Z Liu

University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

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Publications (23)184.76 Total impact

  • Z Liu, L A Diaz
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    ABSTRACT: Bullous pemphigoid (BP) was first described by Lever in 1953 as a subepidermal blistering disease. Immunohistological features of BP include dermal-epidermal junction separation with an inflammatory cell infiltrate in the upper dermis, and autoantibodies in patients' circulation and bound to the basement membrane zone (BMZ). These autoantibodies show a linear staining at the dermal-epidermal junction (DEJ) and recognize two major hemidesmosomal proteins, the BP230 (BPAG1) and BP180 (BPAG2). An IgG passive transfer mouse model of BP was developed, that recapitulates the key features of human BP. Using this in vivo model system, key cellular and molecular events leading to BP disease phenotype are identified, including IgG binding to its target, complement activation, mast cell degranulation, neutrophil infiltration and activation. Proteinases and reactive oxygen species released by neutrophils work together to damage BMZ, causing DEJ separation. T cells from BP patients show a specific proliferative response to recombinant BP180 NC16A. These NC16A-responding T lymphocytes express alpha/beta T cell receptors and CD4 memory T cell surface markers and exhibited a Th1/Th2 mixed cytokine profile. After almost a half-century of studies, we have learned a great deal about IgG-mediated tissue injury and begin to understand the autoimmune responses leading to pathogenic IgG production in BP.
    The Journal of Dermatology 12/2001; 28(11):647-50. · 1.77 Impact Factor
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    ABSTRACT: Bullous pemphigoid (BP) is an inflammatory subepidermal blistering disease associated with an IgG autoimmune response to the hemidesmosomal protein BP180. Passive transfer of antibodies to the murine BP180 (mBP180) ectodomain triggers a blistering skin disease in mice that depends on complement activation and neutrophil infiltration and closely mimics human BP. In the present study, we show that mast cells (MCs) play a crucial role in experimental BP. Wild-type mice injected intradermally with pathogenic anti-mBP180 IgG exhibited extensive MC degranulation in skin, which preceded neutrophil infiltration and subsequent subepidermal blistering. In contrast, mice genetically deficient in MCs or MC-sufficient mice pretreated with an inhibitor of MC degranulation failed to develop BP. Further, MC-deficient mice reconstituted in skin with MCs became susceptible to experimental BP. Despite the activation of complement to yield C3a and C5a, in the absence of MCs, accumulation of neutrophils at the injection site was blunted. The lack of response due to MC deficiency was overcome by intradermal administration of a neutrophil chemoattractant, IL-8, or by reconstitution of the injection sites with neutrophils. These findings provide the first direct evidence to our knowledge that MCs play an essential role in neutrophil recruitment during subepidermal blister formation in experimental BP.
    Journal of Clinical Investigation 11/2001; 108(8):1151-8. · 12.81 Impact Factor
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    ABSTRACT: We have identified the key protein substrate of gelatinase B/MMP-9 (GB) that is cleaved in vivo during dermal-epidermal separation triggered by antibodies to the hemidesmosomal protein BP180 (collagen XVII, BPAG2). Mice deficient in either GB or neutrophil elastase (NE) are resistant to blister formation in response to these antibodies in a mouse model of the autoimmune disease bullous pemphigoid. Disease develops upon complementation of GB -/- mice with NE -/- neutrophils or NE -/- mice with GB -/- neutrophils. Only NE degrades BP180 and produces dermal-epidermal separation in vivo and in culture. Instead, GB acts upstream to regulates NE activity by inactivating alpha1-proteinase inhibitor (alpha1-PI). Excess NE produces lesions in GB -/- mice without cleaving alpha1-PI. Excess alpha1-PI phenocopies GB and NE deficiency in wild-type mice.
