The Immunometabolomic Interface Receptor Hydroxycarboxylic Acid Receptor 2 Mediates the Therapeutic Effects of Dimethyl Fumarate in Autoantibody-Induced Skin Inflammation.

The drug dimethyl fumarate (DMF) is in clinical use for the treatment of psoriasis and multiple sclerosis. In addition, it has recently been demonstrated to ameliorate skin pathology in mouse models of pemphigoid diseases, a group of autoimmune blistering diseases of the skin and mucous membranes. However, the mode of action of DMF in inflammatory skin diseases has remained elusive. Therefore, we have investigated here the mechanisms by which DMF improves skin pathology, using the antibody transfer model of bullous pemphigoid-like epidermolysis bullosa acquisita (EBA). Experimental EBA was induced by transfer of antibodies against collagen VII that triggered the infiltration of immune cells into the skin and led to inflammatory skin lesions. DMF treatment reduced the infiltration of neutrophils and monocytes into the skin explaining the improved disease outcome in DMF-treated animals. Upon ingestion, DMF is converted to monomethyl fumarate that activates the hydroxycarboxylic acid receptor 2 (HCA2). Interestingly, neutrophils and monocytes expressed Hca2. To investigate whether the therapeutic effect of DMF in EBA is mediated by HCA2, we administered oral DMF to Hca2-deficient mice (Hca2-/-) and wild-type littermates (Hca2+/+) and induced EBA. DMF treatment ameliorated skin lesions in Hca2+/+ but not in Hca2-/- animals. These findings demonstrate that HCA2 is a molecular target of DMF treatment in EBA and suggest that HCA2 activation limits skin pathology by inhibiting the infiltration of neutrophils and monocytes into the skin.

Skin microbiota-associated inflammation precedes autoantibody induced tissue damage in experimental epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita (EBA) is a chronic autoimmune blistering skin disease characterized by autoantibodies against type VII collagen (COL7). Immunization of SJL/J mice with recombinant murine COL7 results in break of tolerance and skin blisters. Strikingly, despite circulating autoantibodies, the same genetic background and identical environmental conditions, 20% of mice remain healthy. To elucidate the regulation of the transition from the presence of autoantibodies to overt autoimmune disease, we characterized the innate and adaptive immune response of mice that remain healthy after immunization and compared it to mice that developed skin disease. Both clinically healthy and diseased SJL/J mice showed circulating autoantibodies and deposition of complement-fixing IgG2c autoantibodies and C3 at the dermal-epidermal junction. However, only in diseased animals significant neutrophil infiltration and increase in FcgRIV expression were observed in the skin. In contrast, the expression of T cell signature cytokines in the T cell zone of the draining lymph node was comparable between clinically healthy and diseased animals after immunization. Surprisingly, health was associated with a decreased expression of CD11c, TNFA and KC (CXCL1) in the skin prior to immunization and could be predicted with a negative predictive value of >80%. Furthermore, mice that did not develop clinical disease showed a significantly higher richness and distinctly clustered diversity of their skin microbiota before immunization. Our data indicate that the decision whether blisters develop in the presence of autoantibodies is governed in the skin rather than in the lymph node, and that a greater richness of cutaneous bacterial species appears to be protective.

Conditional depletion of mast cells has no impact on the severity of experimental epidermolysis bullosa acquisita.

The role of mast cells (MCs) in autoimmunity is the matter of an intensive scientific debate. Based on observations in different MC-deficient mouse strains, MCs are considered as fundamental players in autoimmune diseases. However, most recent data suggest that the outcome of such diseases is strongly affected by the individual mouse strain used. By the use of two c-Kit mutant MC-deficient mouse strains and one c-Kit-independent strain, we here investigated the role of MCs in a systemic Ab transfer model of epidermolysis bullosa acquisita, a subepidermal autoimmune blistering skin disease characterized by autoantibodies against type VII collagen. While C57BL/6J-Kit(W-sh/W-sh) mice developed an unexpected increased blistering phenotype, no significant differences to WT controls were seen in WBB6F1 -Kit(W/W-v) or the novel Mcpt5-Cre iDTR animals. Interestingly, in a local Ab transfer model, which induces a localized disease, we showed that application of high concentrations of anti-COL7 (where COL7 is type VII collagen) Abs induced MC activation and MC-dependent edema formation that did, however, not contribute to blister induction. Our results indicate that in the autoimmune disorder epidermolysis bullosa acquisita MCs do not contribute to the immune-mediated tissue injury. Modern c-Kit mutant-independent MC-deficient mouse strains will help to further redefine the role of MCs in autoimmunity.

