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Epstein–Barr virus (EBV) is a ubiquitous human pathogen, infecting > 90% of the adult population. In the vast majority of healthy individuals, infection with EBV runs a relatively benign course. However, EBV is by no means a benign pathogen. Indeed, apart from being associated with at least seven different types of malignancies, EBV infection can cause severe and often fatal diseases—hemophagocytic lymphohistiocytosis, lymphoproliferative disease, B-cell lymphoma—in rare individuals with specific monogenic inborn errors of immunity. The discovery and detailed investigation of inborn errors of immunity characterized by heightened susceptibility to, or increased frequency of, EBV-induced disease have elegantly revealed cell types and signaling pathways that play critical and non-redundant roles in host-defense against EBV. These analyses have revealed not only mechanisms underlying EBV-induced disease in rare genetic conditions, but also identified molecules and pathways that could be targeted to treat severe EBV infection and pathological consequences in immunodeficient hosts, or even potentially enhance the efficacy of an EBV-specific vaccine.

During our life, we are surrounded by continuous threats from a diverse range of invading pathogens. Our immune system has evolved multiple mechanisms to efficiently deal with these threats so as to prevent them from causing disease. Terminal differentiation of mature B cells into plasma cells (PC) - the antibody (Ab) secreting cells of the immune system - is critical for the generation of protective and long-lived humoral immune responses. Indeed, efficient production of antigen (Ag)-specific Ab by activated B cells underlies the success of most currently available vaccines. The mature B-cell pool is composed of several subsets, distinguished from one according to size, surface marker expression, location, and Ag exposure, and they all have the capacity to differentiate into PCs. For a B-cell to acquire the capacity to produce Abs, it must undergo an extensive differentiation process driven by changes in gene expression. Two broad categories of Ags exist that cause B-cell activation and differentiation: T cell dependent (TD) or T cell independent (TI). In addition to the B-cell subset and nature of the Ag, it is important to consider the cytokine environment that can also influence how B-cell differentiation is achieved. Thus, while many cytokines can induce Ab-secretion by B cells after activation with mimics of TD and TI stimuli in vitro, they can have different efficacies and specificities, and can often preferentially induce production of one particular Ig isotype over another. Here, we will provide an overview of in vitro studies (mouse and human origin) that evaluated the role of different cytokines in inducing the differentiation of distinct B-cell subsets to the PC lineage. We will place particular emphasis on IL-21, which has emerged as the most potent inducer of terminal B-cell differentiation in humans. We will also focus on the role of IL-21 and defects in B-cell function and how these contribute to human immunopathologies such as primary immunodeficiencies and B-cell mediated autoimmune conditions.

We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.

X-linked lymphoproliferative disease (XLP) is a rare primary immunodeficiency affecting approximately 1–2 per 1 million males. A key feature of XLP is the exquisite sensitivity of affected individuals to disease induced following EBV infection. However, patients can also develop hypogammaglobulinemia and B-cell lymphoma independently of exposure to EBV. XLP is caused by loss-of function mutations in SH2D1A , which encodes the intracellular adaptor molecule SAP. SAP is predominantly expressed in T cells and NK cells, and functions to regulate signal transduction pathways downstream of the SLAM family of surface receptors to control CD4+ T cell (and by extension B cells), CD8+ T cell and NK cell function, as well as the development of NKT cells. The study of XLP had shed substantial light on the requirements for lymphocyte differentiation and immune regulation, which in turn have the potential to be translated into novel treatments for not only XLP patients but individuals affected by EBV-induced disease, impaired humoral immunity and malignancy.

Since 2013, the International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) has published an updated phenotypic classification of IEI, which accompanies and complements their genotypic classification into ten tables. This phenotypic classification is user-friendly and serves as a resource for clinicians at the bedside. There are now 430 single-gene IEI underlying phenotypes as diverse as infection, malignancy, allergy, autoimmunity, and autoinflammation. We herein report the 2019 phenotypic classification, including the 65 new conditions. The diagnostic algorithms are based on clinical and laboratory phenotypes for each of the ten broad categories of IEI.

