RESUMEN

Bullous pemphigoid (BP) is the most common autoimmune bullous disease: it most commonly affects individuals over 70 years old and impacts severely on their quality of life. BP represents a paradigm for an organ-specific autoimmune disease and is characterized by circulating IgG autoantibodies to hemidesmosomal components: BP180 and BP230. While the crucial role of these autoantibodies in triggering BP inflammatory cascade is fully acknowledged, many ancillary etiological mechanisms need to be elucidated yet. Cutaneous melanoma is due to a malignant transformation of skin melanocytes, that produce and distribute pigments to surrounding keratinocytes. Melanoma is the most fatal skin cancer because of its increasing incidence and its propensity to metastasize. Several data such as: i) reported cases of concomitant melanoma and BP; ii) results from association studies; iii) BP onset following immune check-point inhibitors therapy; iv) expression of BP antigens in transformed melanocytes; and vi) circulating autoantibodies to BP antigens in melanoma patients suggest an intriguing, although unproven, possible association between melanoma and BP. However, a possible causative link is still debated and the putative pathogenetic mechanism underlying this association is unclear. This review aims to describe and discuss the possible relationship between BP and melanoma and give an overview of the speculations for or against this association. Of note, if demonstrated, this association could unwrap considerations of clinical relevance that represent new research frontiers.

Asunto(s)

Autoanticuerpos , Autoantígenos , Melanoma , Penfigoide Ampolloso , Humanos , Penfigoide Ampolloso/inmunología , Penfigoide Ampolloso/etiología , Melanoma/inmunología , Melanoma/etiología , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Autoantígenos/inmunología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/etiología , Colágeno Tipo XVII , Colágenos no Fibrilares/inmunología , Melanocitos/inmunología , Melanocitos/patología , Animales , Relevancia Clínica

RESUMEN

Melanoma incidence is increasing globally. Although novel therapies have improved the survival of primary melanoma patients over the past decade, the overall survival rate for metastatic melanoma remains low. In addition to traditional prognostic factors such as Breslow thickness, ulceration, and mitotic rate, novel genetic and molecular markers have been investigated. In our study, we analyzed the expression of G-protein coupled estrogen receptor 1 (GPER1) and the endodomain of collagen XVII (COL17) in relation to clinicopathological factors in primary cutaneous melanomas with known lymph node status in both sexes, using immunohistochemistry. We found, that GPER1 expression correlated with favorable clinicopathological factors, including lower Breslow thickness, lower mitotic rate and absence of ulceration. In contrast, COL17 expression was associated with poor prognostic features, such as higher tumor thickness, higher mitotic rate, presence of ulceration and presence of regression. Melanomas positive for both GPER1 and COL17 had significantly lower mean Breslow thickness and mitotic rate compared to cases positive for COL17 only. Our data indicate that GPER1 and COL17 proteins may be of potential prognostic value in primary cutaneous melanomas.

Asunto(s)

Autoantígenos , Biomarcadores de Tumor , Colágeno Tipo XVII , Melanoma , Colágenos no Fibrilares , Receptores de Estrógenos , Receptores Acoplados a Proteínas G , Neoplasias Cutáneas , Humanos , Melanoma/patología , Melanoma/metabolismo , Femenino , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Pronóstico , Masculino , Receptores de Estrógenos/metabolismo , Persona de Mediana Edad , Biomarcadores de Tumor/metabolismo , Anciano , Colágenos no Fibrilares/metabolismo , Colágenos no Fibrilares/genética , Autoantígenos/metabolismo , Adulto , Melanoma Cutáneo Maligno , Anciano de 80 o más Años