    Cell 10/2000; 102(5):647-55. · 31.96 Impact Factor
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    ABSTRACT: Bullous pemphigoid (BP) is an autoimmune skin disease characterized by subepidermal blisters and autoantibodies against 2 hemidesmosome-associated proteins, BP180 and BP230. The immunopathologic features of BP can be reproduced in mice by passive transfer of anti-BP180 antibodies. Lesion formation in this animal model depends upon complement activation and neutrophil recruitment. In the present study, we investigated the role of neutrophil elastase (NE) in antibody-induced blister formation in experimental BP. Abnormally high levels of caseinolytic activity, consistent with NE, were detected in extracts of lesional skin and blister fluid of mice injected with anti-BP180 IgG. The pathogenic anti-BP180 IgG failed to induce subepidermal blistering in NE-null (NE(-/-)) mutant mice. NE(-/-) mice reconstituted with neutrophils from wild-type mice became susceptible to experimental BP. Wild-type mice given NE inhibitors (alpha1-proteinase inhibitor and Me-O-Suc-Ala-Ala-Pro-Val-CH(2)Cl), but not mice given cathepsin G/chymase inhibitors (alpha1-antichymotrypsin or Z-Gly-Leu-Phe-CH(2)Cl), were resistant to the pathogenic activity of anti-BP180 antibodies. Incubation of murine skin with NE induced BP-like epidermal-dermal detachment. Finally, NE cleaved BP180 in vitro and in vivo. These results implicate NE directly in the dermal-epidermal cleavage induced by anti-BP180 antibodies in the experimental BP model.
    Journal of Clinical Investigation 02/2000; 105(1):113-23. · 12.81 Impact Factor
  • Chest 08/1999; 116(1 Suppl):17S-18S. · 5.85 Impact Factor
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    ABSTRACT: Polymorphonuclear leukocytes (PMN) release gelatinase B in response to variable stimuli. Gelatinase B degrades basement membrane components in vitro, and inhibition of matrix metalloproteinase activity blunts PMN migration through a prototype basement membrane (Matrigel) and amnionic membranes. Accordingly, it has been speculated that gelatinase B is necessary for PMN emigration. To test this hypothesis we induced acute inflammation in the lungs, peritoneum, and skin in mice with a null mutation of the gelatinase B gene (gelatinase B-/-) and littermate controls (gelatinase B+/+). At 3, 6, 12, and 24 h after intratracheal instillation of LPS, the emigration of PMN in the lung, as determined by PMN in bronchoalveolar lavage fluid, was similar in gelatinase B-/- and gelatinase B+/+ mice. The number of PMN in the peritoneal cavity 4 h after thioglycollate-induced peritonitis was also comparable in gelatinase B-/- and gelatinase B+/+ mice. At 4 h after an intradermal injection of interleukin-8, numerous PMN were present extravascularly in the dermis in both gelatinase B-/- and gelatinase B+/+ mice and the myeloperoxidase activities of the skin at the injection sites were indistinguishable between the two types of mice. PMN from gelatinase B-/- mice migrated through Matrigel in response to zymosan-activated serum with the same efficiency as did PMN from gelatinase B+/+ mice. In vitro, gelatinase B-/- PMN killed Staphylococcus aureus and Klebsiella pneumoniae as effectively as did PMN from gelatinase B+/+ mice. These findings indicate that gelatinase B is not required for PMN emigration, and suggest that the antibacterial function of PMN is preserved despite gelatinase B deficiency.
    American Journal of Respiratory Cell and Molecular Biology 07/1999; 20(6):1303-9. · 4.15 Impact Factor
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    ABSTRACT: Pemphigus vulgaris and pemphigus foliaceus are two closely related, but clinically and histologically distinct, autoimmune skin diseases. The autoantigens for pemphigus vulgaris and pemphigus foliaceus are desmoglein 3 and desmoglein 1, respectively. The anti-desmoglein 1 antibodies in pemphigus foliaceus and anti-desmoglein 3 antibodies in pemphigus vulgaris are pathogenic as determined by immunoglobulin G passive transfer animal models. More than 50% of pemphigus vulgaris sera also contain anti-desmoglein 1 autoantibodies; however, the pathogenicity of the anti-desmoglein 1 autoantibodies in pemphigus vulgaris remains unknown. In this study, we used soluble recombinant extracellular domains of desmoglein 1 and desmoglein 3 to obtain affinity-purified anti-desmoglein 1 and anti-desmoglein 3 autoantibodies from pemphigus vulgaris sera and examined the pathogenicity of each fraction separately using the passive transfer mouse model. By immunoprecipitation, the purified anti-desmoglein 1 and anti-desmoglein 3 showed no cross-reactivity. The anti-desmoglein 1 autoantibodies in pemphigus vulgaris induced typical pemphigus foliaceus lesions in neonatal mice, whereas the anti-desmoglein 3 fraction induced pemphigus vulgaris-like lesions. In addition, the pathogenic anti-desmoglein 1 and anti-desmoglein 3 autoantibodies in pemphigus vulgaris had predominant IgG4 subclass specificity. These findings suggest that the anti-desmoglein 1 antibodies in pemphigus vulgaris are pathogenic.