Abstract The International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) reports here the 2022 updated phenotypic classification, which accompanies and complements the most-recent genotypic classification. This phenotypic classification is aimed for clinicians at the bedside and focuses on clinical features and laboratory phenotypes of specific IEI. In this classification, 485 IEI underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity and auto-inflammation are described, including 55 novel monogenic defects and 1 autoimmune phenocopy. Therefore, all 485 diseases of the genetic classification are presented in this paper in the form of colored tables with essential clinical or immunological phenotype entries.

Key Points Naive CD4 + T cells have the potential to differentiate into specialized effector cell populations that have distinct functions during infection; T follicular helper (T FH ) cells are the effector CD4 + T cell population responsible for mediating the activation and differentiation of B cells to generate protective humoral (antibody-based) immunity. T FH cells are defined as CD4 + T cells that migrate to follicles and interact with antigen-specific B cells to support their differentiation into memory or plasma cells. They can be identified from other CD4 + T cells on the basis of their unique surface phenotype, as they express the highest levels of CXC-chemokine receptor 5 (CXCR5), together with the surface receptors inducible T cell co-stimulator (ICOS) and programmed cell death protein 1 (PD1), the transcriptional repressor B cell lymphoma 6 (BCL-6) and the cytokine interleukin-21 (IL-21).They also lack expression of CC-chemokine receptor 7 (CCR7) and IL-7 receptor-α (IL-7Rα), and are hence defined as CD4 + CXCR5 hi PD1 hi ICOS hi BCl-6 + IL-21 + CCR7 − IL-7Rα − cells. T FH cell differentiation is dependent on interactions with antigen-presenting dendritic cells and B cells that are mediated through specific receptor–ligand pairs, including cytokines and their receptors. Collectively, these signals induce the expression of a range of transcription factors that induce the differentiation of the activated CD4 + T cell to a T FH cell fate. Many molecules have been found to regulate T FH cell formation, including: CD28, ICOS, CD40 ligand (CD40L) and SLAM-associated protein (SAP)-associated receptors; signal transducer and activator of transcription 3 (STAT3)-activating cytokines IL-6 and IL-21 (particularly in combination); and BCL-6, MAF, basic leucine zipper transcriptional factor ATF-like (BATF) and interferon-regulatory factor 4. Although originally identified as cells that are important for controlling responses to conventional T cell-dependent antigens, additional subsets of T FH cells have now been characterized, such as natural killer T FH cells and γδ T FH cells, which presumably contribute to immune responses against lipid, glycolipid and phosphopeptide antigens. Moreover, a distinct subset of regulatory T (T Reg ) cells — follicular T Reg cells — seem to co-evolve with T FH cells and to restrain T FH cell function. T FH cells are associated with numerous immunopathologies that are characterized by aberrant humoral immune responses. These include primary and acquired immunodeficiencies, systemic and organ-specific autoimmune diseases and T cell malignancies. Thus, targeting the pathways that are important for T FH cell formation in an attempt to either attenuate or enhance their function represents an attractive novel therapeutic strategy to treat these conditions. An increasing number of studies have highlighted novel aspects of the differentiation and function of T follicular helper (T FH ) cells. Tangye et al . discuss these recent findings with a particular focus on the role of human T FH cells in disease pathogenesis. Antibody production is an important feature of the vertebrate immune system. Antibodies neutralize and clear pathogens, thereby protecting against infectious diseases. Such humoral immunity has great longevity, often persisting for the host's lifetime. Long-lived humoral immunity depends on help provided by CD4 + T cells, namely T follicular helper (T FH ) cells, which support the differentiation of antigen-specific B cells into memory and plasma cells. T FH cells are stringently regulated, as aberrant T FH cell activity is involved in immunopathologies such as autoimmunity, immunodeficiencies and lymphomas. The elucidation of the mechanisms that regulate T FH cell differentiation, function and fate should highlight targets for novel therapeutics.