RESUMEN

The 16th non-collagenous domain (NC16A) of BP180 is the main antigenic target of autoantibodies in bullous pemphigoid (BP) and mucous membrane pemphigoid (MMP). Commercially available assays detect serum autoantibodies against NC16A in the majority of BP (80%-90%) and in approximately 50% of MMP patients. However, a standardized test system for detecting antibodies against other regions of BP180 is still lacking. Moreover, anti-BP180 autoantibodies have been found in neurological conditions such as multiple sclerosis and Parkinson disease. This study aimed at identifying primary epitopes recognized by BP autoantibodies on the BP180 ectodomain. Serum samples of 51 BP and 30 MMP patients both without anti-NC16A reactivity were included along with 44 multiple sclerosis and 75 Parkinson disease sera. Four overlapping His-tagged proteins covering the entire BP180 ectodomain (BP180(ec)1-4) were cloned, expressed, purified and tested for reactivity by immunoblot. IgG antibodies to BP180(ec)3 were detected in 98% of BP, 77% of MMP and 2% of normal human sera. Only weak reactivity was detected for neurological diseases against BP180(ec)1, BP180(ec)2 and BP180(ec)4, in 3%, 11% and 7% of tested multiple sclerosis sera, respectively. 8% of Parkinson disease sera reacted with BP180(ec)2 and 9% with BP180(ec)4. In conclusion, this study successfully identified epitopes recognized by BP autoantibodies outside the NC16A domain in pemphigoid diseases. These findings contribute to a better understanding of the immune response in BP and MMP with potential implications for a future diagnostic assay for NC16A-negative pemphigoid patients.

Asunto(s)

Autoanticuerpos , Autoantígenos , Colágeno Tipo XVII , Esclerosis Múltiple , Colágenos no Fibrilares , Enfermedad de Parkinson , Penfigoide Benigno de la Membrana Mucosa , Penfigoide Ampolloso , Humanos , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/sangre , Colágenos no Fibrilares/inmunología , Penfigoide Ampolloso/inmunología , Penfigoide Ampolloso/sangre , Autoantígenos/inmunología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/sangre , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Penfigoide Benigno de la Membrana Mucosa/inmunología , Penfigoide Benigno de la Membrana Mucosa/sangre , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Epítopos/inmunología , Dominios Proteicos , Femenino , Masculino , Anciano

RESUMEN

Bullous pemphigoid (BP) is a type 2 inflammation- and immunity-driven skin disease, yet a comprehensive understanding of the immune landscape, particularly immune-stromal crosstalk in BP, remains elusive. Herein, using single-cell RNA sequencing (scRNA-seq) and in vitro functional analyzes, we pinpoint Th2 cells, dendritic cells (DCs), and fibroblasts as crucial cell populations. The IL13-IL13RA1 ligand-receptor pair is identified as the most significant mediator of immune-stromal crosstalk in BP. Notably, fibroblasts and DCs expressing IL13RA1 respond to IL13-secreting Th2 cells, thereby amplifying Th2 cell-mediated cascade responses, which occurs through the specific upregulation of PLA2G2A in fibroblasts and CCL17 in myeloid cells, creating a positive feedback loop integral to immune-stromal crosstalk. Furthermore, PLA2G2A and CCL17 contribute to an increased titer of pathogenic anti-BP180-NC16A autoantibodies in BP patients. Our work provides a comprehensive insight into BP pathogenesis and shows a mechanism governing immune-stromal interactions, providing potential avenues for future therapeutic research.

Asunto(s)

Quimiocina CCL17 , Células Dendríticas , Fibroblastos , Penfigoide Ampolloso , Análisis de la Célula Individual , Células Th2 , Humanos , Penfigoide Ampolloso/inmunología , Penfigoide Ampolloso/genética , Análisis de la Célula Individual/métodos , Fibroblastos/metabolismo , Fibroblastos/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Quimiocina CCL17/genética , Quimiocina CCL17/metabolismo , Células Th2/inmunología , Autoanticuerpos/inmunología , Transcriptoma , Interleucina-13/metabolismo , Interleucina-13/genética , Interleucina-13/inmunología , Colágenos no Fibrilares/inmunología , Colágenos no Fibrilares/genética , Colágenos no Fibrilares/metabolismo , Inflamación/inmunología , Inflamación/genética , Inflamación/metabolismo , Perfilación de la Expresión Génica/métodos , Masculino , Femenino , Autoantígenos/inmunología , Autoantígenos/metabolismo , Autoantígenos/genética , Colágeno Tipo XVII , Células Mieloides/metabolismo , Células Mieloides/inmunología , Células del Estroma/metabolismo , Células del Estroma/inmunología

Asunto(s)

