Epidermolysis bullosa acquisita: autoimmunity to anchoring fibril collagen

Epidermolysis bullosa acquisita (EBA) is a rare and acquired autoimmune subepidermal bullous disease of skin and mucosa. EBA includes various distinct clinical manifestations resembling genetic dystrophic epidermolysis bullosa (DEB), Bullous pemphigus, Brunsting-Perry pemphigoid, or cicatricial pemphigoid. These patients have autoantibodies against type VII collagen (C7), an integral component of anchoring fibrils (AFs), which are responsible for attaching the dermis to the epidermis. Destruction or perturbation of the normal functioning AFs clinically results in skin fragility, blisters, erosions, scars, milia, and nail loss, all features reminiscent of genetic dystrophic epidermolysis bullosa. These anti-C7 antibodies are "pathogenic" because when injected into a mouse, the mouse develops an EBA-like blistering disease. Currently, treatment is often unsatisfactory; however, some success has been achieved with colchicine, dapsone, photopheresis, plasmapheresis, infliximab, rituximab, and IVIG.     

Epidermolysis bullosa acquisita: Autoimmunity to anchoring fibril collagen

Epidermolysis bullosa acquisita (EBA) is a rare and acquired autoimmune subepidermal bullous disease of skin and mucosa. EBA includes various distinct clinical manifestations resembling genetic dystrophic epidermolysis bullosa (DEB), Bullous pemphigus, Brunsting–Perry pemphigoid, or cicatricial pemphigoid. These patients have autoantibodies against type VII collagen (C7), an integral component of anchoring fibrils (AFs), which are responsible for attaching the dermis to the epidermis. Destruction or perturbation of the normal functioning AFs clinically results in skin fragility, blisters, erosions, scars, milia, and nail loss, all features reminiscent of genetic dystrophic epidermolysis bullosa. These anti-C7 antibodies are “pathogenic” because when injected into a mouse, the mouse develops an EBA-like blistering disease. Currently, treatment is often unsatisfactory; however, some success has been achieved with colchicine, dapsone, photopheresis, plasmapheresis, infliximab, rituximab, and IVIG.     

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.     

Diagnosis and classification of pemphigus and bullous pemphigoid

Pemphigus and bullous pemphigoid represent the two major groups of autoimmune blistering diseases. Pemphigus has three major variants: pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus and is characterized by autoantibodies directed against the cell surface of keratinocytes, producing acantholysis that in turn leads to intraepithelial blisters in the skin and/or mucous membranes. In bullous pemphigoid, the autoantibodies are present at the dermo-epidermal junction and attack the hemidesmosomes, causing subepidermal blister formation. The classification of the major variants of both the pemphigus group and bullous pemphigoid can be based on the combination of clinical, histopathological and immunopathological criteria. Many tools are available for the diagnosis of these entities including biopsy, direct and indirect immunofluorescence, immunoprecipitation, immunoblotting and ELISA. However, currently there are no generally accepted criteria for the diagnosis of these disorders. The present review provides a proposal for diagnostic criteria.     

Granulocyte-derived elastase and gelatinase B are required for dermal-epidermal separation induced by autoantibodies from patients with epidermolysis bullosa acquisita and bullous pemphigoid

Epidermolysis bullosa acquisita (EBA) and bullous pemphigoid (BP) are two clinically and immunologically distinct autoimmune subepidermal blistering skin diseases associated with IgG autoantibodies against the dermal-epidermal junction. BP antibodies are directed against the hemidesmosomal antigens BP180 and BP230, and those in patients with EBA target type VII collagen, a major component of anchoring fibrils. While the pathogenetic mechanisms of subepidermal blistering in BP have been previously studied using a passive transfer mouse model, the effector pathways of blister formation in EBA are largely unknown. Autoantibodies to type VII collagen and BP180 have recently been shown to induce leucocyte-mediated subepidermal cleavage in cryosections of human skin. The aim of the present study was to identify human leucocyte protease(s) instrumental in dermal-epidermal separation induced by autoantibodies to type VII collagen and BP180. When incubated with cryosections of human skin pretreated with IgG from patients with EBA or BP but not from patients with anti-laminin 5 mucous membrane pemphigoid or healthy controls, granulocytes were recruited to the dermal-epidermal junction and induced subepidermal splits. A combination of broad-range protease inhibitors as well as inhibitors of serine and matrix metalloproteases completely abolished dermal-epidermal separation induced by EBA or BP autoantibodies. When characterizing the proteases involved more specifically, selective inhibition of human leucocyte elastase or gelatinase B/MMP-9 was also found to result in suppression of blistering. These findings strongly suggest that elastase and gelatinase B are essential for granulocyte-mediated proteolysis resulting in dermal-epidermal separation in EBA and BP patients' skin.     

