RESUMEN
BACKGROUND: Bullous pemphigoid (BP), the by far most frequent autoimmune blistering skin disease (AIBD), is immunopathologically characterized by autoantibodies against the two hemidesmosomal proteins BP180 (collagen type XVII) and BP230 (BPAG1 or dystonin). Several comorbidities and potentially disease-inducing medication have been described in BP, yet a systematic analysis of these clinically relevant findings and autoantibody reactivities has not been performed. OBJECTIVE: To determine associations of autoantibody reactivities with comorbidities and concomitant medication. METHODS: In this prospective multicenter study, 499 patients diagnosed with BP in 16 European referral centers were included. The relation between anti-BP180 NC16A and anti-BP230 IgG ELISA values at the time of diagnosis as well as comorbidities and concomitant medication collected by a standardized form were analysed. RESULTS: An association between higher serum anti-BP180 reactivity and neuropsychiatric but not atopic and metabolic disorders was observed as well as with the use of insulin or antipsychotics but not with dipeptidyl peptidase-4 (DPP4) inhibitors, inhibitors of platelet aggregation and L-thyroxine. The use of DPP4 inhibitors was associated with less anti-BP180 and anti-BP230 reactivity compared with BP patients without these drugs. This finding was even more pronounced when compared with diabetic BP patients without DPP4 inhibitors. Associations between anti-BP180 and anti-BP230 reactivities were also found in patients using insulin and antipsychotics, respectively, compared with patients without this medication, but not for the use of inhibitors of platelet aggregation, and L-thyroxine. CONCLUSION: Taken together, these data imply a relation between autoantibody reactivities at the time of diagnosis and both neuropsychiatric comorbidities as well as distinct concomitant medication suggesting a link between the pathological immune mechanisms and clinical conditions that precede the clinically overt AIBD.
Asunto(s)
Antipsicóticos , Inhibidores de la Dipeptidil-Peptidasa IV , Insulinas , Penfigoide Ampolloso , Enfermedad del Suero , Antipsicóticos/efectos adversos , Autoanticuerpos , Autoantígenos , Vesícula , Dipeptidil Peptidasa 4/uso terapéutico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Distonina , Humanos , Hipoglucemiantes/uso terapéutico , Inmunoglobulina G , Insulinas/uso terapéutico , Colágenos no Fibrilares , Estudios Prospectivos , Tiroxina/uso terapéuticoRESUMEN
Background: Bullous pemphigoid (BP) is the most frequent autoimmune blistering disease of the skin affecting the elderly. BP is immunopathologically characterized by autoantibodies against BP180 and BP230. With the growing evidence of cell-mediated autoimmunity in the pathogenesis of BP, it still remains unclear whether mast cells (MCs) are involved, due to conflicting data obtained from Kit-dependent MC-deficient mouse models. Objectives: To clarify the role of MCs in experimental BP; the dynamics in cutaneous MC numbers, associated immune cells and the development of disease in Kit-independent MC-deficient mouse model. Methods: Employing a recently established murine adult passive transfer model of BP induced by the transfer of pathogenic immunoglobulin G (IgG), lesional skin biopsies were investigated histologically and immunohistochemically for the time-dependent MC accumulation and dermal infiltration. Results: The numbers of cutaneous MCs increased following the induction of BP, in part, maintained by MC proliferation. Numbers of T cells, neutrophils and eosinophils in the skin also increased after BP induction, with eosinophils showing a preferential co-localization with MCs. Furthermore, clinical disease manifestation in MC-deficient Mcpt5Cre/Dicer fl/fl mice remained unchanged compared to MC-sufficient Dicer fl/fl mice. The composition of the immune cell infiltration including as T cells, neutrophils and eosinophils was largely unaffected by the absence of MCs. Conclusion: MCs do not play a pivotal role in the pathogenesis of passive IgG-transfer mediated BP model. Their increase in number may be a bystander effect following tissue injury. We therefore suggest caution regarding the selection of MCs as sole targets for the development of novel drugs for BP.