Autoanticuerpos , Autoantígenos , Colágeno Tipo XVII , Desmocolinas , Colágenos no Fibrilares , Pénfigo , Humanos , Pénfigo/inmunología , Pénfigo/patología , Desmocolinas/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Colágenos no Fibrilares/inmunología , Autoantígenos/inmunología , Femenino , Masculino , Persona de Mediana Edad

RESUMEN

OBJECTIVE: To diagnose and explore the genetic etiology of a neonate with Hereditary epidermolysis bullosa. METHODS: A neonate who was admitted to Suqian Hospital Affiliated to Xuzhou Medical University on July 10, 2021 was selected as the study subject. Peripheral blood samples were collected from the child and his parents for the extraction of genomic DNA. And target gene capture and next-generation sequencing were carried out. Candidate variants were verified by Sanger sequencing and pathogenicity analysis. RESULTS: The child was found to harbor compound heterozygous variants of the COL17A1 gene, namely c.997C>T (p.Q333X) and c.3481dupT (p.Y1161fs*2), which were respectively inherited from his father and mother. Both variants were predicted to be pathogenic. CONCLUSION: The child was diagnosed with Generalized atrophic benign epidermolysis bullosa due to the compound heterozygous variants of the COL17A1 gene.

Asunto(s)

Colágeno Tipo XVII , Epidermólisis Ampollosa , Femenino , Humanos , Recién Nacido , Masculino , Epidermólisis Ampollosa/genética , Heterocigoto , Mutación

Asunto(s)

Autoanticuerpos , Autoantígenos , Linfocitos B , Colágeno Tipo XVII , Inmunoglobulina A , Inmunoglobulina G , Colágenos no Fibrilares , Penfigoide Benigno de la Membrana Mucosa , Humanos , Autoanticuerpos/inmunología , Inmunoglobulina A/inmunología , Penfigoide Benigno de la Membrana Mucosa/inmunología , Penfigoide Benigno de la Membrana Mucosa/diagnóstico , Colágenos no Fibrilares/inmunología , Inmunoglobulina G/inmunología , Autoantígenos/inmunología , Linfocitos B/inmunología , Femenino , Masculino , Anciano

RESUMEN

Tumor dormancy is the underpinning for cancer relapse and chemoresistance, leading to massive cancer-related death in colorectal cancer (CRC). However, our comprehension of the mechanisms dictating tumor dormancy and strategies for eliminating dormant tumor cells remains restricted. In this study, we identified that collagen XVII (COL17A1), a hemidesmosomal transmembrane protein, can promote the dormancy of CRC cells. The upregulation of COL17A1 was observed to prolong quiescence periods and diminish drug susceptibility of CRC cells. Mechanistically, COL17A1 acts as a scaffold, enhancing the crosstalk between mTORC2 and Akt, thereby instigating the mTORC2-mediated dormant signaling. Notably, the activation of mTORC2 is contingent upon the intracellular domain of COL17A1, regardless of its ectodomain shedding. Our findings underscore a pivotal role of the COL17A1-mTORC2 axis in CRC dormancy, suggesting that mTORC2-specific inhibitors may hold therapeutic prospects for the eradication of dormant tumor cells.

Asunto(s)

Colágeno Tipo XVII , Neoplasias Colorrectales , Diana Mecanicista del Complejo 2 de la Rapamicina , Colágenos no Fibrilares , Transducción de Señal , Humanos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Colágenos no Fibrilares/metabolismo , Colágenos no Fibrilares/genética , Línea Celular Tumoral , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Autoantígenos/metabolismo , Ratones , Ratones Desnudos , Proliferación Celular , Ratones Endogámicos BALB C

