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Upogebiamajor (De Haan, 1841) is known for forming huge burrows in sandy, intertidal areas that can extend to depths of over 2 m. Despite its widespread distribution in East Asia and Russia, the genetic relatedness of its regional populations remains uncertain, likely owing to difficulties in specimen collection. Therefore, to appraise the phylogeographic patterns, genetic diversity, and morphological variety of U.major, the mitochondrial DNA of specimens collected from Japan, Korea and China were subjected to molecular phylogenetic analyses of COI genes, alongside morphological assessment. As a result, we discovered four principal groups; of these, Group 1 consisted predominantly of Japanese specimens, while Groups 3 and 4 were interpreted as having originated from the continent. Group 2 exhibited genetic segregation from both continental and Japanese descent. Group 1 mostly comprising Japanese specimens implies that the planktonic larvae of U.major were disseminated north and south by ocean currents encompassing the Japanese archipelago. In contrast, individuals probably originating from the continent were discovered in Lake Notoro, Hokkaido and Matsukawa-ura, Fukushima in northeastern Japan, indicating possible introduction from the continent through ocean currents or unintentional introduction with other organisms imported. Additionally, one of the specimens collected from Matsukawa-ura exhibited significant genetic and morphological differences from other specimens, suggesting the possibility of being a subspecies. The outcomes of this study not only offer valuable insights into the origins of distribution of U.major but also introduce a novel challenge of assessing the coexistence of two routes: natural and anthropogenic dispersion.
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BACKGROUND: Pemphigoid diseases are characterized by subepidermal blister formation accompanied by autoantibodies targeting skin component molecules, such as BP180. It is suggested that an epitope-phenotype correlation exists among autoantibodies recognizing BP180. However, it is unclear which regions of BP180 are likely targets for autoantibodies. OBJECTIVE: To elucidate the portions of BP180 where antibodies tend to react under the breakdown of immune tolerance. METHODS: We immunized mice with full-length mouse BP180 (mBP180) to produce anti-mBP180 antibodies. Using the immunized mice, hybridoma cells were established to produce anti-mBP180 antibodies. We analyzed the characteristics of the anti-mBP180 antibodies that were produced in terms of epitopes, immunoglobulin subclasses, and somatic hypermutations. RESULTS: Hybridoma cells derived from immunized mice with full-length mBP180 produced antibodies targeting the intracellular domain (IC) and the shed ectodomain (EC) of mBP180. Using the domain-deleted mBP180 recombinant protein, we revealed that monoclonal anti-mBP180 EC antibodies react to neoepitopes on the 13th collagenous region of cleaved mBP180, which corresponds to the epitopes of linear IgA bullous dermatosis antibodies in human BP180. Furthermore, the subclasses of these antibodies could be distinguished by epitope: The subclass of the anti-mBP180 IC monoclonal antibodies was IgG, whereas that of the anti-mBP180 EC antibodies was IgM. Of note, a clone of these IgM mBP180 EC antibodies was a germline antibody without somatic hypermutation, which is also known as a natural antibody. CONCLUSION: These data suggest that mice potentially have natural antibodies targeting the neoepitopes of cleaved mBP180 EC.
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Colágenos no Fibrilares , Penfigoide Ampolloso , Humanos , Animales , Ratones , Colágenos no Fibrilares/genética , Autoantígenos , Autoanticuerpos , Epítopos , Piel , Inmunoglobulina MAsunto(s)
COVID-19 , Penfigoide Ampolloso , Humanos , Autoanticuerpos , Autoantígenos , Colágenos no FibrilaresRESUMEN
Bullous pemphigoid (BP) is an autoimmune disease characterized by itchy erythema and tense blisters on the whole body. Recent reports have unveiled the pathogenic roles of eosinophils in BP (e.g., dermal-epidermal separation, generation of pruritus). Thus, eosinophils are considered a therapeutic target. Benralizumab is an anti-IL-5 receptor alpha (IL-5Rα) monoclonal antibody (mAb) that is widely used to treat severe eosinophilic asthma. By affecting IL-5Rα, benralizumab depletes eosinophils and basophils due to apoptosis through antibody-dependent cell-mediated cytotoxicity. The efficacies of benralizumab and other biologics, including bertilimumab (anti-eotaxin-1 mAb) and mepolizumab (anti-IL-5 mAb), were evaluated in several clinical trials. Also, reslizumab, an anti-IL-5 mAb, was reported as a successful treatment option in a case of BP. We present a case of severe asthma treated with benralizumab at 8-week intervals for 3 years before BP developed. Histologically, subepidermal blisters without eosinophilic infiltration were observed. Methylprednisolone pulse therapy followed by 40 mg/day (1 mg/kg/day) of oral prednisolone (PSL) was initiated, but the skin lesions worsened. Additional intravenous immunoglobulin and oral azathioprine enabled the oral PSL to be tapered. The benralizumab was discontinued after the onset of BP because the asthma did not worsen. To the best of our knowledge, there have been no reports of BP developing during anti-eosinophil therapy. BP may occur paradoxically via various pathways during treatment with drugs that are typically effective against BP.
