RESUMEN
BACKGROUND: Antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been shown to neutralize the virus in vitro and prevent disease in animal challenge models on reexposure. However, the current understanding of SARS-CoV-2 humoral dynamics and longevity is conflicting. METHODS: The COVID-19 Staff Testing of Antibody Responses Study (Co-Stars) prospectively enrolled 3679 healthcare workers to comprehensively characterize the kinetics of SARS-CoV-2 spike protein (S), receptor-binding domain, and nucleoprotein (N) antibodies in parallel. Participants screening seropositive had serial monthly serological testing for a maximum of 7 months with the Meso Scale Discovery Assay. Survival analysis determined the proportion of seroreversion, while 2 hierarchical gamma models predicted the upper and lower bounds of long-term antibody trajectory. RESULTS: A total of 1163 monthly samples were provided from 349 seropositive participants. At 200 days after symptoms, >95% of participants had detectable S antibodies, compared with 75% with detectable N antibodies. S antibody was predicted to remain detectable in 95% of participants until 465 days (95% confidence interval, 370-575 days) using a "continuous-decay" model and indefinitely using a "decay-to-plateau" model to account for antibody secretion by long-lived plasma cells. S-antibody titers were correlated strongly with surrogate neutralization in vitro (R2 = 0.72). N antibodies, however, decayed rapidly with a half-life of 60 days (95% confidence interval, 52-68 days). CONCLUSIONS: The Co-Stars data presented here provide evidence for long-term persistence of neutralizing S antibodies. This has important implications for the duration of functional immunity after SARS-CoV-2 infection. In contrast, the rapid decay of N antibodies must be considered in future seroprevalence studies and public health decision-making. This is the first study to establish a mathematical framework capable of predicting long-term humoral dynamics after SARS-CoV-2 infection. CLINICAL TRIALS REGISTRATION: NCT04380896.
Asunto(s)
COVID-19 , Glicoproteína de la Espiga del Coronavirus , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Humanos , SARS-CoV-2 , Estudios SeroepidemiológicosRESUMEN
X-linked lymphoproliferative disease (XLP1) is a rare primary immunodeficiency that usually presents in early childhood. Patients with XLP1 have been reported to have absent NKT cells, and it has been suggested that this can be diagnostic for the disorder. Whilst NKT frequency in adults is variable, little is known about their frequency in children. Therefore, we established a paediatric reference range for these cells. In contrast to previous reports, in our cohort of XLP1 patients, NKT cell numbers were found to be variable, and we would advise against using the finding of NKT cells to exclude a diagnosis of XLP1.
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Trastornos Linfoproliferativos , Células T Asesinas Naturales , Adulto , Niño , Preescolar , Estudios de Cohortes , Humanos , Trastornos Linfoproliferativos/diagnóstico , Proteína Asociada a la Molécula de Señalización de la Activación LinfocitariaRESUMEN
This report highlights case of two siblings who developed haemophagocytic lymphohystiocytosis due to distinct genetic abnormalities. Though their presentation was clinically similar, the cases demonstrate that a shared genetic diagnosis among siblings cannot be assumed.
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Linfohistiocitosis Hemofagocítica , Humanos , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/genética , HermanosRESUMEN
The objective of this study was to determine the effectiveness of MRP8/14 as a predictor of disease flare in patients with juvenile idiopathic arthritis (JIA) following the withdrawal of methotrexate (MTX) in a routine clinical setting. All MRP8/14 tests performed at a single centre in a 27-month period were considered for analysis. Patients were assessed against criteria for inactive disease and subsequent disease flare. Decisions on whether or not to stop treatment were recorded. MRP8/14 results were assessed in conjunction with clinical information. Clinicians were also surveyed to investigate if MRP8/14 influenced their decision to discontinue MTX where this was available at that time point. One hundred four cases met the inclusion criteria during the study period. Although there was no significant difference in flares between patients with an elevated or low MRP8/14 value, in those who stopped MTX (n = 22), no patients with a low MRP8/14 (≤ 4000 ng/ml) result flared (follow-up time 12 months). Clinicians reported that for patients with clinically inactive disease and an elevated MRP8/14 result (> 4000 ng/ml), none would advise withdrawal of MTX. Low MRP8/14 was interpreted favourably when considering stopping MTX treatment in patients with JIA. Implementation of MRP8/14 testing has changed clinical practice at this centre. However, the observation that some patients in our cohort who had an elevated MRP8/14 value did not flare after stopping MTX for non-disease-related reasons highlights the need for further biomarkers to predict the risk of flare off medication in JIA and aid clinicians in treatment decisions. Key Points ⢠First study of serum MRP8/14 measurement in clinical practice to inform treatment decisions in patients with JIA. ⢠No patients with a low MRP8/14 test result went on to suffer a disease flare in 12 months of follow follow-up. ⢠Further biomarkers are needed to predict the risk of flare off medication in JIA and treatment decisions.