RESUMEN

BACKGROUND: Bullous pemphigoid (BP), the most common subepidermal autoimmune blistering disease, is classically defined by the presence of IgG autoantibodies directed against the hemidesmosomal proteins BP180 (type XVII collagen) and BP230 and the predominance of skin lesions. Several studies have addressed the role of anti-BP180 IgE in patients and experimental models, while data on anti-BP230 IgE are scarce. OBJECTIVE: To assess anti-BP230 IgE level by ELISA in BP sera and to correlate it with disease severity and clinical characteristics. METHODS: BP sera underwent anti-BP230 IgE ELISA and Western blotting against human BP230 fragments. RESULTS: We demonstrate that 36/154 (23%) of BP sera were positive for anti-BP230 IgE. Anti-BP230 IgE levels had no correlation with clinical phenotype or disease activity per se. Interestingly, anti-BP230 IgE was significantly associated with disease activity within individuals during the course of the disease. Additionally, anti-BP230 IgE and total IgE levels showed a significant correlation. Notably, anti-BP230 IgG correlated interindividually with disease activity. By Western blotting, the C-terminal domain of BP230 fragments (C2; amino acids 2024-2349 and C3; amino acids 2326-2649), provided the best serological assay for anti-BP230 IgE detection. CONCLUSION: As a complementary tool, IgE immunoblotting is recommended to obtain an optimal serological diagnosis, particularly in patients with severe disease without IgG reactivity by BP180- or BP230-specific ELISA. Although the detection of serum anti-BP230 IgE is not of major diagnostic significance, it may be relevant for therapeutic decisions, e.g., for anti-IgE-directed treatment, which has been successfully used in case series of BP.

Asunto(s)

Autoanticuerpos , Autoantígenos , Distonina , Ensayo de Inmunoadsorción Enzimática , Inmunoglobulina E , Inmunoglobulina G , Colágenos no Fibrilares , Penfigoide Ampolloso , Índice de Severidad de la Enfermedad , Humanos , Penfigoide Ampolloso/inmunología , Penfigoide Ampolloso/sangre , Penfigoide Ampolloso/diagnóstico , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Masculino , Femenino , Anciano , Autoantígenos/inmunología , Distonina/inmunología , Anciano de 80 o más Años , Colágenos no Fibrilares/inmunología , Persona de Mediana Edad , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Colágeno Tipo XVII , Adulto , Western Blotting

Asunto(s)

Autoanticuerpos , Moléculas de Adhesión Celular , Kalinina , Penfigoide Benigno de la Membrana Mucosa , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Moléculas de Adhesión Celular/inmunología , Colágeno Tipo XVII , Colágenos no Fibrilares/inmunología , Penfigoide Benigno de la Membrana Mucosa/inmunología

RESUMEN

Bullous pemphigoid (BP), an autoimmune bullous dermatosis, occurs predominantly in older individuals. Nemolizumab, a humanized monoclonal antibody against the interleukin (IL)-31 receptor A, is used to treat severe atopic dermatitis (AD) in Japan. However, it can cause several adverse events, such as exacerbation of AD, erythema, and eosinophilia. Herein, we describe a case of prurigo-type AD developing BP after nemolizumab administration. A 62-year-old man with prurigo-type AD and asthma presented with serious, refractory itching. After nemolizumab injection, his pruritus was relieved for 2 days. However, on day 3, erythema with blisters and erosions suddenly appeared throughout his body. Pathological examination showed typical BP and the patient's serum anti-BP180-NC16a antibody level was 882.5 U/mL. Oral prednisolone (PSL) was initiated and nemolizumab was never used again. Despite high-dose PSL, new blisters continued to develop, with a rapid elevation of anti-BP180-NC16a antibodies to 6930 U/mL. Adding high-dose cyclosporine and intravenous gamma globulin reduced new blister formation after 9 weeks, and PSL and cyclosporine were gradually tapered. Dupilumab, an anti-IL-4 receptor antibody, was initiated after 16 weeks, resulting in continued remission without PSL and cyclosporine. The sudden occurrence of BP in this case suggested that the patient had occult BP before the nemolizumab initiation and that nemolizumab exacerbated BP and made it overt. Blocking the IL-31 pathway may exacerbate inflammation in AD or BP, resulting in the acceleration of blister formation. This may be countered by blocking the IL-4/13 pathway with dupilumab. To our knowledge, this is the first case of nemolizumab-exacerbated BP.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Penfigoide Ampolloso , Receptores de Interleucina , Humanos , Penfigoide Ampolloso/inducido químicamente , Penfigoide Ampolloso/inmunología , Penfigoide Ampolloso/diagnóstico , Penfigoide Ampolloso/tratamiento farmacológico , Masculino , Anticuerpos Monoclonales Humanizados/efectos adversos , Persona de Mediana Edad , Receptores de Interleucina/antagonistas & inhibidores , Receptores de Interleucina/inmunología , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/inmunología , Dermatitis Atópica/inducido químicamente , Colágenos no Fibrilares/inmunología , Colágeno Tipo XVII , Prurigo/inmunología , Prurigo/inducido químicamente , Prurigo/tratamiento farmacológico , Prurigo/diagnóstico , Prurigo/patología , Autoantígenos/inmunología , Prednisolona/uso terapéutico , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Piel/patología , Piel/efectos de los fármacos , Ciclosporina/efectos adversos , Ciclosporina/uso terapéutico

