Editorial : Updates on the pathogenesis of common variable immunodeficiency (CVID)

Non peer reviewe

Protein Kinase C δ: a Gatekeeper of Immune Homeostasis

Human autoimmune disorders present in various forms and are associated with a life-long burden of high morbidity and mortality. Many different circumstances lead to the loss of immune tolerance and often the origin is suspected to be multifactorial. Recently, patients with autosomal recessive mutations in PRKCD encoding protein kinase c delta (PKC) have been identified, representing a monogenic prototype for one of the most prominent forms of humoral systemic autoimmune diseases, systemic lupus erythematosus (SLE). PKC is a signaling kinase with multiple downstream target proteins and with functions in various signaling pathways. Interestingly, mouse models have indicated a special role of the ubiquitously expressed protein in the control of B-cell tolerance revealed by the severe autoimmunity in Prkcd / knockout mice as the major phenotype. As such, the study of PKC deficiency in humans has tremendous potential in enhancing our knowledge on the mechanisms of B-cell tolerance.(VLID)347918

Проектирование технологического процесса изготовления шкива

Цель работы-проектирование технологического процесса изготовления детали "Шкив". В ходе выполнения данной работы было проделано : спроектирован технологический процесс и станочное приспособление, анализ ресурсоэффективности проекта, выявлены вредные факторы и меры их предотвращения.The purpose of the work is the design of the manufacturing process of the “Pulley” part. In the course of this work, the following was done: a technological process and a machine tool were designed, an analysis of the resource efficiency of the project, harmful factors and measures to prevent them were identified

Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency. Patients with CVID are prone to recurrent bacterial infection due to the failure of adequate immunoglobulin production. Monogenetic defects have been identified in ~25% of CVID patients. Recently, mutations in IKZF1, encoding the zinc-finger transcription factor IKAROS which is broadly expressed in hematopoietic cells, have been associated with a CVID-like phenotype. Herein we describe 11 patients with heterozygous IKZF1 variants from eight different families with autosomal dominant CVID and two siblings with an IKZF1 variant presenting with inflammatory bowel disease (IBD). This study shows that mutations affecting the DNA binding domain of IKAROS can impair the interaction with the target DNA sequence thereby preventing heterochromatin and pericentromeric localization (HC-PC) of the protein. Our results also indicate an impairment of pericentromeric localization of IKAROS by overexpression of a truncated variant, caused by an immature stop codon in IKZF1. We also describe an additional variant in TNFSF10, encoding Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL), additionally presented in individuals of Family A. Our results indicate that this variant may impair the TRAIL-induced apoptosis in target cell lines and prohibit the NFκB activation by TRAIL and may act as a modifier in Family A.Fil: Eskandarian, Zoya. Albert Ludwigs University of Freiburg; AlemaniaFil: Fliegauf, Manfred. Albert Ludwigs University of Freiburg; AlemaniaFil: Bulashevska, Alla. Albert Ludwigs University of Freiburg; AlemaniaFil: Proietti, Michele. Albert Ludwigs University of Freiburg; AlemaniaFil: Hague, Rosie. Royal Hospital For Children; Reino UnidoFil: Smulski, Cristian Roberto. Albert Ludwigs University of Freiburg; Alemania. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; ArgentinaFil: Schubert, Desirée. Albert Ludwigs University of Freiburg; AlemaniaFil: Warnatz, Klaus. Albert Ludwigs University of Freiburg; AlemaniaFil: Grimbacher, Bodo. Albert Ludwigs University of Freiburg; Alemania. University College London; Reino Unid

TRAIL-R1 and TRAIL-R2 mediate TRAIL-dependent apoptosis in activated primary human B lymphocytes

The maintenance of B cell homeostasis requires a tight control of B cell generation, survival, activation, and maturation. In lymphocytes upon activation, increased sensitivity to apoptotic signals helps controlling differentiation and proliferation. The death receptor Fas is important in this context because genetic Fas mutations in humans lead to an autoimmune lymphoproliferative syndrome that is similar to lymphoproliferation observed in Fas-deficient mice. In contrast, the physiological role of TNF-related apoptosis-inducing ligand receptors (TRAIL-Rs) in humans has been poorly studied so far. Indeed, most studies have focused on tumor cell lines and on mouse models whose results are difficult to transpose to primary human B cells. In the present work, the expression of apoptosis-inducing TRAIL-R1 and TRAIL-R2 and of the decoy receptors TRAIL-R3 and TRAIL-R4 was systematically studied in all developmental stages of peripheral B cells isolated from the blood and secondary lymphoid organs. Expression of TRAIL-Rs is modulated along development, with highest levels observed in germinal center B cells. In addition, T-dependent and T-independent signals elicited induction of TRAIL-Rs with distinct kinetics, which differed among B cell subpopulations: switched memory cells rapidly upregulated TRAIL-R1 and -2 upon activation while naïve B cells only reached similar expression levels at later time points in culture. Increased expression of TRAIL-R1 and -2 coincided with a caspase-3-dependent sensitivity to TRAIL-induced apoptosis in activated B cells but not in freshly isolated resting B cells. Finally, both TRAIL-R1 and TRAIL-R2 could signal actively and both contributed to TRAIL-induced apoptosis. In conclusion, this study provides a systematic analysis of the expression of TRAIL-Rs in human primary B cells and of their capacity to signal and induce apoptosis. This dataset forms a basis to further study and understand the dysregulation of TRAIL-Rs and TRAIL expression observed in autoimmune diseases. Additionally, it will be important to foresee potential bystander immunomodulation when TRAIL-R agonists are used in cancer treatment.Fil: Staniek, Julian. Albert Ludwigs University of Freiburg; AlemaniaFil: Lorenzetti, Raquel. Albert Ludwigs University of Freiburg; AlemaniaFil: Heller, Bianca. Albert Ludwigs University of Freiburg; AlemaniaFil: Janowska, Iga. Albert Ludwigs University of Freiburg; AlemaniaFil: Schneider, Pascal. Universite de Lausanne; SuizaFil: Unger, Susanne. Albert Ludwigs University of Freiburg; AlemaniaFil: Warnatz, Klaus. Albert Ludwigs University of Freiburg; AlemaniaFil: Seidl, Maximilian. Albert Ludwigs University of Freiburg; AlemaniaFil: Venhoff, Nils. Albert Ludwigs University of Freiburg; AlemaniaFil: Thiel, Jens. Albert Ludwigs University of Freiburg; AlemaniaFil: Smulski, Cristian Roberto. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; ArgentinaFil: Rizzi, Marta. Albert Ludwigs University of Freiburg; Alemani