RESUMEN
BACKGROUND: While clustering of bullous pemphigoid (BP) with neuropsychiatric diseases is well-established, the clinical and immunological profile of BP patients with this comorbidity remains to be decisively determined. OBJECTIVES: To evaluate the burden of neurological and psychiatric comorbidities among patients with BP and to elucidate the clinical, immunological and immunopathological features of patients with BP and comorbid neuropsychiatric conditions. METHODS: We performed a retrospective study encompassing patients diagnosed with BP throughout the years 2009-2020 in a specialized tertiary referral centre. Multivariate logistic regression model was used to identify predictors of neuropsychiatric conditions among patients with BP. RESULTS: The study included 273 patients with BP, of whom 123 (45.1%) presented with comorbid neuropsychiatric disease. Compared to the remaining patients with BP (n = 150), those with pre-existing neuropsychiatric diseases demonstrated older mean [standard deviation (SD)] age [81.7 (9.1) vs. 76.9 (10.1); P < 0.001], female preponderance (65.0% vs. 49.3%; P = 0.009), higher seropositivity rate of anti-BP230 (67.7% vs. 36.5%; P = 0.006) and higher levels of anti-BP180 NC16A IgG [651.3 (1279.6) vs. 370.4 (818.6) U/mL; P = 0.039]. In multivariate analysis, anti-BP230 seropositivity was independently associated with coexistence of BP with neuropsychiatric conditions [adjusted odds ratio (OR), 3.43; 95% CI, 1.24-9.52; P = 0.018]. In a sensitivity analysis confined to patients with neurological diseases (n = 103), older age [82.1 (8.4) vs. 77.2 (10.3); P < 0.001] and increased anti-BP230 seropositivity (68.0% vs. 39.7%; P = 0.018) were identified. CONCLUSIONS: The coexistence of BP with neuropsychiatric diseases is independently associated with the generation of anti-BP230 antibodies.
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Penfigoide Ampolloso , Anciano , Autoanticuerpos , Autoantígenos , Comorbilidad , Distonina , Femenino , Humanos , Colágenos no Fibrilares , Penfigoide Ampolloso/complicaciones , Penfigoide Ampolloso/epidemiología , Estudios RetrospectivosRESUMEN
BACKGROUND: Autoimmune bullous diseases (AIBD) are rare disorders characterized by autoantibody formation against components of adhesion molecules; in pemphigoid diseases (PD), these are proteins of hemidesmosomes and basement membrane, important for cell-matrix adhesion in skin and/or mucous membranes. Incidences of these diseases vary considerably between different populations. OBJECTIVES: To establish a registry prospectively recruiting all AIBD patients in a geographically well-defined region in Northern Germany (Schleswig-Holstein). METHODS: Only patients with verified disease (by clinical presentation, histology, direct and/or indirect immunofluorescence and /or ELISA) living in Schleswig-Holstein were included. Incidences of PD were estimated based on the total number of inhabitants in Schleswig-Holstein, stratified by birth year and sex. RESULTS: Of 67 patients with PD [35 male, 32 female, mean age 75 (standard deviation 14.3 years)], 83% were patients with bullous pemphigoid [n = 56, 28 male, 28 female, mean age 78 (SD 9.9)]. The resulting crude incidences were 23.4 patients/million/year for all pemphigoid patients, 19.6 patients/million/year for bullous pemphigoid (age-standardized 16.9 patients/million/year) with a strong increase in bullous pemphigoid patients in the age group of 85-90 years with 262 patients/million/year. Incidences for bullous pemphigoid were higher in urban compared to rural areas. Other PD (mucous membrane pemphigoid, linear IgA disease, anti-p200 pemphigoid) were less frequent with crude incidences of 2.1, 1.0 and 0.7 patients/million/year, respectively. CONCLUSIONS: This study prospectively analyses the incidence of PD in a carefully defined geographical area. The highest incidence among PD patients was found for bullous pemphigoid. The incidence of bullous pemphigoid is considerably increased compared to previous reports and reveals regional differences. Further studies are needed in order to clarify these findings.
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Enfermedades Autoinmunes , Penfigoide Ampolloso , Enfermedades Cutáneas Vesiculoampollosas , Anciano , Anciano de 80 o más Años , Autoanticuerpos , Enfermedades Autoinmunes/epidemiología , Femenino , Alemania/epidemiología , Humanos , Incidencia , Masculino , Penfigoide Ampolloso/epidemiología , Sistema de RegistrosRESUMEN
BACKGROUND: Bullous pemphigoid (BP) and pemphigus vulgaris (PV) are common autoimmune bullous dermatoses (AIBD) characterized by blisters and erosions. Treatment options are limited and often insufficient. Immune checkpoint receptors play critical roles in immune homoeostasis and self- tolerance. Targeting checkpoint receptors is highly efficient in treatment of various cancers, but often also associated with autoimmune side effects. OBJECTIVES: We therefore aimed to investigate the expression of immune checkpoint receptors in patients with BP and PV. METHODS: We analysed expression of the checkpoint receptors programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin domain 3 (Tim-3) and lymphocyte activation gene 3 (Lag-3) in lesional skin of patients with BP and PV compared to healthy control skin as well as the expression patterns of PD-1 and Tim-3 on various infiltrating immune cells in skin sections of AIBD by immunohistochemistry and immunofluorescence. We also measured serum levels of soluble PD-1, Tim-3 and Lag-3 in AIBD patients by ELISA. RESULTS: We report on increased expression of PD-1 and Tim-3, but not Lag-3, in lesional skin of patients with BP and PV. Investigating the expression pattern of PD-1 and Tim-3 on different cutaneous immune cells, we observed significant upregulation of PD-1 predominantly on infiltrating CD8 T cells and upregulation of Tim-3 on CD8 T cells as well as macrophages. CONCLUSIONS: Our results suggest exploring immune checkpoint receptors as novel therapeutic targets using an agonistic approach in autoimmune bullous diseases.
