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1.
J Clin Immunol ; 43(6): 1093-1103, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37209324

RESUMEN

Autoantibodies (auto-Abs) neutralizing type I interferons (IFNs) are found in the blood of at least 15% of unvaccinated patients with life-threatening COVID-19 pneumonia. We report here the presence of auto-Abs neutralizing type I IFNs in the bronchoalveolar lavage (BAL) of 54 of the 415 unvaccinated patients (13%) with life-threatening COVID-19 pneumonia tested. The 54 individuals with neutralizing auto-Abs in the BAL included 45 (11%) with auto-Abs against IFN-α2, 37 (9%) with auto-Abs against IFN-ω, 54 (13%) with auto-Abs against IFN-α2 and/or ω, and five (1%) with auto-Abs against IFN-ß, including three (0.7%) with auto-Abs neutralizing IFN-α2, IFN-ω, and IFN-ß, and two (0.5%) with auto-Abs neutralizing IFN-α2 and IFN-ß. Auto-Abs against IFN-α2 also neutralize the other 12 subtypes of IFN-α. Paired plasma samples were available for 95 patients. All seven patients with paired samples who had detectable auto-Abs in BAL also had detectable auto-Abs in plasma, and one patient had auto-Abs detectable only in blood. Auto-Abs neutralizing type I IFNs are, therefore, present in the alveolar space of at least 10% of patients with life-threatening COVID-19 pneumonia. These findings suggest that these auto-Abs impair type I IFN immunity in the lower respiratory tract, thereby contributing to hypoxemic COVID-19 pneumonia.


Asunto(s)
COVID-19 , Interferón Tipo I , Humanos , Autoanticuerpos , Interferón-alfa , Lavado Broncoalveolar
2.
J Exp Med ; 218(11)2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-34473196

RESUMEN

Autosomal dominant (AD) NFKB1 deficiency is thought to be the most common genetic etiology of common variable immunodeficiency (CVID). However, the causal link between NFKB1 variants and CVID has not been demonstrated experimentally and genetically, and there has been insufficient biochemical characterization and enrichment analysis. We show that the cotransfection of NFKB1-deficient HEK293T cells (lacking both p105 and its cleaved form p50) with a κB reporter, NFKB1/p105, and a homodimerization-defective RELA/p65 mutant results in p50:p65 heterodimer-dependent and p65:p65 homodimer-independent transcriptional activation. We found that 59 of the 90 variants in patients with CVID or related conditions were loss of function or hypomorphic. By contrast, 258 of 260 variants in the general population or patients with unrelated conditions were neutral. None of the deleterious variants displayed negative dominance. The enrichment in deleterious NFKB1 variants of patients with CVID was selective and highly significant (P = 2.78 × 10-15). NFKB1 variants disrupting NFKB1/p50 transcriptional activity thus underlie AD CVID by haploinsufficiency, whereas neutral variants in this assay should not be considered causal.


Asunto(s)
Inmunodeficiencia Variable Común/genética , Subunidad p50 de NF-kappa B/genética , Animales , Células COS , Línea Celular , Chlorocebus aethiops , Células HEK293 , Haploinsuficiencia/genética , Humanos , FN-kappa B/genética , Fenotipo , Activación Transcripcional/genética
4.
J Clin Endocrinol Metab ; 88(8): 3501-4, 2003 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12915625

RESUMEN

We have found recently that excluding subjects with low serum 25OHD has a significant impact on the PTH reference range (10-46 ng/liter instead of 10-65 ng/liter with the same assay). However, before being used routinely, this new range had to be clinically validated. We thus reviewed the chart of 708 consecutive osteopenic patients who were referred to our unit for a biological exploration in search of secondary causes for their low bone mass. They were classified into two groups. Group 1 (n = 360) included the patients for whom no reasons for high PTH were found after examination of their chart. Group 2 (n = 348) included patients with one of the following potential reasons for an increased PTH concentration: hyper- or hypocalcemia, normocalcemic primary hyperparathyroidism (PHPT), renal hypercalciuria, vitamin D insufficiency, chronic renal failure, use of bisphosphonates, and any chronic disease known to potentially alter calcium metabolism. Among the 360 group 1 patients, 15 (4.2%) had a serum PTH level more than 46 ng/liter, which is not different from the theoretical rate of 3% of normal subjects whose serum PTH may be above the 97th centile of the reference (chi(2) = 2.8; NS). Forty-two group 2 patients had a surgically proven PHPT. Among these, serum PTH was

Asunto(s)
Hormona Paratiroidea/sangre , Vitamina D/sangre , Adulto , Anciano , Enfermedades Óseas Metabólicas/sangre , Calcio/sangre , Difosfonatos/efectos adversos , Difosfonatos/uso terapéutico , Reacciones Falso Negativas , Reacciones Falso Positivas , Femenino , Humanos , Riñón/metabolismo , Fallo Renal Crónico/metabolismo , Masculino , Persona de Mediana Edad , Valores de Referencia
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