    Journal of Investigative Dermatology 06/1999; 112(5):739-43. · 6.19 Impact Factor
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    ABSTRACT: Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease characterized by deposition of autoantibodies at the basement membrane zone. In an experimental BP model in mice, the subepidermal blistering is mediated by antibodies directed against the hemidesmosomal protein BP180 (collagen XVII, BPAG2), and depends on complement activation and neutrophil infiltration. Gelatinase B is present in BP blister fluid and can cleave BP180. In this study we investigated the role of gelatinase B in the immunopathogenesis of experimental BP using mice containing targeted disruption of the gelatinase B (MMP-9, 92 kD gelatinase) gene. Gelatinase B-deficient mice were resistant to the blistering effect of intracutaneous anti-mBP180 antibodies, although these mice showed deposition of autoantibodies at the basement membrane zone and neutrophil recruitment to the skin comparable to that observed in the control mice. Interleukin 8 given intradermally concomitantly with pathogenic anti-mBP180 elicited a significant neutrophil recruitment into the skin in gelatinase B-deficient mice, but blistering did not occur. However, gelatinase B-deficient mice reconstituted with neutrophils from normal mice developed blistering in response to anti-mBP180 antibodies. These results implicate neutrophil-derived gelatinase B in the pathogenesis of experimental BP and might lead to novel therapeutic strategies for BP.
    Journal of Experimental Medicine 09/1998; 188(3):475-82. · 13.21 Impact Factor
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    ABSTRACT: The BP180 antigen, a component of the epidermal anchoring complex, has been identified as one of the major antigenic targets of autoantibodies associated with the blistering skin disease, bullous pemphigoid. Our research group has recently demonstrated that reactivity of bullous pemphigoid autoantibodies to the BP180 ectodomain is almost entirely restricted to a set of four antigenic sites clustered within the membrane-proximal noncollagenous stretch (NC16A). Using a passive transfer mouse model, antibodies to the corresponding noncollagenous region of murine BP180 were shown to trigger an inflammatory subepidermal blistering disease that closely mimics bullous pemphigoid. We now report the development of an enzyme-linked immunoabsorbent assay system that is extremely sensitive in detecting disease-specific autoantibodies in the sera of bullous pemphigoid patients. The target antigen in this assay is a recombinant form of the BP180 NC16A domain that contains all four of the well-defined bullous pemphigoid-associated antigenic sites. Of 50 randomly selected bullous pemphigoid sera tested, 47 (94%) were positive in this assay, whereas no specific reactivity was detected in any of the 107 controls. Interestingly, all three of the bullous pemphigoid sera that were negative in this assay had been obtained from patients who were already undergoing treatment. The NC16A enzyme-linked immunosorbent assay is more sensitive than any of the standard techniques for detecting circulating bullous pemphigoid autoantibodies, including other enzyme-linked immunosorbent assays, immunoblotting, and indirect immunofluorescence. Finally, the NC16A enzyme-linked immunosorbent assay provides immunologic information that cannot be obtained from direct immunofluorescence studies of skin biopsies, and that may well be relevant in the diagnosis and treatment of bullous pemphigoid.