Recent advancement on autoantigens,autoantibodies and inflammatory cells in subepidermal autoimmune bullous diseases

Subepidermal autoimmune bullous diseases (SABD) are some autoimmune skin diseases that can present in a variety of forms and can be a challenging disease to treat. An overview of the different forms of SABD are discussed including bullous pemphigoid (BP), epidermolysis bullosa acquisita (EBA), cicatricial pemphigoid (CP), bullous systemic lupus erythematosus (BSLE), and Anti-p200 pemphigoid. Emphasis on recent advancement is presented. In recent years, improved Knowledge of the mechanisms of intercellular and cell-matrix adhesion has led to better understanding of the blistering process in some SABD. Defects of such structures cause the subepidermal bullous diseases and have also led to the discovery of new diseases (e.g. anti-p200-pemphigoid). Recent studies have outlined the important role of autoantibodies, mast cell lymphocytes and their cytokines in pathogenesis of SABD.     

Epidermolysis bullosa acquisita: A comprehensive review

Epidermolysis bullosa acquisita is a rare autoimmune blistering disease which results in vesicle and bullae formation on the skin and erosions on the mucous membranes. EBA is mediated by autoantibodies to collagen VII. Clinically, it can present with numerous phenotypes, though the most common are the mechanobullous and inflammatory variants. Patients with mechanobullous EBA develop non-inflammatory bullae and erosions at sites of trauma while patients with the non-mechanobullous type develop inflammatory lesions which often mimic other blistering conditions including bullous pemphigoid, linear IgA bullous disease, and mucous membrane pemphigoid. Diagnosis is established by having a consistent clinical presentation, DIF, and autoantibodies against collagen VII. In apparent “seronegative” patients, the diagnosis is challenging due to the need for confirmatory tests which are often not routinely accessible outside of the specialized center. In light of EBA's rarity, and lack of any randomized controlled trials, treatment guidelines rely on the small case series presented in the literature. There has been variable success utilizing the arsenal of immunosuppressants and biologics. Development of experimental murine models has facilitated a deeper understanding of EBA's pathogenesis and allows for preclinical testing of numerous novel drug targets predominantly targeting inhibition of neutrophil activation. We herein review the presentation, diagnosis, treatments, and future avenues of research in EBA.     

Autoimmune bullous diseases the spectrum of infectious agent antibodies and review of the literature

Pemphigus and bullous pemphigoid are two autoimmune diseases that have a similar pathogenesis. Both have a genetic predisposition which promotes the production of auto-antibodies targeted against different components of the epidermal desmosome and hemidesmosome. Environmental factors play an important role in the pathogenesis of this autoimmune disease. Among these, the role of infectious agents was debated as a causative factor. We sought to determine a possible connection between various infectious agents and autoimmune bullous disease (ABD). A cohort of 148 serum samples of patients with pemphigus, bullous pemphigoid and controls was screened for evidence of a prior infection with HBV, HCV, EBV, CMV, Helicobacter pylori, Toxoplasma gondii and Treponema pallidum, utilizing the Bio-Rad BioPlex 2200 system as well as ELISA assays to complete the panel. HBV, HCV, H. pylori, T. gondii and CMV were demonstrated to have significantly higher prevalence of antibodies in patients with pemphigus and bullous pemphigoid in comparison to controls. Among them, we found a novel association between H. pylori and ABD. Our study suggests a contributing role for HBV, HCV, H. pylori, T. gondii and CMV in inducing ABD in the genetically susceptible host.     

