Background Atopic diseases are characterized by IgE antibody responses that are dependent on cognate CD4 T cell help and T cell‐produced IL‐4 and IL‐13. Current models of IgE cell differentiation point to the role of IgG memory B cells as precursors of pathogenic IgE plasma cells. The goal of this work was to identify intrinsic features of memory B cells that are associated with IgE production in atopic diseases. Methods Peripheral blood B lymphocytes were collected from individuals with physician diagnosed asthma or atopic dermatitis (AD) and from non‐atopic individuals. These samples were analyzed by spectral flow cytometry, single cell RNA sequencing (scRNAseq), and in vitro activation assays. Results We identified a novel population of IgG memory B cells characterized by the expression of IL‐4/IL‐13 regulated genes FCER2/CD23, IL4R, IL13RA1, and IGHE, denoting a history of differentiation during type 2 immune responses. CD23+IL4R+IgG+ memory B cells had increased occurrence in individuals with atopic disease. Importantly, the frequency of CD23+IL4R+IgG+ memory B cells correlated with levels of circulating IgE. Consistently, in vitro stimulated B cells from atopic individuals generated more IgE+ cells than B cells from non‐atopic subjects. Conclusions These findings suggest that CD23+IL4R+ IgG+ memory B cells transcribing IGHE are potential precursors of IgE plasma cells and are linked to pathogenic IgE production.

Emerging evidence suggests that brain derived extracellular vesicles (EVs) and particles (EPs) can cross blood-brain barrier and mediate communication among neurons, astrocytes, microglial, and other cells of the central nervous system (CNS). Yet, a complete understanding of the molecular landscape and function of circulating EVs & EPs (EVPs) remain a major gap in knowledge. This is mainly due to the lack of technologies to isolate and separate all EVPs of heterogeneous dimensions and low buoyant density. In this review, we aim to provide a comprehensive understanding of the neurosecretome, including the extracellular vesicles that carry the molecular signature of the brain in both its microenvironment and the systemic circulation. We discuss the biogenesis of EVPs, their function, cell-to-cell communication, past and emerging isolation technologies, therapeutics, and liquid-biopsy applications. It is important to highlight that the landscape of EVPs is in a constant state of evolution; hence, we not only discuss the past literature and current landscape of the EVPs, but we also speculate as to how novel EVPs may contribute to the etiology of addiction, depression, psychiatric, neurodegenerative diseases, and aid in the real time monitoring of the “living brain”. Overall, the neurosecretome is a concept we introduce here to embody the compendium of circulating particles of the brain for their function and disease pathogenesis. Finally, for the purpose of inclusion of all extracellular particles, we have used the term EVPs as defined by the International Society of Extracellular Vesicles (ISEV).

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Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured 4,701 circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict adverse COVID-19 outcomes in 417 subjects and tested these models in a separate cohort of 569 individuals. For severe COVID-19, a baseline model including age and sex provided an area under the receiver operator curve (AUC) of 65% in the test cohort. Selecting 92 proteins from the 4,701 unique protein abundances improved the AUC to 88% in the training cohort, which remained relatively stable in the testing cohort at 86%, suggesting good generalizability. Proteins selected from different adverse COVID-19 outcomes were enriched for cytokine and cytokine receptors, but more than half of the enriched pathways were not immune-related. Taken together, these findings suggest that circulating proteins measured at early stages of disease progression are reasonably accurate predictors of adverse COVID-19 outcomes. Further research is needed to understand how to incorporate protein measurement into clinical care.

Two years into the SARS-CoV-2 pandemic, the post-acute sequelae of infection are compounding the global health crisis. Often debilitating, these sequelae are clinically heterogeneous and of unknown molecular etiology. Here, a transcriptome-wide investigation of this new condition was performed in a large cohort of acutely infected patients followed clinically into the post-acute period. Gene expression signatures of post-acute sequelae were already present in whole blood during the acute phase of infection, with both innate and adaptive immune cells involved. Plasma cells stood out as driving at least two distinct clusters of sequelae, one largely dependent on circulating antibodies against the SARS-CoV-2 spike protein and the other antibody-independent. Altogether, multiple etiologies of post-acute sequelae were found concomitant with SARS-CoV-2 infection, directly linking the emergence of these sequelae with the host response to the virus.