    Journal of Investigative Dermatology 12/1997; 109(5):679-83. · 6.19 Impact Factor
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    ABSTRACT: Bullous pemphigoid is a blistering skin disease associated with autoantibodies against the BP180 antigen, a transmembrane component of the hemidesmosome. Anti-BP180 antibodies have been demonstrated to be pathogenic in a passive transfer mouse model. One extracellular site on human BP180 (MCW-1) was previously shown to be recognized by 50-60% of bullous pemphigoid sera. To facilitate the identification of additional autoantibody-reactive epitopes, recombinant forms of the BP180 ectodomain were generated using both bacterial and mammalian expression systems. One recombinant protein, sec180e, that was expressed in COS-1 cells and that contained the entire BP180 ectodomain, provided us with a tool to detect conformational epitopes. Bullous pemphigoid sera immunoadsorbed against the major noncollagenous NC16A domain no longer reacted with sec180e, indicating that autoantibody reactivity to the BP180 ectodomain is restricted to the NC16A region. Immunoblot analysis of bullous pemphigoid sera immunoadsorbed with a series of recombinant NC16A peptides revealed the presence of three novel autoantigenic sites that, along with the MCW-1 epitope, are clustered within the N-terminal 45 amino acid stretch of NC16A. All 15 bullous pemphigoid sera tested reacted with a recombinant protein containing this BP180 segment. No disease-associated epitopes were detectable within the remaining 28 amino acids of NC16A. Thus, bullous pemphigoid patient autoantibodies react with a set of epitopes on the BP180 ectodomain that are highly clustered. This autoantibody-reactive region on human BP180 shows overlap with the corresponding murine BP180 site that is targeted by antibodies that are pathogenic in the mouse model of bullous pemphigoid. These findings suggest new directions for the development of diagnostic and therapeutic tools for this disease.
    Journal of Investigative Dermatology 11/1997; 109(4):573-9. · 6.19 Impact Factor
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    ABSTRACT: Pemphigus vulgaris (PV) is a dermatosis mediated by autoantibodies against desmoglein 3 (Dsg3). It was known that intraperitoneal (i.p.) injections of PV IgG and PV F(ab')2, but not of PV Fab, into neonatal mice reproduced the key features of the disease in these animals. It was proposed that crosslinking of antigen by bivalent PV autoantibodies may trigger acantholysis in PV. In the present study, we have used subcutaneous (s.c.) injections of PV IgG and its proteolytic fragments into neonatal mice to test equimolar amounts of these autoantibody fractions. Mice developed clinical and histological features of PV in a dose-dependent manner following a similar time course. PV IgG and Fab fractions induced acantholysis as early as 2 hr after the injection. It was also demonstrated that sc injections of PV Fab were more effective in inducing disease than ip injections. PV autoantibodies may bind an "adhesive site" of Dsg3 and impair its function, thus triggering acantholysis.
    Clinical Immunology and Immunopathology 11/1997; 85(1):90-6.
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    ABSTRACT: Bullous pemphigoid (BP) is an inflammatory subepidermal blistering disease associated with an IgG autoimmune response to the hemidesmosomal protein, BP180. Using a passive transfer mouse model, our group has shown previously that antibodies to the murine BP180 (mBP180) ectodomain are capable of triggering a blistering skin disease that closely mimics human BP. In this study, we investigated the role of neutrophils in the immunopathogenesis of this disease model. BALB/c mice depleted of circulating neutrophils by treatment with neutrophil-specific antibodies were no longer susceptible to the pathogenic effects of anti-mBP180 IgG. IgG and complement were deposited at the dermal-epidermal junction of these animals, but there was no evidence of inflammatory infiltration or blistering. C5-deficient mice, which are resistant to the pathogenic activity of anti-mBP180 IgG, could be made susceptible to this IgG-mediated blistering disease by intradermal administration of a neutrophil chemoattractant, IL-8 or C5a. Intraperitoneal injection of IL-8, which sequesters neutrophils in the peritoneal cavity, interferes with anti-mBP180-induced neutrophilic infiltration of the skin and prevented the development of BP disease in BALB/c mice. These findings provide the first direct evidence that neutrophils recruited to the skin via a C5-dependent pathway play an essential role in subepidermal blister formation in experimental BP, and suggest new directions for disease intervention.
    Journal of Clinical Investigation 10/1997; 100(5):1256-63. · 12.81 Impact Factor
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    ABSTRACT: Recent understanding of the mechanism of immunoglobulin G (IgG) catabolism has yielded new insight into antibody-mediated diseases. We proposed that beta2-microglobulin (beta2m)-deficient mice have been protected from systemic lupus erythematosis (SLE)-like syndromes because they lack the beta2m-associated IgG protection receptor (FcRn) and therefore catabolize IgG, including pathogenic IgG autoantibodies, considerably more rapidly than normal mice. Such an hypothesis would predict that beta2m-deficient mice would also be resistant to experimental bullous pemphigoid, a disease with a pathogenesis thought to be much simpler than SLE, being the result of antibody directed toward a pathogenic epitope on the epidermal hemidesmosome that anchors basal keratinocytes to the basement membrane. To test this hypothesis, we administered pathogenic rabbit antibody directed toward the hemidesmosome to beta2m-deficient mice and to normal control mice, both intraperitoneally and intradermally, and assessed the mice clinically, histologically, and immunologically for manifestations of skin disease. We found that the beta2m-deficient mice were protected when the antibody was given intraperitoneally whereas intradermal administration resulted in blisters only slightly less severe than those seen in normal mice. These data would indicate that autoantibody-mediated inflammation might be prevented or controlled by appropriate modulation of FcRn function.