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Enfermedades Autoinmunes , Receptor 2 Celular del Virus de la Hepatitis A , Penfigoide Ampolloso , Pénfigo , Receptor de Muerte Celular Programada 1 , HumanosAsunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Psoriasis/tratamiento farmacológico , Piodermia Gangrenosa/inducido químicamente , Sacroileítis/inducido químicamente , Adulto , Fármacos Dermatológicos/efectos adversos , Femenino , Humanos , Psoriasis/complicacionesRESUMEN
Bullous pemphigoid (BP) is considered to be a humorally mediated autoimmune disease, but autoreactive T-cells and T-regulatory cells (Tregs) have also been implicated in this disease. Tregs and the programmed death-1 (PD-1) : programmed death ligand (PD-L) pathway are both critical in terminating immune response, and elimination of either can result in breakdown of tolerance and development of autoimmunity. We report a patient with metastatic malignant melanoma (MM), who underwent pembrolizumab (anti-PD-1) therapy following unsuccessful treatment with ipilimumab [anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4]. The patient developed BP with increasing serum titres of anti-BP180 IgG autoantibodies and increasing disease severity during pembrolizumab therapy. High doses of corticosteroids and methotrexate were needed to control the BP. Following the termination of pembrolizumab therapy, imaging showed complete regression of all metastatic sites. This result may indicate a crucial role for T-cell suppressive activity in controlling and preventing BP.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/efectos adversos , Melanoma/tratamiento farmacológico , Penfigoide Ampolloso/inducido químicamente , Neoplasias Cutáneas/tratamiento farmacológico , Femenino , Humanos , Melanoma/secundario , Persona de Mediana Edad , Penfigoide Ampolloso/tratamiento farmacológico , Penfigoide Ampolloso/inmunología , Neoplasias Cutáneas/secundarioRESUMEN
Interleukin (IL)-22 production triggered by innate immune mechanisms has been identified as key to efficient intestinal anti-bacterial host defence and preservation of homeostasis. We hypothesized that glucocorticoid therapy may impair IL-22 expression, which should promote intestinal epithelial damage with the potential of subsequent bacterial translocation. High-dose corticosteroid therapy in Crohn's disease has been associated with an increased rate of abscess formation and ultimately with a higher risk of developing postoperative infectious complications, including abdominal sepsis. Thus, we sought to investigate effects of the prototypic glucocorticoid dexamethasone on IL-22 production in the context of bacterial infection. Enhanced IL-22 plasma levels were detectable in rat sepsis. Moreover, heat-inactivated Staphylococcus epidermidis, used as a prototypic activator of innate immunity, induced robust production of IL-22 by human peripheral blood mononuclear cells (PBMC). Here, we report for the first time that dexamethasone mediates remarkable suppression of IL-22 as detected in S. epidermidis-activated PBMC and rat sepsis, respectively. The data presented herein suggest that insufficient IL-22 function may contribute to impaired intestinal host defence in the context of corticosteroid therapy.
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Dexametasona/uso terapéutico , Glucocorticoides/uso terapéutico , Interleucinas/inmunología , Peritonitis/inmunología , Infecciones Estafilocócicas/inmunología , Staphylococcus epidermidis , Animales , Estudios de Casos y Controles , Células Cultivadas , Depresión Química , Dexametasona/análogos & derivados , Expresión Génica/efectos de los fármacos , Humanos , Interleucina-10/genética , Interleucina-10/inmunología , Interleucina-8/genética , Interleucina-8/inmunología , Interleucinas/genética , Masculino , Modelos Animales , Peritonitis/tratamiento farmacológico , ARN Mensajero/análisis , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Infecciones Estafilocócicas/tratamiento farmacológico , Interleucina-22RESUMEN
The flavanol (-)-epicatechin has been found to protect against damage inflicted by peroxynitrite, an inflammatory intermediate. Here, epicatechin was tested in systems of increasing complexity. The compound efficiently protected against nitration of protein tyrosine residues by peroxynitrite (IC(50) approximately 0.02 mol epicatechin/mol peroxynitrite). However, at epicatechin concentrations completely preventing nitration of tyrosine by peroxynitrite, protection against the oxidative inactivation of glyceraldehyde-3-phosphate dehydrogenase or soybean lipoxygenase-1 was marginal (IC(50) > 1 mol epicatechin/mol peroxynitrite), approximately two orders of magnitude less. Likewise, epicatechin was relatively ineffective against oxidation of thiols in cell lysates, and against the oxidation of 2',7'-dichlorodihydrofluorescein in cultured cells. The activation of the kinases Akt/protein kinase B, ERK1/2 and p38-MAPK by peroxynitrite in murine aorta endothelial cells was not altered by epicatechin, suggesting that activation of these kinases is due to processes other than tyrosine nitration.