Metabolite analysis distinguishes between mice with epidermolysis bullosa acquisita and healthy mice.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a rare skin blistering disease with a prevalence of 0.2/ million people. EBA is characterized by autoantibodies against type VII collagen. Type VII collagen builds anchoring fibrils that are essential for the dermal-epidermal junction. The pathogenic relevance of antibodies against type VII collagen subdomains has been demonstrated both in vitro and in vivo. Despite the multitude of clinical and immunological data, no information on metabolic changes exists. METHODS: We used an animal model of EBA to obtain insights into metabolomic changes during EBA. Sera from mice with immunization-induced EBA and control mice were obtained and metabolites were isolated by filtration. Proton nuclear magnetic resonance (NMR) spectra were recorded and analyzed by principal component analysis (PCA), partial least squares discrimination analysis (PLS-DA) and random forest. RESULTS: The metabolic pattern of immunized mice and control mice could be clearly distinguished with PCA and PLS-DA. Metabolites that contribute to the discrimination could be identified via random forest. The observed changes in the metabolic pattern of EBA sera, i.e. increased levels of amino acid, point toward an increased energy demand in EBA. CONCLUSIONS: Knowledge about metabolic changes due to EBA could help in future to assess the disease status during treatment. Confirming the metabolic changes in patients needs probably large cohorts.

Epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita (EBA) is a chronic autoimmune subepidermal bullous disease with clinical features similar to the genetic form of dystrophic epidermolysis bullosa. EBA is characterized by the presence of autoantibodies against type VII collagen which is a major component of the anchoring fibrils at the dermal-epidermal junction. EBA can be divided into two main clinical types; mechanobullous and inflammatory EBA. Mechanobullous EBA, referred to as classic EBA, presents with skin fragility, blisters and dystrophic changes on trauma-prone areas. Inflammatory EBA resembles other autoimmune subepidermal bullous diseases. Compelling evidence from mouse models supports a pathogenic role of autoantibodies against type VII collagen in EBA. Treatment of EBA is often unsatisfactory. The most widely used systemic treatment is corticosteroids. Colchicine and dapsone have been reported to be good treatment modalities when combined with corticosteroids. Some intractable cases of EBA have successfully been treated with intravenous immunoglobulin or rituximab.

Pathogenesis of epidermolysis bullosa acquisita, an autoimmune subepidermal bullous disease.

Autoimmune bullous diseases (ABDs) are organ-specific autoimmune diseases, in which blisters on the skin and mucous membranes develop through binding of pathogenic autoantibodies to target antigens. There are two major ABD groups: the pemphigus group, showing autoantibodies to desmosomal components; and the subepidermal ABD group, showing autoantibodies to hemidesmosomal components in the epidermal basement membrane zone. Recent immunological, biochemical and molecular biological studies revealed many new autoantigens, including desmocollins, various plakin family proteins and integrins. A revised ABD classification includes new disease entities such as paraneoplastic pemphigus, IgA pemphigus and anti-laminin γ1 pemphigoid. In addition to systemic corticosteroids and various immunosuppressive agents, various adjuvant therapies for ABDs have developed. Among them, intravenous immunoglobulin (IVIG) is a promising therapy, although the therapeutic mechanisms are still unknown. Various disease models for ABDs have developed, particularly for pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa acquisita (EBA), and these have provided insights into the pathogenesis of various ADBs that suggest possible new treatment strategies. However, the fundamental mechanisms in disruption of immune-tolerance are still unknown. EBA shows autoimmunity to type VII collagen, the major component of anchoring fibrils, and EBA pathogenesis has been studied in various disease models. Previous studies suggested that, following binding of autoantibodies to type VII collagen, activation of complement, cytokine release, neutrophil migration, Fcγ receptors (FcgRs) and metalloproteinases play important roles in induction of subepidermal blisters. In this issue of the Journal of Pathology, Kasperkiewicz and colleagues reveal important roles of activating FcgRIV and inhibitory FcgRIIB in EBA pathogenesis that were recognized by conducting elegant studies using both genetic analysis and functional animal model methods. The expression equilibrium of the activating and inhibitory FcgRs can be modulated towards the inhibitory FcgRIIB by IVIG therapy, resulting in beneficial clinical effects of IVIG in EBA and other autoimmune skin-blistering diseases.