    Journal of Experimental Medicine 09/1997; 186(5):777-83. · 13.21 Impact Factor
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    ABSTRACT: Epidermal blister formation is the hallmark of three cutaneous autoimmune diseases: pemphigus foliaceous (PF), pemphigus vulgaris (PV) and bullous pemphigoid (BP). In PF and PV, blistering is due to acantholysis (cell-cell detachment) in the subcorneal and suprabasal epidermal layers, respectively, while BP is characterized by detachment of the basal epidermal cells from the underlying dermis. For several years, we have focused our research efforts on elucidating the pathogenic mechanisms operating in these bullous diseases. Early studies performed by our research group and others revealed that in all three diseases, the patients produce autoantibodies that bind to target antigens located on the surface of cells that are undergoing detachment. Thus it was hypothesized that these anti-epidermal autoantibodies played a role in initiating blister formation. We recognized that elucidating the normal mechanisms of epidermal cell-cell and cell-dermis adhesion would help us understand the abnormal epidermal cell detachment seen in these patients. We hypothesized that under normal conditions these adhesive mechanisms in the epidermis are complex and dynamic and mediated by the interaction of cell surface molecules unique to each layer of the epidermis. Also, we postulated that PV, PF and BP autoantibodies may cause cell detachment by impairing the function of their respective epidermal cell surfaces. Support for this hypothesis has come from recent studies which showed that PV and PF autoantibodies recognize distinct, yet related, desmosomal glycoproteins in the cadherin family of calcium-dependent adhesion molecules. The epidermal antigen in PV is desmoglein-3 (dsg3), while in PF it is desmoglein-1 (dsg1). These anti-epidermal autoantibodies have been shown to be pathogenic in passive transfer experiments. Neonatal mice injected with these antibodies develop intraepidermal blisters characteristic of the corresponding human disease. Autoantibodies in BP react with BP180 and BP230, two major components of the hemidesmosome, a cell structure involved in dermal-epidermal adhesion. Recent passive transfer mouse model studies performed in our laboratory have shown that anti-BP180 antibodies can induce subepidermal blistering in the experimental animals. Moreover, the pathogenic mechanism was shown to be dependent on complement activation and recruitment of neutrophils to the dermal-epidermal junction. In conclusion, desmosomal glycoproteins are the targets of autoimmune injury in PV and PF. The anti-epidermal autoantibodies may cause intraepidermal blisters by impairing the function of dsg1 and dsg3. In BP the hemidesmosome is the target. It appears that antiBP180 antibodies cause subepidermal blister formation by triggering a complement- and neutrophil-mediated inflammatory process.
    Clinical & Experimental Immunology 02/1997; 107 Suppl 1:9-15. · 3.41 Impact Factor
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    ABSTRACT: Several components of the basement membrane zone (BMZ) have been identified as antigenic targets in autoimmune bullous diseases. We report a novel disease with autoantibodies to a BMZ antigen that is different from the targets described so far. The patient suffering from this disorder showed tense bullae and severe mucous membrane involvement rapidly responding to oral tetracyclines and colchicine. Histopathologic findings resembled those of dermatitis herpetiformis. Direct immunofluorescence microscopy showed linear deposits of IgG and C3 at the BMZ. By indirect immunofluorescence studies on split human skin, using both 1 M NaCl and suction blistering for dermal-epidermal separation, IgG antibodies localized exclusively to the dermal side of the split. The antibodies were mainly of the IgG4 sub-class. By Western blot analysis of epidermal and dermal extracts, the patient's serum unequivocally reacted with a dermal antigen of 200 kDa. It did not recognize bullous pemphigoid antigens (the autoantigen of epidermolysis bullosa acquisita), purified preparations of laminin-1 and laminin-5, or the recently described 105-kDa BMZ antigen. By immunoblotting of concentrated conditioned SCC-25 medium, the patient's antibodies reacted with a band of 200 kDa and several bands of lower molecular weight. No reactivity was seen with extracts of cultured human fibroblasts. By indirect immunogold electron microscopy, immunoreactants localized to the lower lamina lucida. After clearance of skin lesions, both indirect immunofluorescence and Western blot analysis became negative. This patient suffers from a novel autoimmune bullous disease with autoantibodies to a 200-kDa antigen of the BMZ.
