308 research outputs found
Correction to: A Novel Case of IFNAR1 Deficiency Identified a Common Canonical Splice Site Variant in DOCK8 in Western Polynesia: The Importance of Validating Variants of Unknown Significance in Under-Represented Ancestries
No full textIn this article, Alberto Pinzon-Charry, Cindy S Ma and Stuart G. Tangye should have been denoted as equally contributing authors. The original version has been corrected
Impact of SARS-CoV-2 infection and COVID-19 on patients with inborn errors of immunity
No full text: Since the arrival of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, its characterization as a novel human pathogen, and the resulting coronavirus disease 2019 (COVID-19) pandemic, over 6.5 million people have died worldwide-a stark and sobering reminder of the fundamental and nonredundant roles of the innate and adaptive immune systems in host defense against emerging pathogens. Inborn errors of immunity (IEI) are caused by germline variants, typically in single genes. IEI are characterized by defects in development and/or function of cells involved in immunity and host defense, rendering individuals highly susceptible to severe, recurrent, and sometimes fatal infections, as well as immune dysregulatory conditions such as autoinflammation, autoimmunity, and allergy. The study of IEI has revealed key insights into the molecular and cellular requirements for immune-mediated protection against infectious diseases. Indeed, this has been exemplified by assessing the impact of SARS-CoV-2 infection in individuals with previously diagnosed IEI, as well as analyzing rare cases of severe COVID-19 in otherwise healthy individuals. This approach has defined fundamental aspects of mechanisms of disease pathogenesis, immunopathology in the context of infection with a novel pathogen, and therapeutic options to mitigate severe disease. This review summarizes these findings and illustrates how the study of these rare experiments of nature can inform key features of human immunology, which can then be leveraged to improve therapies for treating emerging and established infectious diseases
Activated PI3Kδ breaches multiple B cell tolerance checkpoints and causes autoantibody production
No full textAntibody-mediated autoimmune diseases are a major health burden. However, our understanding of how self-reactive B cells escape self-tolerance checkpoints to secrete pathogenic autoantibodies remains incomplete. Here, we demonstrate that patients with monogenic immune dysregulation caused by gain-of-function mutations in PIK3CD, encoding the p110δ catalytic subunit of phosphoinositide 3-kinase (PI3K), have highly penetrant secretion of autoreactive IgM antibodies. In mice with the corresponding heterozygous Pik3cd activating mutation, self-reactive B cells exhibit a cell-autonomous subversion of their response to self-antigen: instead of becoming tolerized and repressed from secreting autoantibody, Pik3cd gain-of-function B cells are activated by self-antigen to form plasmablasts that secrete high titers of germline-encoded IgM autoantibody and hypermutating germinal center B cells. However, within the germinal center, peripheral tolerance was still enforced, and there was selection against B cells with high affinity for self-antigen. These data show that the strength of PI3K signaling is a key regulator of pregerminal center B cell self-tolerance and thus represents a druggable pathway to treat antibody-mediated autoimmunity.sponsorship: This work was supported by National Health and Medical Research Council (NHMRC) program grants (1016953 and 1113904 to S.G. Tangye, R. Brink, and C.C. Goodnow), NHMRC project grants (1088215 to E.K. Deenick; 1127157 to S.G. Tangye and E.K. Deenick), NHMRC Principal Research Fellowships (1042925 to S.G. Tangye; 1105877 to R. Brink), a Fulbright Senior Scholarship (to S.G. Tangye), the Office of Health and Medical Research of the New South Wales Government, the Jeffrey Modell Foundation, the John Brown Cook Foundation, the Ross Trust, and a Bench-to-Bedside grant from the National Institute of Allergy and Infectious Diseases, National Institutes of Health. G. Uzel and L.D. Notarangelo are supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. (National Health and Medical Research Council (NHMRC)|1016953, National Health and Medical Research Council (NHMRC)|1113904, NHMRC|1088215, NHMRC|1127157, NHMRC|1042925, NHMRC|1105877, Fulbright Senior Scholarship, Office of Health and Medical Research of the New South Wales Government, Jeffrey Modell Foundation, John Brown Cook Foundation, Ross Trust, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, National Institute of Allergy and Infectious Diseases|ZIAAI001222, National Health and Medical Research Council of Australia|1088215, National Health and Medical Research Council of Australia|1127157, National Health and Medical Research Council of Australia|1105877)status: Publishe
Plasmacytoid DCs Induce Gutsy Plasma Cells
No full textImmunoglobulin (Ig) A is critical for protective immune responses at mucosal surfaces. In this issue of Immunity, Tezuka et al. (2011) identify an important relay between stromal cells and plasmacytoid dendritic cells that regulates IgA production by murine B cells
Cytokine-mediated regulation of plasma cell generation: IL-21 takes center stage
No full textDuring 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 to prevent them causing disease. 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 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 Ag 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 also influences 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 Ig isotype over another. Here, we will provide an overview of in vitro studies (mouse and human origin) that evaluated the role the 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
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