The cartilage matrix protein subdomain of type VII collagen is pathogenic for epidermolysis bullosa acquisita

Epidermolysis bullosa acquisita (EBA) is an acquired bullous disease of the skin characterized by IgG autoantibodies against type VII (anchoring fibril) collagen. We previously defined four immunodominant antigenic epitopes within the noncollagenous 1 (NC1) domain of type VII collagen. In this study, we produced an additional recombinant fusion protein from the NC1 domain corresponding to the N-terminal 227 amino acids (residues 1 to 227), which contains homology with cartilage matrix protein (CMP). Using enzyme-linked immunosorbent assay and immunoblot analysis, we tested sera from EBA patients (n = 32), bullous systemic lupus erythematosus patients (n = 3), bullous pemphigoid patients (n = 15), and normal humans (n = 12). Twenty-six of 32 EBA sera and two of three bullous systemic lupus erythematosus sera reacted with the CMP domain, whereas none of the control sera did. Affinity-purified anti-CMP EBA antibodies injected into hairless mice produced the clinical, histological, immunological, and ultrastructural features of EBA. F(ab')(2) fragments generated from anti-CMP EBA autoantibodies did not induce disease. Our studies provide the first evidence that EBA autoantibodies to the CMP subdomain of NC1 are pathogenic and induce blister formation. This is the first antigenic epitope on type VII collagen demonstrated to be a pathogenic target for EBA autoantibodies.     

An Extract from Cultured Human Keratinocytes that Contains the Major Autoantigens Related to Autoimmune Bullous Skin Diseases

Autoantibodies characteristic of autoimmune bullous skin diseases (AIBDs) can be detected by immunoblotting on epidermal, dermal, or bovine muzzle extracts. However, none of those substrates contain all the autoantigens involved in AIBDs, and the diagnosis requires the use of various substrates. Human keratinocytes were cultured under such conditions that they expressed the major autoantigens associated with AIBDs. Forty-two sera with antiepidermal antibodies were immunoblotted on the keratinocyte extract. Bands corresponding to desmoglein III, desmoglein I, BPAg2, BPAg1, and type VII collagen were found in 38 sera. Desmoplakins I and II were revealed by specific monoclonal antibodies. A review of the patients' charts showed a perfect correlation between the blots and the diagnoses of pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, cicatricial pemphigoid, and epidermolysis bullosa acquisita. Four sera revealing no band typical of AIBD were from patients with no autoimmune skin disease. Therefore, a single extract of keratinocytes can be used for the differential diagnosis of AIBDs.     

Epidermal adhesion molecules and basement membrane components as target structures of autoimmunity

 Intraepidermal and dermal-epidermal cohesion are of paramount importance for the integrity of the skin. Some constituent molecules of keratinocyte adhesion complexes and basement membrane-associated structures are the targets of antibody-mediated autoimmune reactions that give rise to various (muco-)cutaneous blistering diseases. The current state of our knowledge about these molecules – along with the main clinical, histological, and immunohistochemical features of the corresponding autoimmune diseases and their pathogenetic mechanisms – comprise the subjects surveyed in this review. Among the desmosomal cadherins (desmogleins and desmocollins) that mediate epidermal cell–cell adhesion, it has been demonstrated that desmoglein 1 and desmoglein 3 are the autoantigens of pemphigus foliaceus and pemphigus vulgaris, respectively, both diseases that result in intraepidermal blistering. Further, desmocollin autoantibodies may be involved in IgA pemphigus. Paraneoplastic pemphigus is associated with autoantibodies directed against the desmosomal plaque protein, desmoplakin. Of the constituents of hemidesmosomes, the plaque protein, BP230 (BPAG1), and the collagen-like transmembrane protein, BP180 (BPAG2), are the autoantigens of bullous pemphigoid and pemphigoid gestationis, the manifestations of both of which include subepidermal blistering. Several diseases arise from autoimmune reactions against certain proteins associated with the basement membrane located beneath hemidesmosomes, for example laminin 5 (cicatricial pemphigoid), ladinin (LAD-1; linear IgA disease), uncein, and collagen VII (epidermolysis bullosa acquisita), the last of which is the constituent protein of the anchoring fibrils. Such recent advances in the elucidation of the molecular nature of autoantigens may serve as the basis for the development of novel molecule-based therapeutic strategies. Received: 12 September1997 / Accepted: 27 October 1997     