    Journal of Investigative Dermatology 04/1996; 106(3):465-70. · 6.19 Impact Factor
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    ABSTRACT: A novel member of the ubiquitin carrier protein family, designated E2EPF, has been cloned by our laboratory and expressed in a bacterial system in an active form. Ubiquitin carrier proteins, or E2s, catalyze one step in a multistep process that leads to the covalent conjugation of ubiquitin to substrate proteins. In this paper, we show that recombinant E2EPF catalyzes auto/multiubiquitination, the conjugation of multiple ubiquitin molecules to itself. Multiubiquitination has been shown previously to be required for targeting of a substrate protein for rapid degradation. Using a rabbit reticulocyte lysate system, E2EPF was shown to support the degradation of a model substrate in an ATP- and ubiquitin-dependent fashion. In contrast to a previous study which showed that selective protein degradation in one system is dependent upon multiubiquitination via the lysine 48 residue of ubiquitin, multiubiquitination, and proteolytic targeting by E2EPF was shown here to be independent of the lysine 48 multiubiquitin linkage. This functional characterization of E2EPF revealed a combination of features that distinguishes this enzyme from all previously characterized members of the ubiquitin carrier protein family. These results also suggest several possible autoregulatory models for E2EPF involving auto- and multiubiquitination.
    Journal of Biological Chemistry 03/1996; 271(5):2817-22. · 4.65 Impact Factor
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    ABSTRACT: Bullous pemphigoid (BP) and herpes gestationis (HG) are subepidermal blistering diseases associated with an autoimmune response directed against BP180, an epidermal hemidesmosomal glycoprotein. The pathogenic relevance of this Ag/Ab system was established by the recent demonstration that IgG Abs reactive with the murine form of BP180 (mBP180) are capable of triggering a subepidermal blistering disease after passive transfer into neonatal BALB/c mice. The aim of the present study was to determine the fine specificity of the pathogenically relevant Abs in this experimental model of BP. Four high titer rabbit-anti-mBP180 antisera were included in this analysis--only two of which exhibited pathogenic activity in the passive transfer model. Immunoblot analysis using a panel of mBP180 deletion mutants revealed that each of the four rabbit sera reacted with at least three distinct sites on the mBP180 ectodomain; however, this technique failed to distinguish between the reactivity patterns of the pathogenic and nonpathogenic sera. An alternative technique, liquid phase immunoadsorption analysis, was used to identify one mBP180 antigenic site, comprising 9 to 12 amino acids and designated mBP1, that was specifically recognized by the two pathogenic sera. Pre-adsorption of pathogenically active IgG preparations with fusion proteins containing the mBP1 antigenic site resulted in complete blocking of immunofluorescence reactivity with the murine basement membrane zone (BMZ) and in complete neutralization of pathogenic activity. Anti-BMZ reactivity displayed by nonpathogenic Abs was not altered or diminished by pre-adsorption with this same mBP180 recombinant protein. These findings should help to elucidate the immunopathologic mechanisms responsible for human BP and HG and may have significant implications in the diagnosis and treatment of these autoimmune diseases.