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Antirreumáticos , Artritis Juvenil , Antirreumáticos/uso terapéutico , Artritis Juvenil/tratamiento farmacológico , Biomarcadores , Humanos , Metotrexato/uso terapéutico , Brote de los Síntomas , Resultado del TratamientoRESUMEN
Accumulation of human CD21low B cells in peripheral blood is a hallmark of chronic activation of the adaptive immune system in certain infections and autoimmune disorders. The molecular pathways underpinning the development, function, and fate of these CD21low B cells remain incompletely characterized. Here, combined transcriptomic and chromatin accessibility analyses supported a prominent role for the transcription factor T-bet in the transcriptional regulation of these T-bethighCD21low B cells. Investigating essential signals for generating these cells in vitro established that B cell receptor (BCR)/interferon-γ receptor (IFNγR) costimulation induced the highest levels of T-bet expression and enabled their differentiation during cell cultures with Toll-like receptor (TLR) ligand or CD40L/interleukin-21 (IL-21) stimulation. Low proportions of CD21low B cells in peripheral blood from patients with defined inborn errors of immunity (IEI), because of mutations affecting canonical NF-κB, CD40, and IL-21 receptor or IL-12/IFNγ/IFNγ receptor/signal transducer and activator of transcription 1 (STAT1) signaling, substantiated the essential roles of BCR- and certain T cellderived signals in the in vivo expansion of T-bethighCD21low B cells. Disturbed TLR signaling due to MyD88 or IRAK4 deficiency was not associated with reduced CD21low B cell proportions. The expansion of human T-bethighCD21low B cells correlated with an expansion of circulating T follicular helper 1 (cTfh1) and T peripheral helper (Tph) cells, identifying potential sources of CD40L, IL-21, and IFNγ signals. Thus, we identified important pathways to target autoreactive T-bethighCD21low B cells in human autoimmune conditions, where these cells are linked to pathogenesis and disease progression.
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Linfocitos B/inmunología , Receptores de Complemento 3d/inmunología , Proteínas de Dominio T Box/inmunología , Linfocitos T/inmunología , Adulto , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To estimate the ability of maternal serum markers and uterine artery Doppler in predicting preeclampsia. METHODS: In this nested case-control study, maternal serum concentrations of cystatin C, beta2-microglobulin, serum amyloid A, C-reactive protein (CRP), and neopterin were measured, and resistance index of uterine artery blood flow was assessed in 45 women in whom preeclampsia subsequently developed and in 125 women with normal pregnancy outcome. Univariable regression analysis was performed to estimate correlations between serum markers and resistance index for the development of preeclampsia. Significant variables were identified using multiple logistic regressions. RESULTS: Maternal serum markers were measured at a median gestational age of 14.7 weeks (interquartile range 3.1) in control group members and 16.3 weeks (interquartile range 4.8) in the case group members, and uterine resistance index was measured at the second-trimester scan. Univariable logistic regression showed that women with subsequent preeclampsia had increased levels of cystatin C, beta2-microglobulin, neopterin, CRP, and resistance index. Cystatin C, CRP, and resistance index remained independently associated with preeclampsia when multiple logistic regression was applied. Receiver-operating characteristic curve analysis showed that a combination of markers had a better area under the curve (AUC; 0.825) than when used in isolation (cystatin C, AUC 0.725; CRP, AUC 0.634; resistance index, AUC 0.728). Sensitivity of uterine artery resistance index, cystatin C, and CRP combined for predicting preeclampsia was 69.2% for a screen-positive rate of 15%. CONCLUSION: Maternal serum cystatin C, CRP, and uterine artery mean resistance index are independent predictors of preeclampsia. There is improved prediction of preeclampsia when serum markers are combined with Doppler indices.
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Proteína C-Reactiva/metabolismo , Cistatina C/sangre , Preeclampsia/sangre , Preeclampsia/diagnóstico por imagen , Ultrasonografía Prenatal , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Humanos , Neopterin/sangre , Embarazo , Primer Trimestre del Embarazo , Segundo Trimestre del Embarazo , Curva ROC , Adulto Joven , Microglobulina beta-2/sangreRESUMEN
The balance between trophoblast cathepsin and decidual cystatin C expression is pivotal in physiological trophoblast development. Defective trophoblast invasion is characteristic of preeclampsia and may involve derangement of the cathepsin/cystatin C balance. We conducted a prospective nested case-control study of healthy women with singleton pregnancies in the first trimester of pregnancy. Maternal serum cystatin C concentrations in those subsequently developing preeclampsia (n = 30) were compared to controls with normal outcome (n = 90). The median cystatin C concentration in early pregnancy was significantly higher (P = .0001) in those who subsequently developed preeclampsia (median 0.65 mg/L) when compared to normal pregnancy (median 0.57 mg/L). Of the 30 women developing preeclampsia, 14 (47%) had cystatin C above the 80th centile (0.67 mg/L) for the controls. Maternal serum cystatin C concentrations in early pregnancy may be of value in identifying women at high risk of developing preeclampsia.