RESUMEN
Increased IgE is a typical feature of allergic rhinitis. Local class-switch recombination has been intimated but B cell precursors and mechanisms remain elusive. Here we describe the dynamics underlying the generation of IgE-antibody secreting cells (ASC) in human nasal polyps (NP), mucosal tissues rich in ASC without germinal centers (GC). Using VH next generation sequencing, we identified an extrafollicular (EF) mucosal IgD+ naïve-like intermediate B cell population with high connectivity to the mucosal IgE ASC. Mucosal IgD+ B cells, express germline epsilon transcripts and predominantly co-express IgM. However, a small but significant fraction co-express IgG or IgA instead which also show connectivity to ASC IgE. Phenotypically, NP IgD+ B cells display an activated profile and molecular evidence of BCR engagement. Transcriptionally, mucosal IgD+ B cells reveal an intermediate profile between naïve B cells and ASC. Single cell IgE ASC analysis demonstrates lower mutational frequencies relative to IgG, IgA, and IgD ASC consistent with IgE ASC derivation from mucosal IgD+ B cell with low mutational load. In conclusion, we describe a novel mechanism of GC-independent, extrafollicular IgE ASC formation at the nasal mucosa whereby activated IgD+ naïve B cells locally undergo direct and indirect (through IgG and IgA), IgE class switch.
Asunto(s)
Formación de Anticuerpos/inmunología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Inmunoglobulina D/inmunología , Inmunoglobulina E/inmunología , Mucosa Nasal/inmunología , Mucosa Nasal/metabolismo , Adulto , Formación de Anticuerpos/genética , Células Productoras de Anticuerpos/inmunología , Células Productoras de Anticuerpos/metabolismo , Biología Computacional , Perfilación de la Expresión Génica , Centro Germinal/inmunología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hipersensibilidad/etiología , Hipersensibilidad/metabolismo , Cambio de Clase de Inmunoglobulina/genética , Cambio de Clase de Inmunoglobulina/inmunología , Isotipos de Inmunoglobulinas/genética , Isotipos de Inmunoglobulinas/inmunología , Inmunofenotipificación , Pólipos Nasales/etiología , Pólipos Nasales/metabolismo , Pólipos Nasales/patología , Polen/inmunología , Estaciones del Año , Hipermutación Somática de InmunoglobulinaRESUMEN
This study investigated the effects of acute antioxidant supplementation on endothelial function, exercise blood flow and oxidative stress biomarkers in 9 young African American compared to 10 Caucasian males (25.7±1.2 years). We hypothesized that African American males would have lower exercise blood flow and endothelial responsiveness compared to Caucasian males, and these responses would be improved following antioxidant supplementation. Ultrasonography was used to measure blood flow during handgrip exercise. Endothelial function was assessed using flow-mediated dilation, and lipid peroxidation was assessed by measuring levels of malondialdehyde-thiobarbituric acid reactive substances. African American males exhibited lower endothelial function than Caucasians at baseline (8.3±1.7 vs. 12.2±1.7%) and the difference was ameliorated with antioxidant supplementation (10.7±1.9% vs. 10.8±1.8%), but the interaction was not significant (p=0.10). There were no significant changes in malondialdehyde-thiobarbituric acid reactive substances following antioxidant supplementation. There was a significant increase in brachial blood flow and forearm vascular conductance with exercise but no differences with antioxidant supplementation. There were no group differences in exercise responses and no differences with antioxidant supplementation, suggesting a lack of influence of oxidative stress during exercise in this cohort.