    The Journal of Immunology 01/1996; 155(11):5449-54. · 5.52 Impact Factor
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    ABSTRACT: BP is an organ-specific autoimmune disease characterized by blistering of the skin due to a detachment of the epidermis from the underlying connective tissue layer and by the production of autoantibodies directed against the cutaneous basement membrane zone. A 180-kD epidermal protein, BP180, has been identified as one of the major antigenic targets of these autoantibodies and, interestingly, has been localized to the epidermal hemidesmosome, a cellular structure involved in anchoring basal epithelial cells to the basement membrane. An immunodominant and potentially pathogenic epitope associated with BP has recently been mapped by our laboratory to a site on the extracellular domain of the human BP180 antigen. This antigenic site, designated the MCW-1 epitope, has been shown to be recognized by the majority of sera from patients with either BP or HG, a pregnancy-associated subepidermal bullous disease. Unfortunately, the MCW-1 epitope is absent from the murine BP180 molecule; therefore, human autoantibodies directed against this site could not be tested directly for pathogenicity using the conventional passive transfer mouse model. As an alternative approach, rabbit antibodies were prepared against the segment of murine BP180 that is homologous with the MCW-1 epitope region and were tested for pathogenicity by passive transfer experiments. Remarkably, neonatal mice injected with these antibodies developed a subepidermal blistering disease that faithfully reproduced all of the key immunopathological features of BP and HG--deposition of lgG and complement at the dermal-epidermal junction, inflammatory infiltration of the upper dermis, and frank, subepidermal blistering. These results strongly suggest that the autoimmune response against the human BP180 MCW-1 epitope is relevant in the pathogenesis of blister formation in BP and HG patients. This animal model is currently being used to further dissect the pathophysiology of these autoimmune disorders.
    Proceedings of the Association of American Physicians 08/1995; 107(2):237-41.
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    ABSTRACT: Bullous pemphigoid (BP) is a blistering skin disease associated with an IgG autoimmune response directed against the ectodomain of the hemidesmosomal protein, BP180. An animal model of BP has recently been developed by our laboratory based on the passive transfer of rabbit antimurine BP180 antibodies into neonatal BALB/c mice. The experimental animals develop a blistering disease that reproduces all of the key immunopathological features of BP. In the present study we have investigated the role of complement in the pathogenesis of subepidermal blistering in the mouse model of BP. We demonstrate the following. (a) Rabbit anti-murine-BP180 IgG was effective in inducing cutaneous blisters in a C5-sufficient mouse strain, but failed to induce disease in the syngeneic C5-deficient strain; (b) neonatal BALB/c mice, pretreated with cobra venom factor to deplete complement, became resistant to the pathogenic effects of the anti-BP180 IgG; (c) F(ab')2 fragments generated from the anti-BP180 IgG exhibited no pathogenic activity in the mouse model; and (d) histologic evaluation of the skin of mice described in points b and c above showed minimal or no neutrophilic cell infiltration in the upper dermis. Thus, anti-BP180 antibodies trigger subepidermal blistering in this BP model via complement activation. This experimental model of BP should greatly facilitate future studies on the pathophysiology of autoantibody-mediated diseases of the dermal-epidermal junction.
    Journal of Clinical Investigation 05/1995; 95(4):1539-44. · 12.81 Impact Factor
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    ABSTRACT: An immunodominant and potentially pathogenic epitope associated with bullous pemphigoid (BP) and herpes gestationis (HG) has recently been mapped by our laboratory to a noncollagenous stretch of the extracellular domain of the human BP180 antigen. This antigenic site, designated the MCW-1 epitope, has been shown to be recognized by the majority of BP and HG sera. Interestingly, the MCW-1 epitope is absent from the murine BP180 molecule, and therefore, human autoantibodies directed against this site could not be tested for pathogenicity using the conventional passive transfer mouse model. Alternatively, rabbit antibodies were prepared against recombinant forms of the human MCW-1 epitope and the murine NC16A domain and were tested for pathogenicity by passive transfer experiments. Neonatal mice injected with rabbit antimurine BP180 IgG developed a subepidermal blistering disease that closely mimicked BP and HG at the clinical, histological and immunological levels. Rabbit IgG specific for the human MCW-1 epitope was not pathogenic. These results suggest that the autoantibodies against the MCW-1 epitope of the human BP180 antigen found in BP and HG sera may be relevant in the pathogenesis of blister formation in these patients.
    Dermatology 02/1994; 189 Suppl 1:34-7. · 2.02 Impact Factor

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Institutions

  • 2000–2001
    • University of North Carolina at Chapel Hill
      • Department of Dermatology
      Chapel Hill, NC, United States
  • 1992–2000
    • Medical College of Wisconsin
      • Department of Dermatology
      Milwaukee, WI, United States
  • 1999
    • University of Washington Seattle
      • Division of Pulmonary and Critical Care Medicine
      Seattle, WA, United States