Inborn errors of immunity reveal molecular requirements for generation and maintenance of human CD4 IL-9-expressing cells.

Background: CD4 T cells play essential roles in adaptive immunity. Distinct CD4 T-cell subsets-T1, T2, T17, T22, T follicular helper, and regulatory T cells-have been identified, and their contributions to host defense and immune regulation are increasingly well defined. IL-9-producing T9 cells were first described in 2008 and appear to play both protective and pathogenic roles in human immunity.

Clinical efficacy of SARS-CoV-2 Omicron-neutralizing antibodies in immunoglobulin preparations for the treatment of agammaglobulinemia in patients with primary antibody deficiency.

Immunocompromised individuals are at significantly elevated risk for severe courses of coronavirus disease 2019 (COVID-19). In addition to vaccination, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies (nAbs) have been applied throughout the pandemic, with time of treatment onset and potency against the currently prevailing virus variant identified as relevant factors for medical benefit. Using data from the European Society for Immunodeficiencies (ESID) registry, the present study evaluated COVID-19 cases in three groups of patients with inborn errors of immunity (IEI; 981 agammaglobulinemia patients on immunoglobulin replacement therapy (IGRT); 8960 non-agammaglobulinemia patients on IGRT; 14 428 patients without IGRT), and the neutralizing capacity of 1100 immunoglobulin lots against SARS-CoV-2 ("Wuhan" and Omicron strains), throughout 3 years.

Comparison of machine learning methods in the early identification of vasculitides, myositides and glomerulonephritides.

Background: Rare disease diagnoses are often delayed by years, including multiple doctor visits, and potential imprecise or incorrect diagnoses before receiving the correct one. Machine learning could solve this problem by flagging potential patients that doctors should examine more closely.

Methods: Making the prediction situation as close as possible to real situation, we tested different masking sizes.

Low and high serum IgG associates with respiratory infections in a young and working age population.

Background: We investigated health consequences and genetic properties associated with serum IgG concentration in a young and working age general population.

Methods: Northern Finland Birth Cohort 1966 (NFBC1966, n = 12,231) health data have been collected from birth to 52 years of age. Relationships between life-long health events, medications, chronic conditions, lifestyle, and serum IgG concentration measured at age 46 years (n = 5430) were analysed.

The GAIN Registry - a New Prospective Study for Patients with Multi-organ Autoimmunity and Autoinflammation.

Patient registries are a very important and essential tool for investigating rare diseases, as most physicians only see a limited number of cases during their career. Diseases of multi-organ autoimmunity and autoinflammation are especially challenging, as they are characterized by diverse clinical phenotypes and highly variable expressivity. The GAIN consortium (German multi-organ Auto Immunity Network) developed a dataset addressing these challenges.

Inflammation and Neutrophil Oxidative Burst in a Family with NFKB1 p.R157X LOF and Sterile Necrotizing Fasciitis.

Loss-of-function (LOF) mutations in NFKB1, coding for p105, may cause common variable immunodeficiency due to dysregulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κΒ) pathway. Monoallelic LOF variants of NFKB1 can predispose to uncontrolled inflammation including sterile necrotizing fasciitis or pyoderma gangrenosum. In this study, we explored the impact of a heterozygous NFKB1 c.

STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2D CD8 T cell dysregulation and accumulation.

The association between cancer and autoimmune disease is unexplained, exemplified by T cell large granular lymphocytic leukemia (T-LGL) where gain-of-function (GOF) somatic STAT3 mutations correlate with co-existing autoimmunity. To investigate whether these mutations are the cause or consequence of CD8 T cell clonal expansions and autoimmunity, we analyzed patients and mice with germline STAT3 GOF mutations. STAT3 GOF mutations drove the accumulation of effector CD8 T cell clones highly expressing NKG2D, the receptor for stress-induced MHC-class-I-related molecules.

Long-term follow up of families with pathogenic NFKB1 variants reveals incomplete penetrance and frequent inflammatory sequelae.

Nuclear factor κ light-chain enhancer of activated B cells (NF-κB) family of evolutionarily conserved transcription factors are involved in key cellular signaling pathways. Previously, hypogammaglobulinemia and common variable immunodeficiency (CVID)-like phenotypes have been associated with NFKB1 variants and loss-of-function NFKB1 variants have been reported as the most common monogenic cause for CVID among Europeans. Here, we describe a Finnish cohort of NFKB1 carriers consisting of 31 living subjects in six different families carrying five distinct heterozygous variants.

Characterization of Expanded Gamma Delta T Cells from Atypical X-SCID Patient Reveals Preserved Function and IL2RG-Mediated Signaling.

Abnormally high γδ T cell numbers among individuals with atypical SCID have been reported but detailed immunophenotyping and functional characterization of these expanded γδ T cells are limited. We have previously reported atypical SCID phenotype caused by hypomorphic IL2RG (NM_000206.3) c.

Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome.

Background: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity.

Objective: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants.

Methods: We identified 191 patients from 33 countries with 72 unique mutations.

The 2022 Update of IUIS Phenotypical Classification for Human Inborn Errors of Immunity.

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.

Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee.

We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 55 novel monogenic gene defects, and 1 phenocopy due to autoantibodies, that have either been discovered since the previous update (published January 2020) or were characterized earlier but have since been confirmed or expanded in subsequent studies. While variants in additional genes associated with immune diseases have been reported in the literature, this update includes only those that the committee assessed that reached the necessary threshold to represent novel inborn errors of immunity.

Inborn Errors of Immunity on the Island of Ireland - a Cross-Jurisdictional UKPID/ESID Registry Report.

The epidemiology of inborn errors of immunity (IEI) in the Republic of Ireland was first published in 2005 but has not been updated since. IEI prevalence data from Northern Ireland was last published in 2018. Using data from the United Kingdom Primary Immune Deficiency (UKPID) and European Society for Immunodeficiencies (ESID) registries, we reviewed all registered cases of IEI affecting adult patients ≥ 18 years of age from the two largest immunology specialist centres in Northern Ireland and the Republic of Ireland, respectively and calculated the combined minimum adult prevalence of IEI on the island of Ireland for the first time.

Immune response to a conserved enteroviral epitope of the major capsid VP1 protein is associated with lower risk of cardiovascular disease.

Background: Major cardiac events including myocardial infarction (MI) are associated with viral infections. However, how specific infections contribute to the cardiovascular insults has remained largely unclear.

Methods: We employed next generation phage display mimotope-variation analysis (MVA) to explore the link between antibody-based immune response and severe cardiovascular conditions.

Pulmonary manifestations in a cohort of patients with inborn errors of immunity: an 8-year follow-up study.

Background: Inborn errors of immunity (IEIs) are a group of congenital diseases caused by genetic defects in the development and function of the immune system. The involvement of the respiratory tract is one of the most common presentations in IEIs.

Methods: Overall, 117 patients with diagnosed IEIs were followed-up within 8 years at the National Research Institute of Tuberculosis and Lung Diseases (NRITLD).