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Asma , Penfigoide Ampolloso , Eosinofilia Pulmonar , Humanos , Penfigoide Ampolloso/inducido químicamente , Penfigoide Ampolloso/tratamiento farmacológico , Penfigoide Ampolloso/complicaciones , Vesícula , Asma/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Eosinofilia Pulmonar/complicaciones , Prednisolona/uso terapéuticoRESUMEN
Bullous pemphigoid (BP) is the most common autoimmune blistering disorder. Several factors, including an antidiabetic (dipeptidyl peptidase-4 inhibitor [DPP-4i]), have been reported to trigger BP. To identify the genetic variants associated with BP, GWAS and HLA fine-mapping analyses were conducted. The 21 cases of noninflammatory BP induced by DPP-4i (i.e., DPP-4i-induced noninflammatory BP) and 737 controls (first cohort) and the 8 cases and 164 controls (second cohort) were included in the GWAS. Combining GWAS satisfied the genome-wide significant association of HLA-DQA1 (chromosome 6, rs3129763 [T/C]) with the risk of DPP-4i-induced noninflammatory BP (allele T carrier of 72.4% [21 of 29] in cases vs. 15.3% [138 of 901] in controls; dominant model, OR = 14, P = 1.8 × 10-9). HLA fine mapping revealed that HLA-DQA1∗05 with serine at position 75 of HLA-DQα1 (Ser75) had the most significant association with the combined cohort of DPP-4i-induced noninflammatory BP (79.3% [23 of 29] cases vs. 16.1% [145 of 901] controls; dominant model, OR = 21, P = 2.0 × 10-10). HLA-DQα1 Ser75 polymorphism was located inside the functional pocket of HLA-DQ molecules, suggesting the impact of HLA-DQα1 Ser75 on DPP-4i-induced noninflammatory BP.
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Pemphigoid diseases are a group of autoimmune disorders characterized by subepidermal blistering in the skin and mucosa. Among them, mucous membrane pemphigoid (MMP) autoantibodies are characterized by targeting multiple molecules in the hemidesmosomes, including collagen XVII, laminin-332, and integrin a6/ß4. Traditionally, recombinant proteins of the autoantigens have been employed to identify circulating autoantibodies by immune assays. However, developing an efficient detection system for MMP autoantibodies has been challenging because the autoantibodies have heterogeneous profiles and the antibody titers are typically low. In this study, we introduce an ELISA that takes advantage of a native autoantigen complex rather than simple recombinant proteins. We generated HaCaT keratinocytes with a DDDDK-tag knocked in at the COL17A1 locus by CRISPR/Cas9-mediated gene editing. Immunoprecipitation using the DDDDK-tag isolated a native complex that contained full-length and processed collagen XVII and integrin α6/ß4. Then, we used the complex proteins to prepare an ELISA system and enrolled 55 MMP cases to validate its diagnostic performance. The sensitivity and specificity of the ELISA for detecting MMP autoantibodies were 70.9% and 86.7%, respectively, far superior to those of conventional assays. In autoimmune diseases such as MMP, in which autoantibodies target various molecules, isolating the antigen-protein complexes can help establish a diagnostic system.
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Autoanticuerpos , Cadherinas Desmosómicas , Pénfigo , Humanos , Autoanticuerpos/inmunología , Desmogleína 3/inmunología , Cadherinas Desmosómicas/inmunología , Membrana Mucosa , Pénfigo/tratamiento farmacológico , Pénfigo/inmunología , Enfermedades Cutáneas Bacterianas/inmunología , Desmogleína 1/inmunologíaAsunto(s)
Aborto Retenido , Colitis Ulcerosa , Dermatosis Bullosa IgA Lineal , Femenino , Embarazo , Humanos , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/tratamiento farmacológico , Dermatosis Bullosa IgA Lineal/complicaciones , Dermatosis Bullosa IgA Lineal/tratamiento farmacológico , Inmunoglobulina ARESUMEN
[This corrects the article DOI: 10.3389/fimmu.2022.865241.].
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Chronic blistering at the skin and/or mucous membranes, accompanied by a varying degree of inflammation, is the clinical hallmark of pemphigoid diseases that impose a major medical burden. Pemphigoid diseases are caused by autoantibodies targeting structural proteins of the epithelial basement membrane. One major pathogenic pathway of skin blistering and inflammation is activation of myeloid cells following Fc gamma receptor-dependent binding to the skin-bound immune complexes. This process requires activation of specific kinases, such as PI3Kδ, which have emerged as potential targets for the treatment of pemphigoid diseases. Yet, it is unknown if global cutaneous kinase activity present in lesional pemphigoid disease correlates with therapeutic effects following treatment with a given target-selective kinase inhibitor. To address this, we here first determined the kinase activity in three different mouse models of pemphigoid diseases: Antibody transfer-induced mucous membrane pemphigoid (MMP), antibody transfer-induced epidermolysis bullosa acquisita (EBA) and immunization-induced EBA. Interestingly, the kinome signatures were different among the three models. More specifically, PI3Kδ was within the kinome activation network of antibody transfer-induced MMP and immunization-induced EBA, but not in antibody transfer-induced EBA. Next, the therapeutic impact of the PI3Kδ-selective inhibitor parsaclisib was evaluated in the three model systems. In line with the kinome signatures, parsaclisib had therapeutic effects in antibody transfer-induced MMP and immunization-induced EBA, but not in autoantibody-induced EBA. In conclusion, kinase activation signatures of inflamed skin, herein exemplified by pemphigoid diseases, correlate with the therapeutic outcomes following kinase inhibition, demonstrated here by the PI3Kδ inhibitor parsaclisib.
