RESUMEN
BACKGROUND: Increasing evidence links genetic defects affecting actin-regulatory proteins to diseases with severe autoimmunity and autoinflammation, yet the underlying molecular mechanisms are poorly understood. Dedicator of cytokinesis 11 (DOCK11) activates the small Rho guanosine triphosphatase (GTPase) cell division cycle 42 (CDC42), a central regulator of actin cytoskeleton dynamics. The role of DOCK11 in human immune-cell function and disease remains unknown. METHODS: We conducted genetic, immunologic, and molecular assays in four patients from four unrelated families who presented with infections, early-onset severe immune dysregulation, normocytic anemia of variable severity associated with anisopoikilocytosis, and developmental delay. Functional assays were performed in patient-derived cells, as well as in mouse and zebrafish models. RESULTS: We identified rare, X-linked germline mutations in DOCK11 in the patients, leading to a loss of protein expression in two patients and impaired CDC42 activation in all four patients. Patient-derived T cells did not form filopodia and showed abnormal migration. In addition, the patient-derived T cells, as well as the T cells from Dock11-knockout mice, showed overt activation and production of proinflammatory cytokines that were associated with an increased degree of nuclear translocation of nuclear factor of activated T cell 1 (NFATc1). Anemia and aberrant erythrocyte morphologic features were recapitulated in a newly generated dock11-knockout zebrafish model, and anemia was amenable to rescue on ectopic expression of constitutively active CDC42. CONCLUSIONS: Germline hemizygous loss-of-function mutations affecting the actin regulator DOCK11 were shown to cause a previously unknown inborn error of hematopoiesis and immunity characterized by severe immune dysregulation and systemic inflammation, recurrent infections, and anemia. (Funded by the European Research Council and others.).
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Actinas , Anemia , Factores de Intercambio de Guanina Nucleótido , Inflamación , Animales , Humanos , Ratones , Actinas/genética , Actinas/metabolismo , Anemia/etiología , Anemia/genética , Modelos Animales de Enfermedad , Factores de Intercambio de Guanina Nucleótido/deficiencia , Factores de Intercambio de Guanina Nucleótido/genética , Hematopoyesis , Inflamación/etiología , Inflamación/genética , Pez Cebra/genética , Pez Cebra/metabolismoRESUMEN
BACKGROUND: Lipoid proteinosis (LP), also known as Urbach-Wiethe disease, is a rare autosomal recessive genodermatosis, caused by mutations in the ECM1 gene. This results in the deposition of periodic acid-Schiff (PAS)-positive, hyaline-like material on the skin, mucosae and internal organs. OBJECTIVES: To present a case report of LP and a systematic review to synthesize the scientific literature on the management of this uncommon and frequently missed diagnosis. METHODS: We present a case report of a 48-year-old man with LP who exhibited significant improvement after oral acitretin therapy. To address the lack of large case-control studies on LP treatment, we performed a systematic review of the literature following the PRISMA 2020 criteria. The search was conducted in PubMed, Web of Science, Cochrane and Scopus databases from inception until June 2023. To assess the methodological quality of case reports and case series, we used the Joanna Briggs Collaboration critical appraisal tool. RESULTS: We included 25 studies that met eligibility criteria. Data from 44 patients with a histopathologically confirmed diagnosis were analysed. Treatment ranged from systemic therapies (acitretin, etretinate, dimethyl sulfoxide, corticosteroids, penicillamine) to surgical or laser procedures. Regarding methodological quality, the main discrepancies arose in the reporting of participant characteristics and treatment interventions. CONCLUSIONS: Low-dose oral acitretin could have potential in managing LP, exhibiting fewer side-effects compared with other therapeutic agents. Further research is needed to establish more comprehensive and evidence-based treatment guidelines.
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Acitretina , Proteinosis Lipoidea de Urbach y Wiethe , Humanos , Proteinosis Lipoidea de Urbach y Wiethe/genética , Proteinosis Lipoidea de Urbach y Wiethe/patología , Proteinosis Lipoidea de Urbach y Wiethe/tratamiento farmacológico , Proteinosis Lipoidea de Urbach y Wiethe/diagnóstico , Masculino , Acitretina/uso terapéutico , Persona de Mediana Edad , Queratolíticos/uso terapéutico , Resultado del TratamientoRESUMEN
PURPOSE: To describe the ophthalmic findings and diagnosis of a case of intravascular large B-cell lymphoma. METHODS: Clinical case observational report. CLINICAL CASE: A Spanish 51-year-old man referred to our hospital with a diagnosis of panuveitis. The patient presented with blurred vision, photophobia, fever, and weight loss. Ocular examination revealed anterior uveitis, vitritis, and multiple round and oval creamy spots on the posterior pole. Fluorescein angiography, optical coherence tomography (OCT), and angio-OCT were used for the ocular examination. The diagnosis of lymphoma was formulated on the basis of a random normal skin biopsy, which showed significant CD20 cellularity within the vessels and extensive CD3 expression. CONCLUSIONS: Intravascular lymphoma is a rare form of extranodal diffuse large B-cell lymphoma, often with delayed diagnosis because of the nonspecific symptoms. Hence, random skin biopsy could be useful in the diagnosis.
