A case of anti-BP230 antibody-positive bullous pemphigoid receiving DPP-4 inhibitor.

Bullous pemphigoid (BP) is a cutaneous autoimmune blistering disorder. Recently, it has been reported that dipeptidyl peptidase-4 inhibitors (DPP4i) is associated with the development of BP (DPP4i-BP). Patients with DPP4i-BP have autoantibodies (autoAbs) preferentially targeting full-length BP180, but not the BP180NC16a domain. In this report, we described a case of anti-BP230 antibody (Ab)-positive BP receiving DPP4i. A 78-year-old male with a medical history of type 2 diabetes receiving vildagliptin at 100 mg daily for 38 months was referred to our hospital with itching blisters on his body and extremities. Skin biopsy showed subepidermal bulla with eosinophil infiltration. Direct immunofluorescence staining revealed a linear staining pattern with complement C3 and IgG at the subepidermal basement membrane zone. By laboratory testing, autoAbs against BP180NC16a and full-length BP180 were negative by enzyme-linked immunosorbent assay (ELISA); however, anti-BP230 Abs were positive by ELISA (index: 123.91). His HLA genotype was DQB1*04:01 and 05:01. Based on these results, we diagnosed the patient with anti-BP230 Abs-positive BP associated with DPP4i. To the best of our knowledge, this is the first case of DPP4i-BP with only anti-BP230 Abs. Further accumulation of DPP4i-BP cases is needed to clarify the relationship between overall features of DPP4i-BP and anti-BP230 Abs.

BIOCHIP mosaic for the diagnosis of autoimmune bullous diseases in Chinese patients.

BACKGROUND: Autoimmune blistering diseases (AIBDs) are a group of fatal diseases with specific autoantibodies. BIOCHIP mosaic is a novel and all-in-one measure used for the rapid diagnosis of AIBDs. OBJECTIVES: To evaluate the diagnostic accuracy based on BIOCHIP mosaic (FA1501-1005-60) in Chinese patients with AIBDs. MATERIALS AND METHODS: Seventy-seven patients with AIBDs and 20 controls were enrolled. The BIOCHIP mosaic was performed using both serum and plasma samples. RESULTS: Based on BIOCHIP mosaic, the data from paired plasma and serum samples demonstrated a high degree of concordance (Cohen's kappa = 0.896-1.000) for autoantibodies against Dsg1, Dsg3, BP180-NC16A-4X, BP230gC, prickle-cell desmosomes, and pemphigoid antigens. Moreover, BIOCHIP mosaic also demonstrated a high degree of consistency for the detection rate of anti-Dsg1, Dsg3, plakins, BP180-NC16A-4X and non-collagenous domain of type VII collagen autoantibodies for the diagnosis of pemphigus foliaceus (77.3%), pemphigus vulgaris (88.6%), paraneoplastic pemphigus (100.0%), bullous pemphigoid (92.8%) and epidermolysis bullosa acquisita (99.0%), respectively. CONCLUSION: Using BIOCHIP mosaic, serum and plasma samples may be used interchangeably at 1/10 dilution. Overall, the BIOCHIP mosaic was shown to be a useful and accurate tool for the diagnosis of AIBDs.

Preferential Reactivity of Dipeptidyl Peptidase-IV Inhibitor-Associated Bullous Pemphigoid Autoantibodies to the Processed Extracellular Domains of BP180.

Bullous pemphigoid (BP) is a common autoimmune blistering disease in which autoantibodies target the hemidesmosomal components BP180 and/or BP230 in basal keratinocytes. In BP, 80 to 90% of autoantibodies target the juxtamembranous extracellular non-collagenous 16th A (NC16A) domain of BP180. Recently, the administration of dipeptidyl peptidase-IV inhibitors (DPP4i), which are widely used as antihyperglycemic drugs, has been recognized to be a causative factor for BP. DPP4i-associated BP (DPP4i-BP) autoantibodies tend to target epitopes on non-NC16A regions of BP180, and the pathomechanism for the development of the unique autoantibodies remains unknown. To address the characteristics of DPP4i-BP autoantibodies in detail, we performed epitope analysis of 18 DPP4i-BP autoantibodies targeting the non-NC16A domains of BP180 using various domain-specific as well as plasmin-digested polypeptides derived from recombinant BP180. Firstly, Western blotting showed that only one DPP4i-BP serum reacted with the epitopes on the intracellular domain of BP180, and no sera reacted with the C-terminal domain of the molecule. In addition, only 2 DPP4i-BP sera reacted with BP230 as determined by enzyme-linked immunosorbent assay. Thus, DPP4i-BP autoantibodies were found to mainly target the non-NC16A mid-portion of the extracellular domain of BP. Interestingly, Western blotting using plasmin-digested BP180 as a substrate revealed that all of the DPP4i-BP sera reacted more intensively with the 97-kDa processed extracellular domain of BP180, which is known as the LABD97 autoantigen, than full-length BP180 did. All of the DPP4i-BP autoantibodies targeting the LABD97 autoantigen were IgG1, and IgG4 was observed to react with the molecule in only 7 cases (38.9%). In summary, the present study suggests that IgG1-class autoantibodies targeting epitopes on the processed extracellular domain of BP180, i.e., LABD97, are the major autoantibodies in DPP4i-BP.

