel and relevant.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AR032081-18
Application #
6029935
Study Section
Special Emphasis Panel (NSS)
Program Officer
Moshell, Alan N
Project Start
1988-07-01
Project End
1999-12-31
Budget Start
1999-07-01
Budget End
1999-12-31
Support Year
18
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Dermatology
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Lin, Lan; Betsuyaku, Tomoko; Heimbach, Lisa et al. (2012) Neutrophil elastase cleaves the murine hemidesmosomal protein BP180/type XVII collagen and generates degradation products that modulate experimental bullous pemphigoid. Matrix Biol 31:38-44
Heimbach, Lisa; Li, Zhuowei; Berkowitz, Paula et al. (2011) The C5a receptor on mast cells is critical for the autoimmune skin-blistering disease bullous pemphigoid. J Biol Chem 286:15003-9
Lin, Lan; Bankaitis, Eric; Heimbach, Lisa et al. (2011) Dual targets for mouse mast cell protease-4 in mediating tissue damage in experimental bullous pemphigoid. J Biol Chem 286:37358-67
Heimbach, L; Li, N; Diaz, A et al. (2009) Experimental animal models of bullous pemphigoid. G Ital Dermatol Venereol 144:423-31
Liu, Zhi; Sui, Wen; Zhao, Minglang et al. (2008) Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model. J Autoimmun 31:331-8
Lessey, Elizabeth; Li, Ning; Diaz, Luis et al. (2008) Complement and cutaneous autoimmune blistering diseases. Immunol Res 41:223-32
Leighty, Lisa; Li, Ning; Diaz, Luis A et al. (2007) Experimental models for the autoimmune and inflammatory blistering disease, Bullous pemphigoid. Arch Dermatol Res 299:417-22
Liu, Zhi; Li, Ning; Diaz, Luis A (2006) Inhibition of pemphigus vulgaris by targeting of the CD40-CD154 co-stimulatory pathway: a step toward antigen-specific therapy? J Invest Dermatol 126:11-3
Liu, Zhi; Zhao, Minglang; Li, Ning et al. (2006) Differential roles for beta2 integrins in experimental autoimmune bullous pemphigoid. Blood 107:1063-9
Zhao, Minglang; Trimbeger, Mary E; Li, Ning et al. (2006) Role of FcRs in animal model of autoimmune bullous pemphigoid. J Immunol 177:3398-405

Showing the most recent 10 out of 56 publications