RESUMEN
BACKGROUND: Cutaneous carcinosarcoma is a rare biphasic tumor comprising malignant epithelial and heterologous mesenchymal elements. Data on the clinical and histopathologic characteristics of this tumor are scarce. The objective of this study was to describe the clinicopathologic and immunohistochemical features of cutaneous carcinosarcoma. METHODS: A descriptive retrospective study was conducted in a tertiary care hospital from Spain. We reviewed the records of eight patients with cutaneous carcinosarcoma who were diagnosed from 2009 to 2019. RESULTS: The mean patient age at diagnosis was 72.13 years (range 44-91 years), and there was a male predilection (6 cases). The most common site of cutaneous carcinosarcoma was the head and neck (5 cases). Carcinosarcomas demonstrated variable histopathological and immunohistochemical features. Follow-up was available for 7-8 patients. There were two cases of local recurrence and one case of metastasis. Two patients died from the tumor during the entire follow-up. CONCLUSIONS: Although the number of cases in this study was limited, our results provide valuable insight into the clinical, histopathologic, and immunohistochemical characteristics of primary cutaneous carcinosarcoma.
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Carcinosarcoma/metabolismo , Carcinosarcoma/patología , Recurrencia Local de Neoplasia/patología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Actinas/metabolismo , Adulto , Anciano de 80 o más Años , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Carcinosarcoma/secundario , Carcinosarcoma/cirugía , Desmina/metabolismo , Femenino , Humanos , Inmunohistoquímica , Queratina-1/metabolismo , Queratina-3/metabolismo , Masculino , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Miogenina/metabolismo , Neprilisina/metabolismo , Estudios Retrospectivos , Neoplasias Cutáneas/cirugía , Factores de Transcripción/metabolismo , alfa 1-Antitripsina/metabolismoRESUMEN
Currently, the diagnosis of kidney allograft rejection relies on individual histological assessments made by expert pathologists according to the Banff classification. In this study, we applied new Computer-Assisted System Technology (newCAST™) by Visiopharm® with the aim of identifying and quantifying the immune cells in inflammatory infiltrates. We searched for distinctive cellular profiles that could be assigned to each rejection category of the Banff schema: antibody-mediated rejection (active and chronic active), borderline, T cell-mediated rejection (TCMR), and mixed rejection. This study was performed with 49 biopsy samples, 42 from patients with rejection and 7 from patients with clinical signs of dysfunction but an absence of histological findings of rejection. Plasma cells, B and T lymphocytes, natural killer cells, and macrophages, with a special focus on the M1 and M2 subsets, were studied. A major difference among the Banff rejection groups was in the total amount of cells/mm2 tissue. Principal component analysis identified some distinctive associations. The borderline category grouped with CD4+ lymphocytes and M1 macrophages, and active antibody-mediated rejection (aAMR) clustered with natural killer cells. Despite these findings, the search for characteristic profiles linked to the rejection types proved to be a very difficult task since the cellular composition varied significantly among individuals within the same diagnostic category. The results of this study will be analyzed from the perspective of reconciling the classic way of diagnosing rejection and the immune situation "in situ" at the time of diagnosis.
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Rechazo de Injerto/inmunología , Trasplante de Riñón , Adolescente , Adulto , Anciano , Aloinjertos , Anticuerpos/inmunología , Linfocitos B/inmunología , Niño , Diagnóstico por Computador , Femenino , Rechazo de Injerto/diagnóstico , Humanos , Inflamación/inmunología , Células Asesinas Naturales/inmunología , Macrófagos/inmunología , Masculino , Persona de Mediana Edad , Fenotipo , Células Plasmáticas/inmunología , Linfocitos T/inmunología , Adulto JovenRESUMEN
INTRODUCTION AND OBJECTIVES: Primary cutaneous B-cell lymphoma (CBCL) is a very low prevalence neoplasm and constitutes 25% of all primary cutaneous lymphomas. Our objective was to discover the epidemiological, clinic and histologic characteristics of CBCL in our area. METHODS: Retrospective descriptive study with patients with histologic diagnosis of CBCL followed up in our department between 2004 and 2015. RESULTS: Twenty-two patients with CBCL were included; 65% were men and 35% were women. Follicle centre lymphoma was the most common subtype (41%). Only 3 cases presented with node involvement and one with bone marrow invasion. Five recurrences were detected and one patient died because of the CBCL. DISCUSSION AND CONCLUSIONS: This is one of the first CBCL series in theSpanish population. The incidence, sex, age, subtype distribution, clinical features and immunohistochemical patterns are very similar to those of the other series.