Pathogenesis of epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering skin disease characterized by autoantibodies to type VII collagen. Clinically, a noninflammatory and an inflammatory variant of EBA can be distinguished. Despite major achievements in the understanding of EBA, current therapeutic options are far from optimal. However, with an emerging and more detailed understanding of the events ultimately leading to blister formation in EBA, novel therapeutic options may become available for patients with EBA. Therefore, this article reviews the current understanding of the pathogenesis of EBA and may indicate possible avenues towards a more targeted therapy for EBA and possibly other antibody-mediated autoimmune diseases.

[Epidermolysis bullosa acquisita]. / Épidermolyse bulleuse acquise.

Epidermolysis bullosa acquisita (EBA) is a rare autoimmune subepidermal bullous disease with autoimmunity to the type VII collagen which is the major component of anchoring fibrils. Clinical manifestations of the classical EBA include skin fragility, blisters over the trauma-prone surfaces and milium cysts. Other presentations of EBA have been reported: mucosal predominant appearance reminiscent of cicatricial pemphigoid, bullous pemphigoid-like presentation and IgA-EBA. Making a definitive diagnosis of EBA could be difficult because specialized tests available in only some laboratories are necessary to confirm the clinical suspicion: immunoelectron microscopy demonstrating immune deposits on anchoring fibrils and immunoblotting or enzyme-linked immunosorbent assay (Elisa) detecting autoantibodies recognizing the type VII collagen. EBA frequently is associated with Crohn's disease and an inflammatory bowel disease must be ruled out in patients with EBA and abdominal manifestations. EBA potentially is serious, has usually a chronical evolution and is difficult to treat.There are no guidelines for treatment of EBA, which is adapted to clinical severity and include dapsone, cyclosporine and rituximab.

Autoimmunity to type VII collagen: epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita (EBA) is an acquired, autoimmune, mechanobullous disease with clinical features reminiscent of genetic dystrophic epidermolysis bullosa (DEB). EBA patients have skin fragility, blisters, scars, and milia formation. DEB is due to a genetic defect in the gene-encoding type VII collagen, which makes anchoring fibrils, structures that attach the epidermis and its underlying basement membrane zone onto the papillary dermis. DEB patients have a decrease in normally functioning anchoring fibrils. EBA patients have the same problem, but their decrease in normally functioning anchoring fibrils is because of an abnormality in their immune system in which they produce anti-type VII collagen antibodies that attack their anchoring fibrils. These IgG anti-type VII collagen antibodies are "pathogenic" because when injected into a mouse, the mouse develops an EBA-like blistering disease. EBA has several distinct clinical presentations. It can present with features similar to DEB. It can also present with features reminiscent of bullous pemphigoid, cicatricial pemphigoid, Brunsting-Perry pemphigoid, or IgA bullous dermatosis. Treatment for EBA is unsatisfactory. Some therapeutic success has been reported with colchichine, dapsone, photopheresis, infliximab, and IVIG.

Epidermolysis bullosa acquisita following bullous pemphigoid, successfully treated with the anti-CD20 monoclonal antibody rituximab.

Epidermolysis bullosa acquisita is a rare autoimmune subepidermal blistering disease, often resisting current treatments, especially systemic corticosteroids. We report a patient having a bullous pemphigoid who relapsed with clinical and immunological features of inflammatory epidermolysis bullosa acquisita. An anti-CD20 monoclonal antibody (rituximab) was proposed because of resistance to high-dose steroids and other immunosuppressive agents. The disease dramatically improved within a few weeks following rituximab infusion allowing the decrease in steroid therapy. Our case illustrates also the possible evolution from bullous pemphigoid to epidermolysis bullosa acquisita that should be suspected when clinical atypia occurs or in case of corticosteroid resistance.