Evaluation of Recombinant Antigen-Based Assays for Diagnosis of Bullous Autoimmune Diseases

The diagnosis of autoimmune bullous diseases is based on clinical observation and on the presence of autoantibodies directed to molecules involved in the adhesion systems of the skin. Immunofluorescence assays are the currently accepted method for detection of autoantibodies; such assays depend greatly on the skill of operators and are difficult to standardize. Recombinant desmoglein-1 (Dsg1), Dsg3, and BP180 peptides, the main autoantigens in pemphigus or bullous pemphigoid, have been used to develop new quantitative enzyme immunoassays (EIA) for the detection of specific antibodies. The present study was undertaken to evaluate the sensitivity and specificity of these immunoassays and to determine the correlation between the results and the clinical aspects of diseases. Serum samples from patients with pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, or mucous membrane pemphigoid, from healthy individuals, and from patients with unrelated autoimmune conditions were tested. Anti-desmoglein reactivity was detected in all the patients with pemphigus and in none of the controls. Patients with the more benign form of cutaneous disease had anti-Dsg1 antibodies, while patients with deeper cutaneous lesions or with mucosal involvement had anti-Dsg3 reactivity also, or exclusively. The BP180-based assay was positive for 66.6% of patients with bullous pemphigoid and for none of the patients with mucous membrane pemphigoid, and no reactivity was detected in the control sera. In conclusion, the anti-Dsg1 and anti-Dsg3 assays are useful in the diagnosis of pemphigus and provide information on the clinical phenotype of the disease. However, the sensitivity of EIA for detection of autoantibodies in bullous pemphigoid should be improved by the use of additional antigens or epitopes.     

Immune mechanism–targeted treatment of experimental epidermolysis bullosa acquisita

Epidermolysis bullosa acquisita (EBA) is an autoimmune bullous dermatosis characterized by chronic mucocutaneous blistering caused by autoantibodies directed against type VII collagen. EBA causes a high morbidity and is difficult to treat. Model systems have significantly broadened our understanding of EBA pathogenesis, leading to the identification of numerous therapeutic targets. Of these, so far, a few have been evaluated for their therapeutic potential in preclinical models. In mice, EBA can be induced by transfer of anti-type VII collagen antibodies or by immunization with the protein. The latter model, immunization-induced EBA, is ideal to test drugs for their therapeutic efficacy. Here, mice with already established disease can be treated for prolonged periods. Albeit time consuming, results from immunization-induced EBA will pave the way for clinical application in patients. As the key pathogenic principle, that is, autoantibody-induced, leukocyte-mediated tissue injury and inflammation, is shared by other diseases, these findings may have translational applications beyond EBA.     

Epidermolysis bullosa acquisita: a disease of autoimmunity to type VII collagen

Epidermolysis bullosa acquisita (EBA) is one of a group of primary blistering diseases characterized by dermal/epidermal separation at the basement membrane (BM) of stratified squamous epithelium and IgG anti-BM autoantibodies (ABM). EBA ABMs can be distinguished from IgG ABMs in all other primary blistering diseases by their reactivity with the BM matrix protein, type VII collagen (C-VII). The clinical and histological features of EBA are highly variable and may be indistinguishable from those of other primary bullous diseases. The diagnosis can be confirmed by one of several methods that directly or indirectly demonstrate IgG ABMs to C-VII. IgG ABMs to C-VII are not specific for EBA. They have been described in SLE patients with and without a secondary blistering eruption, bullous eruption of SLE (BSLE). IgA ABMs to C-VII have been described in a subgroup of patients with linear IgA bullous dermatosis. Recent evidence suggests that autoimmunity to C-VII in EBA and BSLE is regulated by the same genes within the major histocompatibility complex (MHC) and contributes to the pathogenesis of acute inflammation and blisters in both disorders. The finding of ABMs to C-VII in SLE and BSLE, evidence that EBA and BSLE share an immunogenetic predisposition to C-VII autoimmunity, and an apparent association between susceptibility to SLE and EBA suggest a close relationship between SLE and autoimmunity to C-VII.     

