Capture of plasma membrane fragments from target cells by trogocytosis requires signaling in T cells but not in B cells

Upon recognition of their respective cellular partners, T and B cells acquire their antigens by a process of membrane capture called trogocytosis. Here, we report that various inhibitors of actin polymerization or of kinases involved in intracellular signaling partially or fully inhibited trogocytosis by CD8⁺ and CD4⁺ T cells, whereas they had no effect on trogocytosis by B cells. Similarly, trogocytosis by T cells was inhibited at 4°C, whereas in B cells it was independent of temperature, indicating that trogocytosis by B cells does not rely on active processes. By contrast, most inhibitors we tested impaired both T-cell and B-cell activation. The differential effect of inhibitors on T-cell and B-cell trogocytosis was not due to the higher affinity of the B-cell receptor for its cognate antigen compared with the affinity of the T-cell receptor for its own antigen, but it correlated tightly with the abilities of T cells and B cells to form conjugates with their target cells in the presence of inhibitors. Trogocytosis thus has different requirements in different cell types. Moreover, the capture of membrane antigen by B cells is identified as a novel signaling-independent event of B-cell biology.     

Negative selection on human genes underlying inborn errors depends on disease outcome and both the mode and mechanism of inheritance

Genetic variants underlying life-threatening diseases, being unlikely to be transmitted to the next generation, are gradually and selectively eliminated from the population through negative selection. We study the determinants of this evolutionary process in human genes underlying monogenic diseases by comparing various negative selection scores and an integrative approach, CoNeS, at 366 loci underlying inborn errors of immunity (IEI). We find that genes underlying autosomal dominant (AD) or X-linked IEI have stronger negative selection scores than those underlying autosomal recessive (AR) IEI, whose scores are not different from those of genes not known to be disease causing. Nevertheless, genes underlying AR IEI that are lethal before reproductive maturity with complete penetrance have stronger negative selection scores than other genes underlying AR IEI. We also show that genes underlying AD IEI by loss of function have stronger negative selection scores than genes underlying AD IEI by gain of function, while genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. These results are replicated in 1,140 genes underlying inborn errors of neurodevelopment. Finally, we propose a supervised classifier, SCoNeS, which predicts better than state-of-the-art approaches whether a gene is more likely to underlie an AD or AR disease. The clinical outcomes of monogenic inborn errors, together with their mode and mechanisms of inheritance, determine the levels of negative selection at their corresponding loci. Integrating scores of negative selection may facilitate the prioritization of candidate genes and variants in patients suspected to carry an inborn error.

Negative (or purifying) selection is the natural process by which deleterious alleles are selectively purged from the population (1). In diploid species, the strength of negative selection at a given locus is predicted to increase with decreasing fitness and increasing dominance of the genetic variants controlling traits: Variation causing early death in the heterozygous state are the least likely to be transmitted to the next generation, as their carriers have fewer offspring than noncarriers (2). Human genetic variants that cause severe diseases are, thus, expected to be the primary targets of negative selection, particularly for diseases affecting heterozygous individuals. In humans, several studies have ranked protein-coding genes according to their levels of negative selection (3–5). Nevertheless, the extent to which negative selection affects human disease-causing genes, and the factors determining its strength, remain largely unknown, particularly because our knowledge of the severity, mode, and mechanism of inheritance of the corresponding human diseases remains incomplete (3, 6–8).The strength of negative selection at a given gene has been traditionally approximated by comparing the coding sequence of the gene in a given species with that of one or several closely related species; it depends on the proportion of amino acid changes that have accumulated during evolution (9–11). With the advent of high-throughput sequencing, intraspecies metrics have been developed, based on the comparison of the probability of predicted loss-of-function (pLOF) mutations for a gene under a random model with the frequency of pLOF mutations observed in population databases (5, 12, 13), which capture the species-specific evolution of genes. Using an interspecies-based method and a hand-curated version of the Online Mendelian Inheritance in Man (hOMIM) database, a previous study elegantly showed that most human genes for which mutations cause highly penetrant diseases, including autosomal dominant (AD) diseases in particular, evolve under stronger negative selection than genes associated with complex disorders (6). However, other studies based on OMIM genes have reported conflicting results (3, 14–17), probably due to the incompleteness and heterogeneity of the datasets used. Moreover, no study has yet addressed this problem with intraspecies metrics, even though it has been suggested that the choice of the reference species for interspecies metrics contributes to discrepancies across studies (6).We aimed to improve the identification of the drivers of negative selection acting on human disease-causing genes, by developing a negative selection score combining several informative intraspecies and interspecies statistics, focusing on inborn errors of immunity (IEI). IEI, previously known as primary immunodeficiencies (18), are genetic diseases that disrupt the development or function of human immunity. They form a large and expanding group of genetic diseases that has been widely studied, and they are well characterized physiologically (immunologically) and phenotypically (clinically) (19–21). IEI are often symptomatic in early childhood, and at least until the turn of the 20th century and the introduction of antibiotics, most individuals with IEI probably died before reaching reproductive maturity. Accordingly, IEI genes have probably been under strong negative selection from the dawn of humankind until very recently. In this study, we investigated whether the severity of IEI and their mode and mechanism of inheritance have left signatures of negative selection of various intensities in the corresponding human genes. Furthermore, we validated our model on genes underlying inborn errors of neurodevelopment (IEND), another group of well-characterized severe genetic diseases.     