Human memory B cells show plasticity and adopt multiple fates upon recall response to SARS-CoV-2

The B cell response to different pathogens uses tailored effector mechanisms and results in functionally specialized memory B (B$_{m}$) cell subsets, including CD21$^{+}$ resting, CD21$^{–}$CD27$^{+}$ activated and CD21$^{–}$CD27$^{–}$ B$_{m}$ cells. The interrelatedness between these B$_{m}$ cell subsets remains unknown. Here we showed that single severe acute respiratory syndrome coronavirus 2-specific B$_{m}$ cell clones showed plasticity upon antigen rechallenge in previously exposed individuals. CD21$^{–}$ B$_{m}$ cells were the predominant subsets during acute infection and early after severe acute respiratory syndrome coronavirus 2-specific immunization. At months 6 and 12 post-infection, CD21$^{+}$ resting B$_{m}$ cells were the major B$_{m}$ cell subset in the circulation and were also detected in peripheral lymphoid organs, where they carried tissue residency markers. Tracking of individual B cell clones by B cell receptor sequencing revealed that previously fated B$_{m}$ cell clones could redifferentiate upon antigen rechallenge into other B$_{m}$ cell subsets, including CD21$^{–}$CD27$^{–}$ B$_{m}$ cells, demonstrating that single B$_{m}$ cell clones can adopt functionally different trajectories

Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects.

BACKGROUND: Profound combined immunodeficiency can present with normal numbers of T and B cells, and therefore the functional defect of the cellular and humoral immune response is often not recognized until the first severe clinical manifestation. Here we report a patient of consanguineous descent presenting at 13 months of age with hypogammaglobulinemia, Pneumocystis jirovecii pneumonia, and a suggestive family history. OBJECTIVE: We sought to identify the genetic alteration in a patient with combined immunodeficiency and characterize human caspase recruitment domain family, member 11 (CARD11), deficiency. METHODS: Molecular, immunologic, and functional assays were performed. RESULTS: The immunologic characterization revealed only subtle changes in the T-cell and natural killer cell compartment, whereas B-cell differentiation, although normal in number, was distinctively blocked at the transitional stage. Genetic evaluation revealed a homozygous deletion of exon 21 in CARD11 as the underlying defect. This deletion abrogated protein expression and activation of the canonical nuclear factor κB (NF-κB) pathway in lymphocytes after antigen receptor or phorbol 12-myristate 13-acetate stimulation, whereas CD40 signaling in B cells was preserved. The abrogated activation of the canonical NF-κB pathway was associated with severely impaired upregulation of inducible T-cell costimulator, OX40, cytokine production, proliferation of T cells, and B cell-activating factor receptor expression on B cells. CONCLUSION: Thus in patients with CARD11 deficiency, the combination of impaired activation and especially upregulation of inducible T-cell costimulator on T cells, together with severely disturbed peripheral B-cell differentiation, apparently leads to a defective T-cell/B-cell cooperation and probably germinal center formation and clinically results in severe immunodeficiency. This report discloses the crucial and nonredundant role of canonical NF-κB activation and specifically CARD11 in the antigen-specific immune response in human subjects

Diagnostic testing for interstitial lung disease in common variable immunodeficiency: a systematic review

INTRODUCTION: Common variable immunodeficiency related interstitial lung disease (CVID-ILD, also referred to as GLILD) is generally considered a manifestation of systemic immune dysregulation occurring in up to 20% of people with CVID. There is a lack of evidence-based guidelines for the diagnosis and management of CVID-ILD. AIM: To systematically review use of diagnostic tests for assessing patients with CVID for possible ILD, and to evaluate their utility and risks. METHODS: EMBASE, MEDLINE, PubMed and Cochrane databases were searched. Papers reporting information on the diagnosis of ILD in patients with CVID were included. RESULTS: 58 studies were included. Radiology was the investigation modality most commonly used. HRCT was the most reported test, as abnormal radiology often first raised suspicion of CVID-ILD. Lung biopsy was used in 42 (72%) of studies, and surgical lung biopsy had more conclusive results compared to trans-bronchial biopsy (TBB). Analysis of broncho-alveolar lavage was reported in 24 (41%) studies, primarily to exclude infection. Pulmonary function tests, most commonly gas transfer, were widely used. However, results varied from normal to severely impaired, typically with a restrictive pattern and reduced gas transfer. CONCLUSION: Consensus diagnostic criteria are urgently required to support accurate assessment and monitoring in CVID-ILD. ESID and the ERS e-GLILDnet CRC have initiated a diagnostic and management guideline through international collaboration. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD42022276337