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Linfoma de Células B/diagnóstico , Neoplasias Cutáneas/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Linfoma de Células B/epidemiología , Linfoma de Células B/mortalidad , Linfoma de Células B/patología , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , España/epidemiologíaRESUMEN
C3 glomerulopathies (C3G) are a group of severe renal diseases with distinct patterns of glomerular inflammation and C3 deposition caused by complement dysregulation. Here we report the identification of a familial C3G-associated genomic mutation in the gene complement factor Hrelated 1 (CFHR1), which encodes FHR1. The mutation resulted in the duplication of the N-terminal short consensus repeats (SCRs) that are conserved in FHR2 and FHR5. We determined that native FHR1, FHR2, and FHR5 circulate in plasma as homo- and hetero-oligomeric complexes, the formation of which is likely mediated by the conserved N-terminal domain. In mutant FHR1, duplication of the N-terminal domain resulted in the formation of unusually large multimeric FHR complexes that exhibited increased avidity for the FHR1 ligands C3b, iC3b, and C3dg and enhanced competition with complement factor H (FH) in surface plasmon resonance (SPR) studies and hemolytic assays. These data revealed that FHR1, FHR2, and FHR5 organize a combinatorial repertoire of oligomeric complexes and demonstrated that changes in FHR oligomerization influence the regulation of complement activation. In summary, our identification and characterization of a unique CFHR1 mutation provides insights into the biology of the FHRs and contributes to our understanding of the pathogenic mechanisms underlying C3G.
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Complemento C3/metabolismo , Proteínas Inactivadoras del Complemento C3b/genética , Enfermedades Renales/genética , Niño , Complemento C3/química , Proteínas Inactivadoras del Complemento C3b/química , Proteínas Inactivadoras del Complemento C3b/metabolismo , Proteínas del Sistema Complemento/aislamiento & purificación , Proteínas del Sistema Complemento/metabolismo , Femenino , Duplicación de Gen , Hemólisis , Humanos , Proteínas Inmovilizadas/química , Proteínas Inmovilizadas/metabolismo , Riñón/patología , Masculino , Persona de Mediana Edad , Mutagénesis Insercional , Linaje , Unión Proteica , Multimerización de Proteína , Estructura Cuaternaria de Proteína , Análisis de Secuencia de ADNAsunto(s)
Síndromes Mielodisplásicos/diagnóstico , Miositis/diagnóstico , Dolor/diagnóstico , Estomatitis Aftosa/diagnóstico , Antiinflamatorios/uso terapéutico , Proteína C-Reactiva/análisis , Creatina Quinasa/sangre , Humanos , Leucemia/diagnóstico , Masculino , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Miositis/tratamiento farmacológico , Dolor/tratamiento farmacológico , Pancitopenia/diagnóstico , Estomatitis Aftosa/tratamiento farmacológico , Síndrome de Sweet/diagnóstico , Resultado del TratamientoRESUMEN
Introducción y objetivos: El linfoma B cutáneo primario (LBCP) es una neoplasia de muy baja prevalencia y supone un 25% de todos los linfomas cutáneos. Nuestro objetivo era conocer las características epidemiológicas, clínicas e histológicas de los LBCP de nuestra área sanitaria. Métodos: Estudio descriptivo retrospectivo con datos de los pacientes con diagnóstico anatomopatológico de LBCP seguidos entre los años 2004 y 2015 en el Hospital Universitario Virgen del Rocío. Resultados: Se incluyeron 22 casos de pacientes con LBCP. El 65% eran varones frente a un 35% de mujeres. El linfoma centrofolicular supuso el subtipo más frecuente (41%). Tres casos desarrollaron afectación ganglionar y uno, invasión de la médula ósea. Durante el seguimiento se observaron 5 recidivas y un paciente falleció a causa de su LBCP. Discusión y conclusiones: Aportamos una de las primeras series de pacientes con LBCP descritas en población española. La incidencia detectada en nuestra área es similar a las de otras poblaciones descritas en la literatura. Respecto al sexo, la edad, la distribución por subtipos y la presentación clínica e inmunohistoquímica, también se obtuvieron datos similares a los de otras series (AU)
Introduction and objectives: Primary cutaneous B-cell lymphoma (CBCL) is a very low prevalence neoplasm and constitutes 25% of all primary cutaneous lymphomas. Our objective was to discover the epidemiological, clinic and histologic characteristics of CBCL in our area. Methods: Retrospective descriptive study with patients with histologic diagnosis of CBCL followed up in our department between 2004 and 2015. Results: Twenty-two patients with CBCL were included; 65% were men and 35% were women. Follicle centre lymphoma was the most common subtype (41%). Only 3 cases presented with node involvement and one with bone marrow invasion. Five recurrences were detected and one patient died because of the CBCL. Discussion and conclusions: This is one of the first CBCL series in theSpanish population. The incidence, sex, age, subtype distribution, clinical features and immunohistochemical patterns are very similar to those of the other series (AU)