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The hemidesmosome is a cell surface-associated organelle that functions
in cell-matrix adhesion and is critical in maintaining epithelial tissue
organization. Work by our group and others have shown that genetic
defects and immunological reactions involving components of this junction
are the underlying causes of various human diseases associated with severe blistering of the skin.
One such disease, bullous pemphigoid,
is characterized by the production of autoantibodies directed against the hemidesmosome which leads to a detachment of the basal
epidermal cells from the basement membrane. Using autoantibodies obtained from the sera of patients as specific probes, our group cloned
and characterized a key bullous pemphigoid autoantigen, BP180, a novel transmembrane hemidesmosome-associated glycoprotein.
Detailed structural analyses revealed that the BP180 extracellular domain exists as a highly extended homotrimeric complex composed
of a series of articulated rod-like structures. The trimerization of this protein is likely to result from the formation of collagen-like triple
helical and coiled-coil type structures. The BP180 ectodomain is thought to interact with an extracellular matrix molecule, thereby
stabilizing the anchorage of basal keratinocytes to the basement membrane.
The pathogenic relevance of anti-BP180 antibodies was established through the use of an animal model system developed by Dr. Zhi Liu
from our research team. Neonatal mice injected with antibodies that react with a particular noncollagenous site on the extracellular domain
of BP180 were shown to develop an inflammatory blistering skin disease that closely mimics bullous pemphigoid. This model system has
provided us with a unique tool for dissecting the pathogenic mechanism of bullous pemphigoid.
We are currently employing a wide range of molecular genetic technologies aimed at elucidating the structure and function of BP180 and
other epidermal cell surface autoantigens. For example, wild type and mutant forms of BP180 have recently been introduced, via gene
transfer technology, into cultured mammalian cells and transgenic mice. The genetically manipulated cells will be assayed for alterations
in hemidesmosome assembly and cell-matrix attachment properties.
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"Molecular mapping of a pathogenically relevant BP180 epitope
associated with experimentally induced murine bullous pemphigoid",
Z. Liu, L.A. Diaz, S.J. Swartz, J.L. Troy, J.A. Fairley and
G.J. Giudice. J. Immunol., 155, 5449-5454 (1995).
"An animal model for bullous pemphigoid: What can it teach us?",
G.J. Giudice, Z. Liu and L.A. Diaz. Proceed. Assoc. Am. Phys., 107,
237-241 (1995).
"Characterization of a novel keratinocyte ubiquitin carrier protein",
Z. Liu, A.L. Haas, L.A. Diaz, C.A. Conrad and G.J. Giudice.
J. Biol. Chem., 271, 2817-2822 (1996).
"Bullous pemphigoid and cicatricial pemphigoid autoantibodies react
with ultrastructurally separable epitopes on the BP180 ectodomain:
Evidence that BP180 spans the lamina lucida", C. Bedane,
J.R. McMillan, S.D. Balding, P. Bernard, C. Prost, J-M. Bonnetblanc,
L.A. Diaz, R.A.J. Eady and G.J. Giudice. J. Invest. Dermatol., 108,
901-907 (1997).
"A recombinant form of the human BP180 ectodomain forms a
collagen-like homotrimeric complex", S.D. Balding, L.A. Diaz and
G.J. Giudice. Biochemistry, 36, 8821-8830 (1997).
"Tight clustering of extracellular BP180 epitopes recognized by bullous pemphigoid autoantibodies.", Zillikens, D., P.A. Rose, S.D. Balding, Z. Liu, M. Olague-Marchan, L.A. Diaz, and G.J. Giudice. J. Invest. Dermatol. 109:573-579 (1997).
"Identification and characterization of epitopes recognized by T lymphocytes and autoantibodies from patients with herpes gestationis.",
Lin, M-S., M.A. Gharia, S.J. Swartz, L.A. Diaz, and G.J. Giudice. J. Immunol. 162:4991-4997 (1999).
"BP180 gene delivery in junctional epidermolysis bullosa.",
Seitz, C.S., G.J. Giudice, S.D. Balding, M.P. Marinkovich, and P.A. Khavari. Gene Therapy 6:42-47, (1999).
"A critical role for neutrophil elastase in experimental bullous pemphigoid.",
Liu, Z., S.D. Shapiro, X. Zhou, S.S. Twining, R.M. Senior, G.J. Giudice, J.A. Fairley, and L.A. Diaz. J. Clin. Invest. 105: 113-123 (2000).
"The prevalence of antibodies against desmoglein 1 in endemic pemphigus foliaceus in Brazil.",
Warren S.J., M.S. Lin, G.J. Giudice, R.G. Hoffmann, G. Hans-Filho, V. Aoki, E.A. Rivitti, V. Santos, and L.A. Diaz. New Engl. J. Med. 343:23-30 (2000).
"A disease-associated glycine substitution in BP180 (type XVII collagen) leads to a local destabilization of the major collagen triple helix.",
Olague-Marchan, M., M.K. Hacker, L.A. Diaz and G.J. Giudice. Matrix Biol. 19:223-233 (2000).
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