The major autoantigens for pemphigus are desmogleins (Dsgs), cell–cell adhesive structure proteins, one of the desmosomal cadherins. Recent progress in molecular biology has revealed that IgG ...autoantibodies of classical pemphigus react with Dsg1 or Dsg3. Desmocollins (Dscs) also belong to the cadherin supergene family that provides structure to the desmosomes and play an important role in cell‐to‐cell adhesion. In addition to the presence of four desmosomal Dsg isoforms, i.e. Dsg1‐4, Dsc1, 2 and 3, all of which are derived from different genes, Dsc1 has been previously identified as the target antigen of IgA autoantibodies in the subcorneal pustular dermatosis (SPD)‐type of intercellular IgA dermatosis. In addition to the IgA anti‐Dsc1 autoantiboides, the presence of IgG anti‐Dsc autoantibodies is described in patients of some autoimmune bullous diseases. In particular, the current pemphigus detecting autoantibodies to Dscs has shown a tendency in atypical variants of pemphigus. Therefore, autoantibodies against Dscs alone may cause detachment of cell–cell adhesion in the epidermis in some pemphigus. However, except for the findings of a few in vitro and in vivo studies, there is currently no clear evidence for the pathogenicity of anti‐Dsc autoantibodies in pemphigus, whereas significance of anti‐Dsg autoantibodies is well established. This article describes the structure and function of the Dscs, and explores the evidence regarding the pathogenic role of anti‐Dsc autoantibodies in pemphigus.
The pemphigoid group is a category of autoimmune subepidermal blistering diseases in which autoantibodies deposit linearly at the epidermal basement membrane zone (BMZ). The main subtypes of ...pemphigoid mediated by immunoglobulin G autoantibodies are bullous pemphigoid (BP), mucous membrane pemphigoid (MMP) and epidermolysis bullosa acquisita (EBA). To establish the first guidelines approved by the Japanese Dermatological Association for the management of pemphigoid diseases, the Committee for Guidelines for the Management of Pemphigoid Diseases (Including EBA) was founded as part of the Study Group for Rare Intractable Skin Diseases under the Ministry of Health, Labor and Welfare Research Project on Overcoming Intractable Diseases. These guidelines aim to provide current information for the management of BP, MMP and EBA in Japan. Based on evidence, the guidelines summarize the clinical and immunological manifestations, pathophysiologies, diagnostic criteria, disease severity determination criteria, treatment algorithms and treatment recommendations. Because of the rarity of these diseases, there are few clinical studies with a high degree of evidence, so several parts of these guidelines were established based on the opinions of the Committee. To further optimize these guidelines, periodic revision in line with the new evidence is necessary.
Immune checkpoint inhibitors including programmed cell death protein 1 (PD‐1) antibody are used in major breakthrough therapies in cancer, however they cause unique adverse events, termed ...immune‐related adverse events (irAEs). Among the various dermatological irAEs, an autoimmune bullous disease, bullous pemphigoid (BP), the hallmarks of which are circulating autoantibodies to epidermal basement membrane zone (BMZ) including BP180, have been noted. However, the mechanism and timing of autoantibody production in PD‐1 inhibition remains unclear. Herein we report the case of a lichen planus (LP)‐like lesion in presence of anti‐BMZ antibodies, preceding BP in a patient treated with pembrolizumab, a PD‐1 antibody. A 72‐year‐old Japanese woman with a 3‐month history (6 cycles) of pembrolizumab was referred to our department for pruritic purple‐red papules or plaques. Histological finding revealed LP‐like dermatitis. Although pembrolizumab was stopped because of disease progression, she developed edematous erythematous lesions and tense blisters seven weeks later. Based on histopathological findings, direct immunofluorescence (DIF) assay and positive findings on chemiluminescent enzyme immunoassay (CLEIA) for BP180, she was diagnosed with BP and administered oral prednisolone. The blisters and erythemas improved, whereas her respiratory condition worsened and she died 29 days after the development of BP. We performed DIF of formalin‐fixed, paraffin‐embedded specimens biopsied from the LP‐like lesion and revealed IgG deposition at the epidermal BMZ. This finding showed anti‐BMZ antibodies had already existed at LP‐like lesion preceding development of BP; this suggests that the preceding LP‐like lesion induced anti‐BMZ antibody production, resulting in the development of BP.
Pemphigus is a group of autoimmune bullous diseases characterized by the presence of autoantibodies against adhesion molecules, desmogleins, and desmocollins (DSCs). The pathogenicity of anti-DSC3 ...antibodies in pemphigus has been demonstrated; however, its characteristics have not yet been elucidated. We aimed to analyze the characteristics of anti-DSC3 antibodies using DSC3 domain‒swapped desmoglein 2 molecules in which the prosequence and five extracellular (EC) domains of desmoglein 2 were replaced with the corresponding domains of human DSC3. Using these proteins, we established an ELISA and analyzed sera from 56 patients with pemphigus. In 34 pemphigus sera positive for DSC3 full-EC domains, 15 sera (44.1%) were positive for EC2 domain, whereas other domains were rarely positive. We assessed the reactivity to a calcium-dependent epitope in DSC3 by ELISA with EDTA. The reactivity with the EC2 domain was mostly compromised in the presence of EDTA. In the in vitro assay, IgG from patients with paraneoplastic pemphigus preadsorbed with EC2 prevented both reduction of DSC3 and keratinocyte dissociation as compared with that with EDTA-treated EC2. This study revealed a predominant recognition of calcium-dependent epitopes in EC2 domain by anti-DSC3 antibodies and its pathogenicity on keratinocyte adhesion through DSC3 depletion.