RESUMEN

BACKGROUND: Bullous pemphigoid (BP) is an antibody-mediated blistering disease predominantly affecting the elderly. The pathogenesis involves both complement-dependent and complement-independent mechanisms. The therapeutic potential of targeting complement-independent mechanism has not yet been determined. The mainstay of treatment, corticosteroid, has many side effects, indicating the needs of better treatments. OBJECTIVE: We tempted to establish an in vitro model of BP which resembles complement-independent mechanism and to examine the therapeutic potential of a novel anti-inflammatory agent, diacerein. METHODS: Cultured HaCaT cells were treated with purified antibodies from BP patients, with or without diacerein to measure the cell interface presence of BP180, protein kinase C, and the production of proinflammatory cytokines. An open-label, randomized, phase 2 trial was conducted to compare topical diacerein and clobetasol ointments in patients with mild-to-moderate BP (NCT03286582). RESULTS: The reduced presentation of BP180 at cell interface after treating with BP autoantibodies was noticed in immunofluorescence and western blotting studies. The phenomenon was restored by diacerein. Diacerein also reduced the autoantibody-induced increase of pro-inflammatory cytokines. Reciprocal changes of BP180 and protein kinase C at the cell interface were found after treating with BP autoantibodies. This phenomenon was also reversed by diacerein in a dose-dependent manner. The phase 2 trial showed that topical diacerein reduced the clinical symptoms which were comparable to those of topical clobetasol. CONCLUSION: Diacerein inhibited BP autoantibody-induced reduction of BP180 and production of proinflammatory cytokines in vitro and showed therapeutic potential in patients with BP. It is a novel drug worthy of further investigations.

Asunto(s)

Antraquinonas , Autoanticuerpos , Citocinas , Colágenos no Fibrilares , Penfigoide Ampolloso , Anciano , Femenino , Humanos , Masculino , Antraquinonas/farmacología , Antraquinonas/uso terapéutico , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Autoantígenos/inmunología , Línea Celular , Clobetasol/uso terapéutico , Clobetasol/farmacología , Colágeno Tipo XVII , Proteínas del Sistema Complemento/inmunología , Citocinas/metabolismo , Citocinas/inmunología , Células HaCaT , Queratinocitos/inmunología , Queratinocitos/efectos de los fármacos , Colágenos no Fibrilares/inmunología , Penfigoide Ampolloso/inmunología , Penfigoide Ampolloso/tratamiento farmacológico , Penfigoide Ampolloso/patología , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Proteína Quinasa C/inmunología , Resultado del Tratamiento

RESUMEN

OBJECTIVE: To explore the anti-BP230/180 and anti-BP180 antibodies in patients with bullous pemphigoid (BP) combined with neurological diseases, and to analyse the relevant factors. STUDY DESIGN: Analytical study. Place and Duration of the Study: Neurology Department, Cangzhou People's Hospital, Cangzhou, from April 2019 to June 2022. METHODOLOGY: Eighty BP patients were chosen based on associated neurological diseases, they were split into single (n=42) and combined groups (n=38). Expression of anti-BP180/230 antibodies was compared between the two groups. Associations with neurological diseases were analysed and the factors affecting the expression of anti-BP180/230 antibodies were explored. RESULTS: Out of 80 patients, 61 were positive for anti-BP180 antibodies and 58 were positive for anti-BP230 antibodies. The proportion of patients with positive anti-BP230/180 antibodies in the single group was considerably lower than in the combined group (p<0.05). Presence of both nervous system diseases and BP was found to be associated with the presence of anti-BP230/180 antibodies (p<0.001). Univariate analysis showed statistically significant association with age (<70 years, total IgE (>100 IU/ml), and EOS count >0.5 x 109/L (p<0.05). Logistic analysis demonstrated that age, total IgE and EOS count were independent risk factors affecting the expression of anti-BP180 and anti-BP23 antibodies (p<0.05). CONCLUSION: Serum anti-BP230/180 antibodies expression is abnormally high in BP patients having nervous system diseases. Combined nervous system diseases, age, total IgE and EOS count are independent risk factors affecting expression of anti-BP180/230 antibodies. KEY WORDS: Anti-BP180 antibody, Anti-BP230 antibody, Bullous pemphigoid, Nervous system diseases.

