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The essential role of B cells is to produce protective immunoglobulins (Ig) that recognize, neutralize, and clear invading pathogens. This results from the integration of signals provided by pathogens or vaccines and the stimulatory microenvironment within sites of immune activation, such as secondary lymphoid tissues, that drive mature B cells to differentiate into memory B cells and antibody (Ab)-secreting plasma cells. In this context, B cells undergo several molecular events including Ig class switching and somatic hypermutation that results in the production of high-affinity Ag-specific Abs of different classes, enabling effective pathogen neutralization and long-lived humoral immunity. However, perturbations to these key signaling pathways underpin immune dyscrasias including immune deficiency and autoimmunity or allergy. Inborn errors of immunity that disrupt critical immune pathways have identified non-redundant requirements for eliciting and maintaining humoral immune memory but concomitantly prevent immune dysregulation. Here, we will discuss our studies on human B cells, and how our investigation of cytokine signaling in B cells have identified fundamental requirements for memory B-cell formation, Ab production as well as regulating Ig class switching in the context of protective versus allergic immune responses., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Infection with SARS-CoV-2, the etiology of the ongoing COVID-19 pandemic, has resulted in over 450 million cases with more than 6 million deaths worldwide, causing global disruptions since early 2020. Memory B cells and durable antibody protection from long-lived plasma cells (LLPC) are the mainstay of most effective vaccines. However, ending the pandemic has been hampered by the lack of long-lived immunity after infection or vaccination. Although immunizations offer protection from severe disease and hospitalization, breakthrough infections still occur, most likely due to new mutant viruses and the overall decline of neutralizing antibodies after 6 months. Here, we review the current knowledge of B cells, from extrafollicular to memory populations, with a focus on distinct plasma cell subsets, such as early-minted blood antibody-secreting cells and the bone marrow LLPC, and how these humoral compartments contribute to protection after SARS-CoV-2 infection and immunization. [ABSTRACT FROM AUTHOR]

Age‐associated B cells (ABCs) have emerged as critical components of immune responses. Their inappropriate expansion and differentiation have increasingly been linked to the pathogenesis of autoimmune disorders, aging‐associated diseases, and infections. ABCs exhibit a distinctive phenotype and, in addition to classical B cell markers, often express the transcription factor T‐bet and myeloid markers like CD11c; hence, these cells are also commonly known as CD11c+T‐bet+ B cells. Formation of ABCs is promoted by distinctive combinations of innate and adaptive signals. In addition to producing antibodies, these cells display antigen‐presenting and proinflammatory capabilities. It is becoming increasingly appreciated that the ABC compartment exhibits a high degree of heterogeneity, plasticity, and sex‐specific regulation and that ABCs can differentiate into effector progeny via several routes particularly in autoimmune settings. In this review, we will discuss the initial insights that have been obtained on the molecular machinery that controls ABCs and we will highlight some of the unique aspects of this control system that may enable ABCs to fulfill their distinctive role in immune responses. Given the expanding array of autoimmune disorders and pathophysiological settings in which ABCs are being implicated, a deeper understanding of this machinery could have important and broad therapeutic implications for the successful, albeit daunting, task of targeting these cells. [ABSTRACT FROM AUTHOR]

Humoral immunity provides protection from pathogenic infection and is mediated by antibodies following the differentiation of naive B cells (nBs) to antibody‐secreting cells (ASCs). This process requires substantial epigenetic and transcriptional rewiring to ultimately repress the nB program and replace it with one conducive to ASC physiology and function. Notably, these reprogramming events occur within the framework of cell division. Efforts to understand the relationship of cell division with reprogramming and ASC differentiation in vivo have uncovered the timing and scope of reprogramming, as well as key factors that influence these events. Herein, we discuss the unique physiology of ASC and how nBs undergo epigenetic and genome architectural reorganization to acquire the necessary functions to support antibody production. We also discuss the stage‐wise manner in which reprogramming occurs across cell divisions and how key molecular determinants can influence B cell fate outcomes. [ABSTRACT FROM AUTHOR]

Summary: Antibody‐secreting cells (ASC) are the effectors of protective humoral immunity and the only cell type that produces antibodies or immunoglobulins in mammals. In addition to their formidable capacity to secrete massive quantities of proteins, ASC are terminally differentiated and have unique features to become long‐lived plasma cells (LLPC). Upon antigen encounter, B cells are activated through a complex multistep process to undergo fundamental morphological, subcellular, and molecular transformation to become an efficient protein factory with lifelong potential. The ASC survival potential is determined by factors at the time of induction, capacity to migration from induction to survival sites, and ability to mature in the specialized bone marrow microenvironments. In the past decade, considerable progress has been made in identifying factors regulating ASC longevity. Here, we review the intrinsic drivers, trafficking signals, and extrinsic regulators with particular focus on how they impact the survival potential to become a LLPC. [ABSTRACT FROM AUTHOR]

Humoral immunity is a critical component of the coordinated response required to resolve viral infections and mediate protection following pathogen clearance or vaccination. A better understanding of factors shaping the memory B cell response will allow tailored development of efficient preventative vaccines against emerging acute viral infections, therapeutic vaccines, and immunotherapies for chronic viral infections. Here, we use recent data obtained by profiling antigen‐specific B cell responses in hepatitis B as a framework to explore lessons that can be learnt from different viral infections about the diverse influences on humoral immunity. Hepatitis B provides a paradigm where successful B cell responses in resolved or vaccinated individuals can be contrasted to the failed response in chronic infection, while also exemplifying the degree to which B cell responses within infected individuals can differ to two antigens from the same virus. Drawing on studies in other human and murine infections, including emerging data from COVID‐19, we consider the influence of antigen quantity and structure on the quality of the B cell response, the role of differential CD4 help, the importance of germinal center vs extrafollicular responses and the emerging concept that responses residing in non‐lymphoid organs can participate in B cell memory. [ABSTRACT FROM AUTHOR]