Epidermolysis bullosa acquisita associated with psoriasis vulgaris.

We report a case of epidermolysis bullosa acquisita (EBA) associated with psoriasis vulgaris. A 71-year-old woman with psoriasis vulgaris developed subepidermal blisters on the extremities. Direct immunofluorescence demonstrated linear deposit of IgG at the basement membrane zone, which bound to the dermal side of normal human skin split with 1 mol/L NaCl. Immunoblot analysis using recombinant full-length type VII collagen detected a 290-kDa band, confirming the diagnosis of EBA. A literature search for previous reports found a few cases of EBA associated with psoriasis, and all cases, including our own, presented with widespread inflammatory vesicles and bullae, and responded to conventional therapy with corticosteroids and immunosuppressive agents. This study suggests that western blotting using recombinant full-length type VII collagen could be useful for diagnosis of EBA, and that EBA associated with psoriasis may have a tendency to be the inflammatory type.

Paraneoplastic epidermolysis bullosa acquisita associated with multiple myeloma.

Epidermolysis bullosa acquisita is a rare acquired autoimmune subepidermal blistering disease that clinically resembles other vesiculobullous lesions such as pemphigus vulgaris and cicatricial pemphigoid. Multiple myeloma is the most common plasma cell malignant disorder characterized by a single clonal expansion and increased level of a single immunoglobulin. Epidermolysis bullosa acquisita has been reported with other systemic diseases such as lymphoma. In this case report, we present a patient with paraneoplastic epidermolysis bullosa acquisita associated with multiple myeloma.

Epidermolysis bullosa acquisita occurring in 2 patients with hepatitis C.

We report 2 patients with documented chronic hepatitis C infection and epidermolysis bullosa acquisita (EBA). Both patients clinically represent classic EBA, exhibiting skin fragility and blistering occurring both spontaneously and secondary to trauma, which heal with milia and scar formation. EBA often is a disease of altered immune status and debility. Further work is necessary to show whether hepatitis C plays a causative role in EBA in these 2 patients and in general.

Evidence that anti-type VII collagen antibodies are pathogenic and responsible for the clinical, histological, and immunological features of epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering disease characterized by autoantibodies to type VII (anchoring fibril) collagen. Therefore, it is a prototypic autoimmune disease defined by a well-known autoantigen and autoantibody. In this study, we injected hairless immune competent mice with purified immunoglobulin G (IgG) fraction of serum from rabbits immunized with the non-collagenous amino-terminal domain (NC1) of human type VII collagen, the domain known to contain immunodominant epitopes. As a control, identical mice were injected with the IgG fraction of serum from non-immunized rabbits. Mice injected with immune IgG developed subepidermal skin blisters and erosions, IgG deposits at the epidermal-dermal junction of their skin, and circulating anti-NC1 antibodies in their serum-all features reminiscent of patients with EBA. Similar concentrations of control IgG purified from normal rabbits did not induce disease in the mice. These findings strongly suggest that autoantibodies that recognize human type VII collagen in EBA are pathogenic. This murine model, with features similar to the clinical, histological, and immunological features of EBA, will be useful for the fine dissection of immunopathogenic mechanisms in EBA and for the development of new therapeutic interventions.

Paraneoplastic immunobullous disease with an epidermolysis bullosa acquisita phenotype: two cases demonstrating remission with treatment of gynaecological malignancy.

Two cases of paraneoplastic immunobullous disease occurring in women with gynaecological malignancies are reported. Both cases demonstrated mechanobullous mucocutaneous blistering as is typically seen in epidermolysis bullosa acquisita. Their immunopathology, however, favoured a dermal-binding mucous membrane pemphigoid (MMP) (or possibly bullous pemphigoid) for patient 1 and laminin-5 MMP for patient 2. Both patients showed resolution of blistering within 1 year of treatment of their malignancies; uterine and ovarian carcinoma, respectively. These cases are of interest because of their paraneoplastic nature; as well as overlapping clinicoimmunopathological features. In addition, patient 2 is, as far as we are aware, the first report of ovarian-carcinoma-associated laminin-5 MMP.