Asunto(s)

Enfermedades del Sistema Nervioso , Penfigoide Ampolloso , Humanos , Anciano , Colágeno Tipo XVII , Colágenos no Fibrilares , Autoantígenos , Autoanticuerpos , Ensayo de Inmunoadsorción Enzimática , Inmunoglobulina E

RESUMEN

Bullous pemphigoid (BP) is an autoantibody-mediated blistering skin disease characterized by local inflammation and dermal-epidermal separation, with no approved targeted therapy. The Syk tyrosine kinase is critical for various functions of the immune response. Second-generation Syk inhibitors such as entospletinib are currently being tested for hematological malignancies. Our aim was to test the effect of entospletinib in a fully human model system of BP. Incubating BP serum-treated human frozen skin sections with normal human granulocytes and fresh plasma triggered dermal-epidermal separation that was dependent on complement, NADPH oxidase, and protease activity. Entospletinib dramatically reduced dermal-epidermal separation with a half-maximal inhibitory concentration of ≈16 nM. Entospletinib also reduced ROS production, granule release, and spreading of human granulocytes plated on immobilized immune complexes consisting either of a generic antigen-antibody pair or of recombinant collagen type XVII (BPAg2) and BP serum components (supposedly autoantibodies). However, entospletinib did not affect the chemotactic migration of human granulocytes or their responses to nonphysiological stimulation by phorbol esters. Entospletinib had no effect on the survival of granulocytes either. Taken together, entospletinib abrogates dermal-epidermal separation, likely through inhibition of granulocyte responsiveness to deposited immune complexes. Entospletinib or other Syk inhibitors may provide therapeutic benefits in BP.

Asunto(s)

Penfigoide Ampolloso , Quinasa Syk , Humanos , Quinasa Syk/antagonistas & inhibidores , Quinasa Syk/metabolismo , Penfigoide Ampolloso/tratamiento farmacológico , Penfigoide Ampolloso/inmunología , Penfigoide Ampolloso/patología , Epidermis/efectos de los fármacos , Epidermis/patología , Epidermis/inmunología , Pirazinas/farmacología , Pirazinas/uso terapéutico , Granulocitos/efectos de los fármacos , Granulocitos/inmunología , Granulocitos/metabolismo , Dermis/patología , Dermis/citología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Colágeno Tipo XVII , Autoantígenos/inmunología , Colágenos no Fibrilares/inmunología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Imidazoles/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Indazoles , Morfolinas

Asunto(s)

Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Penfigoide Ampolloso , Humanos , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Penfigoide Ampolloso/inducido químicamente , Penfigoide Ampolloso/diagnóstico , Colágeno Tipo XVII

Asunto(s)

Eosinófilos , Penfigoide Ampolloso , Humanos , Basófilos , Inmunoglobulina E , Colágeno Tipo XVII , Autoanticuerpos , Tetraspanina 30