Abstract Background Epidermolysis bullosa acquisita (EBA) is an acquired autoimmune mechanobullous disease. EBA patients possess autoantibodies against type VII collagen which is composed of a ...collagenous domain flanked by non-collagenous NC1 and NC2 domains. It was reported that major epitopes reside within the NC1 domain and minor epitopes reside within NC2 domain. Objective The aim of this study is to develop a sensitive and specific ELISA to facilitate the diagnosis of EBA. Methods We developed ELISAs using recombinant NC1 domain produced by mammalian expression system and recombinant NC2 domain produced by mammalian or bacterial expression system to characterize autoantibodies in EBA. Next, we developed an ELISA using a combination of the NC1 (mammalian expression) and NC2 (bacterial expression). We tested the ELISAs with 49 EBA sera, 55 normal control sera, 20 pemphigus vulgaris and 20 bullous pemphigoid sera. Results When we evaluated the 49 EBA sera using the NC1 and NC2 ELISAs, 38 (77.5%) reacted with NC1 domain only, 7 sera (14.2%) reacted with both NC1 and NC2 domains, and one serum (2%) reacted with NC2 domain only. Therefore, to increase the sensitivity of the assay, we developed an ELISA coated with a mixture of recombinant NC1 and NC2 domains, resulting in 93.8% sensitivity and 98.1% specificity. By analyzing the time course of two EBA patients, ELISA scores fluctuated in parallel with their disease activity. Conclusion We conclude that the NC1 + NC2 ELISA can be a practical assay for the diagnosis and follow up of the antibody titers of EBA patients.
Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease (sAIBD). In addition to disease causing autoantibodies, several leukocyte subsets, including mast cells and eosinophils, play ...key roles in mediating skin inflammation. Detailed immunophenotyping and, more recently, the therapeutic effects of interleukin-4 (IL-4) receptor alpha inhibition in BP pointed to a prominent role of T helper 2 (Th2) cells. Among other cell types, IL-9 is expressed by Th2 and mast cells and potentially drives allergic, Th2-dominated inflammation. Although cytokines in BP have been relatively well investigated, the role of IL-9 has remained enigmatic. This study aimed to evaluate the effect of IL-9 in BP. Serum IL-9 levels were significantly elevated in patients with BP and decreased upon induction of remission. Serum IL-9 levels were not elevated in epidermolysis bullosa acquisita, another sAIBD. The time-course analysis using serum sets from four patients with BP revealed that serum IL-9 was a sensitive biomarker of BP. IL-9-positive cells infiltrated dominantly in BP lesions, especially in the blister fluid, and Th9 cells were abundant. Therefore, IL-9 was elevated in the serum and lesions of BP, which could be a biomarker of BP.
Epidermolysis bullosa acquisita (EBA) is an orphan autoimmune disease. Several clinical phenotypes have been described, but subepidermal blistering is characteristic of all variants. Limited data on ...clinical and immunopathological characteristics and treatment outcomes in EBA are available. To fill this gap, we collected this information from EBA cases, meeting current diagnostic criteria, published between 1971 and 2016.
We identified 1159 EBA cases. This number must be, however, interpreted with caution, as it is not possible to check for multiple reporting. The analysis of all cases indicated that EBA affects all age groups (median: 50 years, range: 1 to 94 years) at an equal gender distribution. Non-mechanobullous (non-MB) forms of EBA were observed in 55% of patients, whereas the mechanobullous variant (MB-EBA) or a combination of both variants was described in 38 or 7% of patients, respectively. Type VII collagen (COL7)-specific autoantibodies were primarily of the IgG isotype, but anti-COL7 IgA, IgM and IgE were also documented. Comparison of the 2 clinical EBA types showed a higher frequency of IgA deposits in non-MB EBA as opposed to MB EBA. Mucous membrane involvement was observed in 23% of patients, and 4.4% of cases were associated with other chronic inflammatory diseases. Of note, IgA deposits were more frequently observed in cases with mucous membrane involvement. Our analysis indicated that EBA is difficult to treat and that the choice of treatment varies widely. Chi square was applied to identify medications associated with complete remission (CR). Considering all EBA cases, intravenous immunoglobulin (IVIG, p = 0.0047) and rituximab (p = 0.0114) were associated with CR. Subgroup analysis demonstrated that no treatment was associated with CR for non-MB EBA, while IVIG (p = 0.003) was associated with CR in MB EBA.
