Collagen XVII (BP180) modulates keratinocyte expression of the proinflammatory chemokine, IL-8.

Collagen XVII (COL17), a transmembrane protein expressed in epidermal keratinocytes (EK), is targeted by pathogenic autoantibodies in bullous pemphigoid. Treatment of EK with anti-COL17 autoantibodies triggers the production of proinflammatory cytokines. In this study, we test the hypothesis that COL17 is involved in the regulation of the EK proinflammatory response, using IL-8 expression as the primary readout.

Functional characterization of an IgE-class monoclonal antibody specific for the bullous pemphigoid autoantigen, BP180.

BP180 (collagen XVII) is the target antigen in several autoimmune diseases including bullous pemphigoid (BP). Both IgE and IgG class autoantibodies have been shown to be pathogenic in BP; however, studies designed to elucidate the patho-mechanisms mediated specifically by the IgE-class autoantibodies are limited by the low levels (ng/mL) of IgE in human sera. In this report, we developed mouse IgE class monoclonal antibodies (MAbs) against the immunodominant NC16A domain of the human BP180 protein and characterized two of the resultant MAbs, designated 395A5 and 395D2.

Neutrophil elastase cleaves the murine hemidesmosomal protein BP180/type XVII collagen and generates degradation products that modulate experimental bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease associated with autoantibodies against the hemidesmosomal proteins BP180 and BP230. In the IgG passive transfer model of BP, blister formation is triggered by anti-BP180 IgG and depends on complement activation, mast cell degranulation, and neutrophil recruitment. Mice lacking neutrophil elastase (NE) do not develop experimental BP.

A novel ELISA reveals high frequencies of BP180-specific IgE production in bullous pemphigoid.

Bullous pemphigoid (BP) is a humoral autoimmune disease directed predominantly against the non-collagenous NC16A domain of the BP180 hemidesmosomal protein. Our laboratory has recently shown, using a mouse xenograft model, that passive transfer of IgE autoantibodies from BP sera induces a skin phenotype that recapitulates the early phases of the disease. Herein, we describe the development of a highly specific and sensitive ELISA to detect circulating IgE autoantibodies that recognize BP180-NC16A.

Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model.

Bullous pemphigoid (BP) is a cutaneous autoimmune inflammatory disease associated with subepidermal blistering and autoantibodies against BP180, a transmembrane collagen and major component of the hemidesmosome. Numerous inflammatory cells infiltrate the upper dermis in BP. IgG autoantibodies in BP fix complement and target multiple BP180 epitopes that are highly clustered within a non-collagen linker domain, termed NC16A.

A pathogenic role for IgE in autoimmunity: bullous pemphigoid IgE reproduces the early phase of lesion development in human skin grafted to nu/nu mice.

Bullous pemphigoid (BP) is an autoimmune disease characterized by subepidermal blistering. Based on previous work, IgG autoantibodies directed against BP180 are thought to be the primary pathogenic agent in BP. In addition to these IgG autoantibodies, however, most BP patients produce IgE class autoantibodies that also react with BP180, and total IgE levels are often elevated in this disease.

The NC16A domain of collagen XVII plays a role in triple helix assembly and stability.

Collagen XVII/BP180 is a transmembrane constituent of the epidermal anchoring complex. To study the role of its non-collagenous linker domain, NC16A, in protein assembly and stability, we analyzed the following recombinant proteins: the collagen XVII extracellular domain with or without NC16A, and a pair of truncated proteins comprising the COL15-NC15 stretch expressed with or without NC16A. All four proteins were found to exist as stable collagen triple helices; however, the two missing NC16A exhibited melting temperatures significantly lower than their NC16A-containing counterparts.

Mapping the binding sites of anti-BP180 immunoglobulin E autoantibodies in bullous pemphigoid.

Bullous pemphigoid (BP) is a subepidermal blistering disease characterized by autoantibodies against the hemidesmosomal protein BP180 (BPAg2, type XVII collagen). NC16A, a non-collagenous stretch of the BP180 ectodomain, is the primary target of pathogenic immunoglobulin (Ig)G autoantibodies and IgE class autoantibodies. This study further characterized the IgE-reactive regions of BP180.

T cell receptor gene usage of BP180-specific T lymphocytes from patients with bullous pemphigoid and pemphigoid gestationis.

BP180 is the autoantigen of different immunobullous diseases, including bullous pemphigoid (BP) and pemphigoid gestationis (PG). Previously, we demonstrated that the NC16A domain of this autoantigen harbors key epitopes of autoantibodies and T cells, indicating that it plays an essential role in the pathogenesis of diseases. Moreover, NC16A-specific T cell clones derived from these patients were shown to express a CD4+ memory T cell phenotype and secrete cytokines that may promote autoantibody production.

A patient with both bullous pemphigoid and epidermolysis bullosa acquisita: an example of intermolecular epitope spreading.

Bullous pemphigoid (BP) and epidermolysis bullosa acquisita are distinct autoimmune blistering disorders. BP is characterized by autoantibodies directed against the NC16A domain of collagen XVII, whereas patients with epidermolysis bullosa acquisita have autoantibodies against the NC1 domain of type VII collagen. We followed up a patient with BP for 9 years.

BP180 (type XVII collagen) and its role in cutaneous biology and disease.

BP180 is a key component of the epidermal anchoring complex and functions to maintain adherence of the epidermis to the basement membrane. Structural studies have revealed that BP180 is a type II transmembrane protein with a long carboxy-terminal collagenous domain that projects into the extracellular region beneath the epidermal hemidesmosome. The collagenous domains have the characteristic tripeptide repeat, Gly-X-Y.

Identification of a potential effector function for IgE autoantibodies in the organ-specific autoimmune disease bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune skin disease characterized by autoantibodies against the hemidesmosomal protein BP180. In addition to IgG autoantibodies, IgE class autoantibodies have been reported in BP patients. Because animal models utilizing only IgG antibodies do not totally replicate human BP, we examined the specificity and potential relevance of IgE autoantibodies in this disease.

Macrophages, but not T and B lymphocytes, are critical for subepidermal blister formation in experimental bullous pemphigoid: macrophage-mediated neutrophil infiltration depends on mast cell activation.

Bullous pemphigoid (BP) is a subepidermal blistering disease associated with autoantibodies against two hemidesmosomal proteins, BP180 and BP230. Numerous inflammatory cells infiltrate the upper dermis in BP. We have previously shown by passive transfer studies that Abs to the ectodomain of murine BP180 are capable of triggering blisters in mice that closely mimic human BP.

Autoimmune responses in patients with linear IgA bullous dermatosis: both autoantibodies and T lymphocytes recognize the NC16A domain of the BP180 molecule.

Linear IgA bullous disease (LABD) is an autoimmune skin disease characterized by subepidermal blisters and IgA autoantibodies directed against the epidermal basement membrane zone (BMZ) of the skin. Various antigens have been identified as targets of IgA autoantibodies including BP180, a type II glycoprotein that spans the BMZ and lamina lucida. Previously, we have identified a subset of LABD patients whose sera contained IgA antibodies against the 16th noncollagenous (NC16A) domain of BP180.