RESUMEN

BACKGROUND: Interest in the use of omalizumab to treat bullous pemphigoid (BP) in the event of resistance or contraindication to conventional therapies is currently based on limited evidence. OBJECTIVES: To assess the effectiveness and safety of omalizumab in BP and to identify predictive factors in response to treatment. METHODS: We conducted a French national multicentre retrospective study including patients with a confirmed diagnosis of BP treated with omalizumab after failure of one or several treatment lines. We excluded patients with clinically atypical BP, as per Vaillant's criteria. The criteria for clinical response to omalizumab were defined according to the 2012 international consensus conference. Anti-BP180-NC16A IgE enzyme-linked immunosorbent assay was performed on sera collected before initiating omalizumab, when available. RESULTS: Between 2014 and 2021, 100 patients treated in 18 expert departments were included. Median age at diagnosis was 77 years (range 20-98). Complete remission (CR) was achieved in 77% of patients, and partial remission in an additional 9%. CR was maintained 'off therapy' in 11.7%, 'on minimal therapy' in 57.1%, and 'on non-minimal therapy' in 31.2%. Median time to CR was 3 months (range 2.2-24.5). Relapse rate was 14%, with a median follow-up time of 12 months (range 6-73). Adverse events occurred in four patients. CR was more frequently observed in patients with an increased serum baseline level of anti-BP180-NC16A IgE (75% vs. 41%; P = 0.011). Conversely, urticarial lesions, blood total IgE concentration or eosinophil count were not predictive of CR. Patients with an omalizumab dosage > 300 mg every 4 weeks showed a similar final outcome to those with a dosage ≤ 300 mg every 4 weeks, but control of disease activity [median 10 days (range 5-30) vs. 15 days (range 10-60); P < 0.001] and CR [median 2.4 months (range 2.2-8.2) vs. 3.9 months (range 2.3-24.5); P < 0.001] were achieved significantly faster. CONCLUSIONS: We report the largest series to date of BP treated by omalizumab and confirm its effectiveness and safety in this indication. Serum baseline level of anti-BP180-NC16A IgE may predict response to treatment.

Asunto(s)

Penfigoide Ampolloso , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Penfigoide Ampolloso/diagnóstico , Colágeno Tipo XVII , Omalizumab/uso terapéutico , Estudios Retrospectivos , Colágenos no Fibrilares , Autoantígenos , Inmunoglobulina E , Autoanticuerpos

RESUMEN

BACKGROUND: Anti-α6ß4 integrin autoantibodies can be observed in some patients with mucous membrane pemphigoid. We have previously identified anti-α6ß4 integrin extracellular domain autoantibodies together with anti-BP180 NC16A antibodies in a patient with DPP-4 inhibitor-induced bullous pemphigoid. However, the significance and impact of anti-α6ß4 integrin antibodies are unknown. OBJECTIVES: To characterize anti-α6ß4 integrin extracellular domain autoantibodies in pemphigoid patients, to determine whether these antibodies inhibit laminin-α6ß4 integrin binding and to observe their systemic effects. METHODS: Anti-α6ß4 integrin autoantibodies were analysed by staining cells expressing the extracellular region of α6ß4 integrin with sera from 20 patients with pemphigoid. The anti-α6ß4 integrin autoantibodies were characterized using different transfectants. The binding of laminins to α6ß4 integrin was studied using cells expressing the activated conformation of α6ß4 integrin and the inhibitory effect of the autoantibodies on the binding of laminins to α6ß4 integrin was tested. Trends in antibody titres and clinical symptoms were quantified and analysed. RESULTS: IgG autoantibodies against the extracellular domain of anti-α6ß4 integrin were found in some patients with pemphigoid. Laminin binding to α6ß4 integrin was observed in the active conformation of α6ß4 integrin, and serum from a patient with a high titre of anti-α6ß4 integrin antibodies inhibited the binding of both laminin-511 and laminin-332 to α6ß4 integrin. α6ß4 integrin is expressed on the basement membrane of both skin and small intestine, and exfoliation was observed in the patient's epidermis and small intestinal epithelium. A reduction in the titre of the anti-α6ß4 integrin antibody was associated with improvement in both skin and gastrointestinal symptoms. CONCLUSIONS: This study demonstrated the presence of anti-α6ß4 integrin extracellular domain-specific autoantibodies in some patients with pemphigoid. In addition, these autoantibodies showed inhibitory activity on α6ß4 integrin-laminin binding. Anti-α6ß4 integrin antibodies can affect the gastrointestinal tract as well as the skin and oral mucosa.