Bullous pemphigoid with hyperkeratosis and palmoplantar keratoderma: Three cases.

The clinical features of bullous pemphigoid are extremely polymorphous. Several atypical forms of bullous pemphigoid have been described, and the diagnosis critically relies on immunopathological findings. We describe three bullous pemphigoid patients characterized by palmoplantar keratoderma, diffused hyperkeratotic cutaneous lesions and extremely high levels of immunoglobulin E serum. The diagnosis of bullous pemphigoid should be taken into account in patients presenting diffused hyperkeratotic cutaneous lesions and palmoplantar keratoderma, even in the absence of blisters. Alteration of the keratinization process, that could occur in patients with genetic mutations in desmosomal and hemidesmosomal genes, may also be due to circulating autoantibodies against hemidesmosomal proteins in these bullous pemphigoid patients.

In vivo optical coherence tomography imaging in a case of mucous membrane pemphigoid and a negative Nikolsky's sign.

There is currently a growing interest in new diagnostic tools of the oral cavity and mucosa which are non-invasive, repeatable and reliable. A diagnosis of a suspected, autoimmune pathology was made regarding a 57-year-old patient with desquamative gingivitis. However, a negative Nikolsky's sign did not seem to indicate a diagnosis of mucous membrane pemphigoid neither was there any indication as to the optimum location for an incisional biopsy. As an imaging method, the use of optical coherence tomography (OCT) has enabled the obtaining of tomographic (cross-sectional) scans of tissue. Such images are acquired prior to and after verifying Nikolsky's sign, thereby enabling the clinician to identify the presence (or not) of subepithelial bullae. Thereafter, an assessment of changes in the subepithelium (the split) can be performed, even in the absence of a suitable clinical picture, such as, for example, a negative Nikolsky's sign. Histological analysis and the use of indirect immunofluorescence have facilitated a diagnosis of mucous membrane pemphigoid, an autoimmune pathology, which can be confirmed with the appearance of subepithelial bullae. OCT was found to be a valid, non-invasive, auxiliary diagnostic device, capable of revealing in vivo and real-time bullae, which were hitherto clinically undetectable.

Structural proteins of the dermal-epidermal junction targeted by autoantibodies in pemphigoid diseases.

The dermal-epidermal junction consists of a network of several interacting structural proteins that strengthen adhesion and mediate signalling events. This structural network consists of hemidesmosomal-anchoring filament complexes connecting the basal keratinocytes to the basement membrane. The anchoring filaments in turn interact with the anchoring fibrils to attach the basement membrane to the underlying dermis. Several of these structural proteins are recognized by autoantibodies in pemphigoid diseases, a heterogeneous group of clinically and immunopathologically diverse entities. Targeted proteins include the two intracellular plakins, plectin isoform 1a and BP230 (also called bullous pemphigoid antigen (BPAG) 1 isoform e (BPAG1e)). Plectin 1a and BP230 are connected to the intermediate filaments and to the cell surface receptor α6ß4 integrin, which in turn is connected to laminin 332, a component of the anchoring filaments. Further essential adhesion proteins are BP180, a transmembrane protein, laminin γ1 and type VII collagen. Latter protein is the major constituent of the anchoring fibrils. Mutations in the corresponding genes of these adhesion molecules lead to inherited epidermolysis bullosa emphasizing the importance of these proteins for the integrity of the dermal-epidermal junction. This review will provide an overview on the structure and function of the proteins situated in the dermal-epidermal junction targeted by autoantibodies.