T-wave alternans for risk stratification and prevention of sudden cardiac death

Despite considerable progress in the management of ischemic heart disease, a substantial proportion of patients continue to experience life-threatening arrhythmic events. The Multicenter Automatic Defibrillator Implantation Trial 2 has recently shown the superiority of implantable cardioverter defibrillators (ICDs) over conventional strategies to prevent sudden death in patients with reduced ejection fraction, but at the expense of potentially unnecessary ICD implantation in a large percentage of patients. T-wave alternans (TWA), which reflects alternation of cellular repolarization, results in a substantial increase in dispersion of repolarization, a prerequisite for reentrant arrhythmias. Recent trials, cumulating close to 3000 patients, have established TWA analysis as a powerful tool for arrhythmia prevention. Based on the most recent estimates, at least one third of post-myocardial infarction patients are expected to be tested negative. With a negative predictive value greater than 90%, TWA might allow for targeting of patients most likely to benefit from ICD therapy. Accurate identification of high-risk patients by noninvasive TWA may allow for improved widespread screening for sudden death prevention in the general population.     

Nephrocalcinosis: initial manifestation of primary Sjögren's syndrome

INTRODUCTION: Nephrocalcinosis is a rare complication of chronic tubulointerstitial nephritis observed in primary Sj?gren's syndrome. It can precede subjective sicca symptoms. OBSERVATION: We report the case of a 50-year-old woman who presented with a primary Sj?gren's syndrome. The first symptoms appeared 10-years-ago while she was affected with a nephrocalcinosis. CONCLUSION: Autoimmune investigations for Sj?gren's syndrome should be initiated in any patient presenting with nephrocalcinosis and distal renal tubular acidosis.     

Current anatomical and etiological aspects of chronic or subacute, surgical, pure mitral valve insufficiency in adults. Apropos of 75 medicosurgical cases

Seventy five medico-surgical cases (52 men, with a mean age at surgery of 59, and 23 women, with a mean age at surgery of 59) collected between 1983 and 1989, in an ethnically homogeneous and geographically stable population (West Brittany) confirmed that the current anatomical and etiological aspects of chronic (or subacute) pure mitral incompetence (MI) have changed radically. While rates for bacterial and ischemic etiologies remain stable, the share of rheumatic MI (14 cases) has fallen considerably, to the advantage of degenerative MI (51 cases) with a heavy male predominance (39 men) with in 33 cases rupture of the main chordae, and tending to affect the lesser mitral cusp more often. A precise diagnosis in terms of lesions and etiology is possible in almost all cases on the basis of clinical history and echocardiographic findings. In a perfectly homogeneous population, chronic surgical pure MI is currently essentially a male disease, of dystrophic origin, in patients in the 6th and 7th decades of life.     

Electrophysiological effects of intravenous magnesium sulfate in man

Magnesium salts have been used for many years to correct a wide variety of arrhythmias. A few experimental studies have been devoted to their electrophysiological effects, but these remain poorly documented in man, hence this study. An electrophysiological investigation was conducted in 24 patients before, and immediately after a bolus intravenous injection of magnesium sulphate in doses of 1.5 g to 12 patients (group I) and 3 g to 12 other patients (group II), followed by a continuous infusion at the rate of 1 mg/min. The drug had no influence on heart rate, duration of QRS, QT and QTc intervals and ventricular refractory period. A small, but statistically significant prolongation of HV (from 57 to 59 ms, p less than 0.05) was observed in group II. Analysis of the results in group I revealed a moderate but significant prolongation of the PR and AH intervals. The electrophysiological effects were distinctly more pronounced in group II patients, with significant prolongation of: PR and AH intervals, effective refractory period of the right atrium and AV node, Wenckebach's point, corrected sinus node recovery time and sinoatrial conduction time. These results demonstrate that magnesium sulphate principally acts on the sinus node, the AV node and the atrium, suggesting a blocking effect on calcium channels.