The most recent updated classification of inborn errors of immunity/primary immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee, was published in January 2020. Within days of completing this report, it was already out of date, evidenced by the frequent publication of genetic variants proposed to cause novel inborn errors of immunity. As the next formal report from the IUIS Expert Committee will not be published until 2022, we felt it important to provide the community with a brief update of recent contributions to the field of inborn errors of immunity. Herein, we highlight studies that have identified 26 additional monogenic gene defects that reach the threshold to represent novel causes of immune defects.

Influenza A, B and C viruses (IAV, IBV and ICV, respectively) circulate globally and infect humans, with IAV and IBV causing the most severe disease. CD8 + T cells confer cross-protection against IAV strains, however the responses of CD8 + T cells to IBV and ICV are understudied. We investigated the breadth of CD8 + T cell cross-recognition and provide evidence of CD8 + T cell cross-reactivity across IAV, IBV and ICV. We identified immunodominant CD8 + T cell epitopes from IBVs that were protective in mice and found memory CD8 + T cells directed against universal and influenza-virus-type-specific epitopes in the blood and lungs of healthy humans. Lung-derived CD8 + T cells displayed tissue-resident memory phenotypes. Notably, CD38 + Ki67 + CD8 + effector T cells directed against novel epitopes were readily detected in IAV- or IBV-infected pediatric and adult subjects. Our study introduces a new paradigm whereby CD8 + T cells confer unprecedented cross-reactivity across all influenza viruses, a key finding for the design of universal vaccines. Cross-protective responses across all strains of influenza virus (IAV, IBV and ICV) are a key goal of universal vaccines against influenza. Kedzierska and colleagues identify cytotoxic T cells present in blood and lungs of healthy people that are directed against all strains of influenza virus.

The advent of flow cytometry has revolutionized the way we approach our research and answer specific scientific questions. The flow cytometer has also become a mainstream diagnostic tool in most hospital and pathology laboratories around the world. In particular the application of flow cytometry has been instrumental to the diagnosis of primary immunodeficiencies (PIDs) that result from monogenic mutations in key genes of the hematopoietic, and occasionally non-hematopoietic, systems. The far-reaching applicability of flow cytometry is in part due to the remarkable sensitivity, down to the single-cell level, of flow-based assays and the extremely user-friendly platforms that enable comprehensive analysis, data interpretation, and importantly, robust and rapid methods for diagnosing PIDs. A prime example is the absence of peripheral blood B cells in patients with agammaglobulinemia due to mutations in or related genes in the BCR signaling pathway. Similarly, the development of intracellular staining protocols to detect expression of SAP, XIAP, or DOCK8 expedites the rapid diagnosis of the X-linked lymphoproliferative diseases or an autosomal recessive form of hyper-IgE syndrome (HIES), respectively. It has also become evident that distinct cohorts of PID patients exhibit unique \"lymphocyte phenotypic signatures\" that are often diagnostic even prior to identifying the genetic lesion. Flow cytometry-based sorting provides a technique for separating specific subsets of immune cells such that they can be studied in isolation. Thus, flow-based assays can be utilized to measure immune cell function in patients with PIDs, such as degranulation by cytotoxic cells, cytokine expression by many immune cells (i.e., CD4 and CD8 T cells, macrophages etc.), B-cell differentiation, and phagocyte respiratory burst . These assays can also be performed using unfractionated PBMCs, provided the caveat that the composition of lymphocytes between healthy donors and the PID patients under investigation is recognized. These functional deficits can assist not only in the clinical diagnosis of PIDs, but also reveal mechanisms of disease pathogenesis. As we move into the next generation of multiparameter flow cytometers, here we review some of our experiences in the use of flow cytometry in the study, diagnosis, and unraveling the pathophysiology of PIDs.