Recombinant IL-6 treatment protects mice from organ specific autoimmune disease by IL-6 classical signalling-dependent IL-1ra induction

Cytokines are key regulators of physiological inflammatory responses, while aberrant cytokine expression contributes to pathogenesis of autoimmune diseases. We noted increased IL-6 levels in human and murine epidermolysis bullosa acquisita (EBA), a prototypic organ-specific autoimmune bullous dermatoses (AIBD) induced by autoantibodies to type VII collagen (COL7). In contrast to rheumatoid arthritis, blockade of IL-6 led to strikingly enhanced experimental EBA, while treatment with recombinant IL-6 was protective. This was due to classical IL-6 signalling and independent of IL-6 trans-signalling, as treatment of mice with sgp130Fc had no impact on EBA manifestation. Induction of EBA in mice led to increased IL-1ra levels in skin and serum, while blockade of IL-6 completely inhibited IL-1ra expression induced by autoantibodies to COL7. In line, treatment of mice with EBA with recombinant IL-6 induced IL-1ra concentrations exceeding those of untreated animals with EBA, and IL-1ra (anakinra) administration significantly impaired experimental EBA induction. We here identified a novel anti-inflammatory pathway in an organ-specific autoimmune disease. Modulation of this IL-1ra pathway by classical IL-6 signalling demonstrates anti-inflammatory and protective activities of IL-6 in vivo.     

Crescentic glomerulonephritis and subepidermal blisters with autoantibodies to alpha5 and alpha6 chains of type IV collagen

We describe a novel autoimmune disease characterized by severe subepidermal bullous eruption and crescentic glomerulonephritis with autoantibodies directed against the noncollagenous domain of the alpha5 and alpha6 chains of type IV collagen. Biopsy of perilesional skin revealed a subepidermal blister with marked polymorphonuclear infiltrate with linear deposits of IgA and C3. Light microscopy of a kidney biopsy specimen revealed a crescentic glomerulonephritis, and immunofluorescence microscopy showed linear basement membrane staining for IgA (3+), C3 (1+), and IgG (1+). No electron-dense deposits were observed by transmission electron microscopy. The patient's autoantibodies reacted with normal human skin and kidney: IgA (3+) and IgG (1+) antibodies stained the basement membrane zones of skin, renal glomerulus, and some tubules. The identity of the target antigen was determined by immunochemical analyses of candidate antigens using the patient's autoantibodies. The patient's IgA and IgG autoantibodies reacted with a 185- to 190-kDa antigen from a human dermal extract that was distinguished from the other dermal or epidermal antigens, including the 145- to 290-kDa (type VII collagen) epidermolysis bullosa acquisita antigen, the 165- to 200-kDa alpha3 laminin mucous membrane cicatricial pemphigoid antigen, and the 230-kDa and the 180-kDa bullous pemphigoid antigens. Patient's IgA and IgG autoantibodies further reacted with the alpha5(IV) and weakly with the alpha6(IV) chains of type IV collagen by Western blot and ELISA. This report expands the repertoire of bullous skin disorders and provides an explanation for the association of anti-type IV collagen autoantibodies and glomerulonephritis with subepidermal blisters.     

Evaluation of recombinant antigen-based assays for diagnosis of bullous autoimmune diseases

The diagnosis of autoimmune bullous diseases is based on clinical observation and on the presence of autoantibodies directed to molecules involved in the adhesion systems of the skin. Immunofluorescence assays are the currently accepted method for detection of autoantibodies; such assays depend greatly on the skill of operators and are difficult to standardize. Recombinant desmoglein-1 (Dsg1), Dsg3, and BP180 peptides, the main autoantigens in pemphigus or bullous pemphigoid, have been used to develop new quantitative enzyme immunoassays (EIA) for the detection of specific antibodies. The present study was undertaken to evaluate the sensitivity and specificity of these immunoassays and to determine the correlation between the results and the clinical aspects of diseases. Serum samples from patients with pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, or mucous membrane pemphigoid, from healthy individuals, and from patients with unrelated autoimmune conditions were tested. Anti-desmoglein reactivity was detected in all the patients with pemphigus and in none of the controls. Patients with the more benign form of cutaneous disease had anti-Dsg1 antibodies, while patients with deeper cutaneous lesions or with mucosal involvement had anti-Dsg3 reactivity also, or exclusively. The BP180-based assay was positive for 66.6% of patients with bullous pemphigoid and for none of the patients with mucous membrane pemphigoid, and no reactivity was detected in the control sera. In conclusion, the anti-Dsg1 and anti-Dsg3 assays are useful in the diagnosis of pemphigus and provide information on the clinical phenotype of the disease. However, the sensitivity of EIA for detection of autoantibodies in bullous pemphigoid should be improved by the use of additional antigens or epitopes.     