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Epidermólisis Ampollosa Adquirida , Penfigoide Benigno de la Membrana Mucosa , Penfigoide Ampolloso , Animales , Complejo Antígeno-Anticuerpo/uso terapéutico , Autoanticuerpos , Inflamación/patología , Ratones , Penfigoide Benigno de la Membrana Mucosa/patología , Fosfatidilinositol 3-Quinasas , Receptores de IgG , Piel , Resultado del TratamientoAsunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV , Penfigoide Ampolloso , Enfermedades Cutáneas Vesiculoampollosas , Humanos , Penfigoide Ampolloso/inducido químicamente , Penfigoide Ampolloso/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Técnica del Anticuerpo Fluorescente Directa , Colágenos no Fibrilares , Hipoglucemiantes , Coloración y Etiquetado , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas , Autoanticuerpos , AutoantígenosRESUMEN
Pemphigoid diseases are autoimmune chronic inflammatory skin diseases, which are characterized by blistering of the skin and/or mucous membranes, and circulating and tissue-bound autoantibodies. The well-established pathomechanisms comprise autoantibodies targeting various structural proteins located at the dermal-epidermal junction, leading to complement factor binding and activation. Several effector cells are thus attracted and activated, which in turn inflict characteristic tissue damage and subepidermal blistering. Moreover, the detection of linear complement deposits in the skin is a diagnostic hallmark of all pemphigoid diseases. However, recent studies showed that blistering might also occur independently of complement. This review reassesses the importance of complement in pemphigoid diseases based on current research by contrasting and contextualizing data from in vitro, murine and human studies.
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Penfigoide Ampolloso , Animales , Autoanticuerpos , Vesícula , Proteínas del Sistema Complemento , Humanos , Ratones , PielRESUMEN
Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease. Although the pathomechanism of BP onset has yet to be elucidated in detail, BP autoantibodies targeting two hemidesmosomal components, BP180 and BP230, are known to play a pivotal role in BP pathogenesis. Thus, the detection and measurement of BP autoantibodies are necessary for diagnosing BP and monitoring the disease activity. Immune assays such as immunofluorescence microscopy, immunoblotting, and ELISAs using BP180 and BP230 detect BP autoantibodies in most BP cases with high specificity; however, BP autoantibodies are sometimes detected in BP patients before the onset of this disease. BP autoantibodies that are detected in patients without typical tense blisters are defined as "preclinical BP autoantibodies". These preclinical BP autoantibodies are detected even in a low percentage of normal healthy individuals. Although the importance of preclinical BP autoantibodies remains elusive, these autoantibodies might be a potential risk factor for subsequent BP development. Therefore, previous comparative epidemiological studies have focused on the prevalence of preclinical BP autoantibodies in populations susceptible to BP (e.g., the elderly) or in diseases with a higher risk of comorbid BP. This mini-review summarizes the literature on the prevalence of preclinical BP autoantibodies in patients with various conditions and diseases, and we discuss the significance of preclinical BP autoantibody detection.
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Colágenos no Fibrilares , Penfigoide Ampolloso , Anciano , Autoanticuerpos , Autoantígenos , Humanos , ImmunoblottingRESUMEN
Immune checkpoint inhibitors (ICI) induce T-cell-mediated antitumour responses. While ICI were initially successfully applied in metastasized melanoma, they are now approved for several tumour entities. Numerous autoimmune disorders have been reported to occur as adverse events of the treatment, among them bullous pemphigoid (BP), with less than 1% of the patients experiencing ICI-induced BP. This number is higher than the estimated prevalence of autoimmune bullous diseases in the general population of Germany, which lies around 0.05%. We here describe our cohort of eight patients, who developed a bullous pemphigoid under or shortly after ICI treatment. Half of them had a severe subtype (as shown by BPDAI >57) and showed a median onset of ICI-BP after 10 months of ICI initiation. Six patients had a palmar and/or plantar involvement, while oral involvement occurred in one case. All patients had linear epidermal IgG depositions in split skin in the indirect immunofluorescence. In four out of five biopsies available for direct immunofluorescence, linear IgG and C3 depositions were detected at the basement membrane, while one patient showed linear IgM staining. Moderate to high levels of FLBP180 autoantibodies were found in seven of eight cases. The disease can still be active after ICI discontinuation, while rituximab might be required for remission. Finally, four tumour samples were stained histochemically for collagen XVII (BP180), but no enhanced expression was found.