Asunto(s)

Penfigoide Ampolloso , Humanos , Autoanticuerpos , Colágeno Tipo XVII , Autoantígenos , Colágenos no Fibrilares , Laminina , Tracto Gastrointestinal , Integrinas

RESUMEN

Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by autoantibodies targeting type XVII collagen (Col17) with the noncollagenous 16A (NC16A) ectodomain representing the immunodominant site. The role of additional extracellular targets of Col17 outside NC16A has not been unequivocally demonstrated. In this study, we showed that Col17 ectodomain-reactive patient sera depleted in NC16A IgG induced dermal-epidermal separation in a cryosection model indicating the pathogenic potential of anti-Col17 non-NC16A extracellular IgG. Moreover, injection of IgG targeting the murine Col17 NC14-1 domains (downstream of NC15A, the murine homologue of human NC16A) into C57BL/6J mice resulted in erythematous skin lesions and erosions. Clinical findings were accompanied by IgG/C3 deposits along the basement membrane and subepidermal blistering with inflammatory infiltrates. Disease development was significantly reduced in either Fc-gamma receptor (FcγR)- or complement-5a receptor-1 (C5aR1)-deficient mice. Inhibition of the neonatal FcR (FcRn), an atypical FcγR regulating IgG homeostasis, with the murine Fc fragment IgG2c-ABDEG, a derivative of efgartigimod, reduced anti-NC14-1 IgG levels, resulting in ameliorated skin inflammation compared with isotype-treated controls. These data demonstrate that the pathogenic effects of IgG targeting the Col17 domain outside human NC16A/murine NC15A are partly attributable to antibody-mediated FcγR- and C5aR1 effector mechanisms while pharmacological inhibition of the FcRn represents a promising treatment for BP. The mouse model of BP will be instrumental in further investigating the role of Col17 non-NC16A/NC15A extracellular epitopes and validating new therapies for this disease. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Asunto(s)

Colágeno Tipo XVII , Penfigoide Ampolloso , Animales , Ratones , Humanos , Penfigoide Ampolloso/tratamiento farmacológico , Receptores de IgG/genética , Autoantígenos/genética , Colágenos no Fibrilares/genética , Ratones Endogámicos C57BL , Autoanticuerpos , Inmunoglobulina G

RESUMEN

Junctional epidermolysis bullosa (JEB) is a rare autosomal recessive genodermatosis with a broad spectrum of phenotypes. Current genotype-phenotype paradigms are insufficient to accurately predict JEB subtype and characteristics from genotype, particularly for splice site variants, which account for over a fifth of disease-causing variants in JEB. This study evaluated the genetic and clinical findings from a JEB cohort, investigating genotype-phenotype correlations through bioinformatic analyses and comparison with previously reported variants. Eighteen unique variants in LAMB3, LAMA3, LAMC2, or COL17A1 were identified from 17 individuals. Seven had severe JEB, 9 had intermediate JEB, and 1 had laryngo-onycho-cutaneous syndrome. Seven variants were previously unreported. Deep phenotyping was completed for all intermediate JEB cases and demonstrated substantial variation between individuals. Splice site variants underwent analysis with SpliceAI, a state-of-the-art artificial intelligence tool, to predict resultant transcripts. Predicted functional effects included exon skipping and cryptic splice site activation, which provided potential explanations for disease severity and in most cases correlated with laminin-332 immunofluorescence. RT-PCR was performed for 1 case to investigate resultant transcripts produced from the splice site variant. This study expands the JEB genomic and phenotypic landscape. Artificial intelligence tools show potential for predicting the functional effects of splice site variants and may identify candidates for confirmatory laboratory investigation. Investigation of RNA transcripts will help to further elucidate genotype-phenotype correlations for novel variants.

Asunto(s)

Colágeno Tipo XVII , Epidermólisis Ampollosa de la Unión , Estudios de Asociación Genética , Kalinina , Laminina , Colágenos no Fibrilares , Índice de Severidad de la Enfermedad , Humanos , Epidermólisis Ampollosa de la Unión/genética , Epidermólisis Ampollosa de la Unión/patología , Laminina/genética , Masculino , Femenino , Colágenos no Fibrilares/genética , Niño , Fenotipo , Moléculas de Adhesión Celular/genética , Preescolar , Autoantígenos/genética , Sitios de Empalme de ARN/genética , Lactante , Adolescente , Adulto , Mutación , Adulto Joven , Genotipo