Antibodies to desmogleins 1 and 3, but not to BP180, induce blisters in human skin grafted onto SCID mice

Pemphigus and bullous pemphigoid (BP) are blistering skin diseases associated with IgG autoantibodies to desmosomal and hemidesmosomal components. When autoantibodies to desmogleins 1 and 3 from patients with pemphigus foliaceus (PF) and pemphigus vulgaris (PV) or rabbit antibodies against the murine hemidesmosomal component BP180 are passively transferred into neonatal mice, they induce blisters in the skin of the mice. To develop an animal model that would duplicate the findings in the skin of the patients more closely, full-thickness human skin from healthy volunteers was grafted onto SCID mice. Injection of the purified IgG fraction from the serum of PF and PV patients led to subcorneal and suprabasal splits in the human grafts and human IgG was deposited intercellularly in the upper and lower layers of the epidermis, respectively. Interestingly, anti-BP180 autoantibodies purified from the serum of BP patients and from a rabbit immunized with recombinant human BP180 strongly bound to the basement membrane zone of the grafts (n=32), fixed murine complement, led to the recruitment of neutrophils to the upper dermis of the graft, but did not induce subepidermal blisters. We report a novel experimental model for PF and PV which should greatly facilitate further studies to dissect the immunopathological mechanisms in these diseases. Specifically, this model can be used to identify pathogenically relevant epitopes on human desmogleins 1 and 3 and to develop novel strategies for the treatment of pemphigus.     

Pemphigoid diseases: pathogenesis, diagnosis, and treatment

Pemphigoid diseases (including bullous pemphigoid, mucous membrane pemphigoid, pemphigoid gestationis, linear IgA dermatosis, lichen planus pemphigoides, and anti-p200 pemphigoid) are a subgroup of autoimmune bullous skin diseases characterized by an autoantibody response toward structural components of the hemidesmosome resulting in subepidermal blistering. By the use of different in vitro systems and experimental animal models, the pathogenic relevance of these autoantibodies has been demonstrated. Recent advances in the understanding of autoantibody responses have led to novel diagnostic tools and a more differentiated therapeutic approach for these disorders. This review covers the most recent understanding of the pathophysiology, diagnosis, and treatment of this group of autoimmune diseases.     

Neonatal Fc receptor deficiency protects from tissue injury in experimental epidermolysis bullosa acquisita

Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering disease caused by autoantibodies against type VII collagen. The neonatal Fc receptor (FcRn) regulates immunoglobulin G (IgG) homeostasis and thus controls serum levels of antibodies. In this study, we investigated the effects of FcRn deficiency on the levels of autoantibodies against type VII collagen and blistering in EBA. For this purpose, rabbit IgG against murine type VII collagen was injected into FcRn-deficient and wild-type (n = 10 per group) mice. Enzyme-linked immunosorbent assay levels of serum IgG against type VII collagen were significantly lower in mutant compared with wild-type mice. Analysis of serum levels of specific autoantibodies induced in FcRn-deficient and wild-type mice (n = 10 per group) by immunization with type VII collagen showed significantly lower serum levels of IgG against type VII collagen in FcRn-deficient mice compared with wild-type animals. Importantly, the extent of blistering disease after injection of IgG against type VII collagen was significantly reduced in FcRn-deficient mice compared to wild-type controls. Our data demonstrate that FcRn maintains levels of pathogenic autoantibodies and thereby promotes tissue injury in experimental EBA. Therefore, modulation of FcRn function using inhibitors may reduce pathogenic IgG levels, offering therapeutic benefit in patients with antibody-mediated diseases.