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Aloinjertos , Trasplante de Riñón , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Aloinjertos/inmunología , Aloinjertos/patología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Trasplante de Riñón/efectos adversos , Proteínas de la Membrana/inmunología , Podocitos/inmunología , Podocitos/patología , RecurrenciaAsunto(s)
Glomeruloesclerosis Focal y Segmentaria , Síndrome Nefrótico , Podocitos , Humanos , ProteinuriaRESUMEN
BACKGROUND: Failure of the glomerular filtration barrier, primarily by loss of slit diaphragm architecture, underlies nephrotic syndrome in minimal change disease. The etiology remains unknown. The efficacy of B cell-targeted therapies in some patients, together with the known proteinuric effect of anti-nephrin antibodies in rodent models, prompted us to hypothesize that nephrin autoantibodies may be present in patients with minimal change disease. METHODS: We evaluated sera from patients with minimal change disease, enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) cohort and from our own institutions, for circulating nephrin autoantibodies by indirect ELISA and by immunoprecipitation of full-length nephrin from human glomerular extract or a recombinant purified extracellular domain of human nephrin. We also evaluated renal biopsies from our institutions for podocyte-associated punctate IgG colocalizing with nephrin by immunofluorescence. RESULTS: In two independent patient cohorts, we identified circulating nephrin autoantibodies during active disease that were significantly reduced or absent during treatment response in a subset of patients with minimal change disease. We correlated the presence of these autoantibodies with podocyte-associated punctate IgG in renal biopsies from our institutions. We also identified a patient with steroid-dependent childhood minimal change disease that progressed to end stage kidney disease; she developed a massive post-transplant recurrence of proteinuria that was associated with high pretransplant circulating nephrin autoantibodies. CONCLUSIONS: Our discovery of nephrin autoantibodies in a subset of adults and children with minimal change disease aligns with published animal studies and provides further support for an autoimmune etiology. We propose a new molecular classification of nephrin autoantibody minimal change disease to serve as a framework for instigation of precision therapeutics for these patients.
Asunto(s)
Autoanticuerpos/sangre , Proteínas de la Membrana/inmunología , Nefrosis Lipoidea/sangre , Nefrosis Lipoidea/etiología , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Masculino , Nefrosis Lipoidea/patología , Podocitos/patologíaRESUMEN
Drug repurposing has the advantage of identifying potential treatments on a shortened timescale. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high-content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce mucin-1 (MUC1) protein abundance. Elevated MUC1 levels predict the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) and correlate with poor clinical outcomes. Our screen identifies fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, fostamatinib reduces MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by the active metabolite R406 promotes MUC1 removal from the cell surface. Our work suggests fostamatinib as a repurposing drug candidate for ALI.
RESUMEN
The induction of adaptive immunity is dependent on the structural organization of LNs, which is in turn governed by the stromal cells that underpin LN architecture. Using a novel fate-mapping mouse model, we trace the developmental origin of mesenchymal LN stromal cells (mLNSCs) to a previously undescribed embryonic fibroblast activation protein-α (FAP)+ progenitor. FAP+ cells of the LN anlagen express lymphotoxin ß receptor (LTßR) and vascular cell adhesion molecule (VCAM), but not intercellular adhesion molecule (ICAM), suggesting they are early mesenchymal lymphoid tissue organizer (mLTo) cells. Clonal labeling shows that FAP+ progenitors locally differentiate into mLNSCs. This process is also coopted in nonlymphoid tissues in response to infection to facilitate the development of tertiary lymphoid structures, thereby mimicking the process of LN ontogeny in response to infection.
Asunto(s)
Embrión de Mamíferos/inmunología , Gelatinasas/inmunología , Ganglios Linfáticos/inmunología , Proteínas de la Membrana/inmunología , Células Madre Mesenquimatosas/inmunología , Modelos Inmunológicos , Serina Endopeptidasas/inmunología , Animales , Embrión de Mamíferos/citología , Endopeptidasas , Gelatinasas/genética , Ganglios Linfáticos/citología , Receptor beta de Linfotoxina/genética , Receptor beta de Linfotoxina/inmunología , Proteínas de la Membrana/genética , Células Madre Mesenquimatosas/citología , Ratones , Ratones Transgénicos , Serina Endopeptidasas/genética , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/inmunologíaRESUMEN
We report an unusual dermatological reaction to bortezomib in a 61-year-old man with AL amyloidosis. Systemic AL amyloidosis is a rare complication of monoclonal gammopathy or myeloma in which abnormally unstable free light chains cause fibrillary deposits in organs leading to multisystem disease. The treatment of AL amyloidosis is directed at the underlying plasma cell dyscrasia and most regimes have been adapted from myeloma, but drug toxicity is more common in AL amyloidosis because of the more extensive nature of the disease. We report a patient who developed asymptomatic purple discolouration of the veins of his left arm several days after receiving the infusion in his left hand, although the infusion itself had been uncomplicated with no extravasation. The discolouration resolved completely within 2 weeks; there was recurrence on a subsequent dose of bortezomib but this also subsided spontaneously. This reaction may have been transient phlebitis or a local vasogenic reaction; its transient nature and the lack of systemic features suggest it is a benign phenomenon. There appears to be no indication for discontinuation of bortezomib treatment or dose alteration in such cases.