Within the limitations of the study, we here document the clinical and immunopathological characteristics and treatment outcomes in a large cohort of EBA patients. The observed associations of single drugs with treatment outcome may serve as a guide to develop clinical trials.
Dipeptidyl peptidase 4 inhibitors (DPP‐4i) are associated with an increased risk of developing bullous pemphigoid (BP) in patients with diabetes. Autoantibodies targeting epitopes on the processed ...BP180, 120‐kDa (LAD‐1), and 97‐kDa (LABD97) linear immunoglobulin (Ig)A dermatosis antigens are the major autoantibodies in DPP‐4i‐associated BP. However, no case of mucous membrane pemphigoid (MMP) developing during treatment with DPP‐4i has been reported. We report a case of MMP associated with DPP‐4i. A man in his late 70s presented with oral mucous membrane erosion and a few blisters on his upper chest and back. He had used linagliptin for diabetes for over 1 year when he presented. The immunological characteristics were similar to DPP4i‐associated BP: higher reactivity to LAD‐1 and LABD97 than to the full‐length BP180. The aphthae achieved remission after oral linagliptin was replaced with sitagliptin. However, 6 months later, the aphthae relapsed and any DPP‐4i was discontinued. The aphthae disappeared, and now he is completely free from lesions associated with MMP. This case suggests that the DPP‐4i may have shared roles in the production of IgG antibodies to LAD‐1 or to LABD97 in the pathogenesis of DPP‐4i‐associated BP and MMP. Our case highlights the possibility of overlooking the mild MMP in DPP‐4i‐treated diabetes patients with mucosal lesions.
Immunoglobulin A (IgA) pemphigus, also known as intercellular IgA dermatosis, is a rare autoimmune bullous disease presenting with IgA anti‐keratinocyte cell surface autoantibodies. Concomitant ...lymphoproliferative disorders have been reported in IgA pemphigus, including IgA monoclonal gammopathy of undetermined significance and IgA type multiple myeloma (MM). A 35‐year‐old Japanese woman with a 3‐year history of pruritic papulovesicles on her lower legs and trunk was referred to our department. Histopathological examination revealed acantholytic blisters, and results of both direct and indirect immunofluorescence were negative. Direct and indirect immunofluorescence were still negative 3 years and 7 months later. Approximately 7 years after her first visit, the patient was re‐referred to us because of disease exacerbation. Histopathological findings revealed subcorneal blistering with acantholysis, in which neutrophil‐dominant inflammatory cells were present. Indirect immunofluorescence was positive for IgA on the epidermal cell surface and both desmoglein (Dsg) 1/3 and (Dsc) desmocollin 1–3 enzyme‐linked immunosorbent assays (ELISAs) for IgA were positive. The histological findings and positive Dsc1 IgA ELISA led to the diagnosis of subcorneal pustular dermatosis (SPD)‐type IgA pemphigus. Further examination revealed hyper‐IgA globulinemia, increased serum IgA‐κ protein, and increased plasma cells in the bone marrow, enabling the diagnosis of IgA type MM. Daratumumab, lenalidomide, and dexamethasone (DLd) therapy was effective for both the MM and the skin lesions, resulting in negative results on Dsg1/3 and Dsc1‐3 IgA ELISAs. The association between IgA pemphigus and IgA type multiple myeloma remains unclear, and only seven cases including the present case have been reported. Literature review revealed associations between SPD‐type and IgA κ chain in IgA pemphigus and MM, and that in most cases the onset or diagnosis of MM was simultaneous or occurred after the diagnosis of IgA pemphigus. Therefore, clinicians should be aware of the development of multiple myeloma during the clinical course of patients with SPD‐type IgA pemphigus.
Pemphigoid vegetans is a rare variant of bullous pemphigoid characterized by vegetative and purulent lesions of the groin, axillae, thighs, hands, eyelids, and perioral regions. The clinical features ...and histological findings of pemphigus vegetans and immunohistochemical characteristics of bullous pemphigoid are shown. An 86‐year‐old woman presented with vegetative lesions in the vulva and groin, and blisters on the head, neck, axillae, and thighs. Although clinically suspected as pemphigus vegetans, skin biopsy showed subepidermal clefts with eosinophil infiltration and eosinophilic pustules in the epidermis. Direct immunofluorescence analysis showed linear deposition of immunoglobulin (Ig)G along the basement membrane zone. Indirect immunofluorescence using 1 mol/L NaCl salt‐split skin showed linear deposition of IgG on the epidermal side. Chemiluminescent enzyme immunoassay and enzyme‐linked immunosorbent assay were positive for BP180 and BP230. Immunoblotting of recombinant protein of the BP180 C‐terminal domain showed positive reactivity. Pemphigoid vegetans was diagnosed and treated successfully with oral corticosteroids. This is the first case of pemphigoid vegetans reported to date with detection of autoantibodies against both BP180 C‐terminal domain and BP230.
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