Interleukin (IL)–12 and IL-23 Are Key Cytokines for Immunity against Salmonella in Humans

Patients with inherited deficiency of the interleukin (IL)–12/IL-23–interferon (IFN)–g axis show increased susceptibility to invasive disease caused by the intramacrophage pathogens salmonellae and mycobacteria. We analyzed data on 154 patients with such deficiency. Significantly more patients with IL-12/IL-23–component deficiency had a history of salmonella disease than did those with IFN-g–component deficiency. Salmonella disease was typically severe, extraintestinal, and caused by nontyphoidal serovars. These findings strongly suggest that IL-12/IL-23 is a key cytokine for immunity against salmonella in humans and that IL-12/IL-23 mediates this protective effect partly through IFN-g–independent pathways. Investigation of the IL-12/IL-23–IFN-g axis should be considered in patients with invasive salmonella disease

Primary deficiency of interleukin-1 receptor-associated kinase (IRAK-4) presenting as fatal pseudomonas aeruginosa bacteremia in two siblings

Interleukin-1 receptor-associated kinase 4 (IRAK-4) deficiency is a primary immunodeficiency of innate immunity. This is the case of a previous healthy toddler and his sibling, who both died of fulminant sepsis due to Pseudomonas aeruginosa. Subsequent genetic analysis demonstrated IRAK-4 deficiency with compound heterozygous splice mutations. Fulminant fatal Pseudomonas aeruginosa sepsis may be the first manifestation of IRAK-4 deficiency

Somatic diversification in the absence of antigen-driven responses is the hallmark of the IgM+IgD+CD27+ B cell repertoire in infants

T cell–dependent immune responses develop soon after birth, whereas it takes 2 yr for humans to develop T cell–independent responses. We used this dissociation to analyze the repertoire diversification of IgM+IgD+CD27+ B cells (also known as “IgM memory” B cells), comparing these cells with switched B cells in children <2 yr of age, with the aim of determining whether these two subsets are developmentally related. We show that the repertoire of IgM+IgD+CD27+ B cells in the spleen and blood displays no sign of antigen-driven activation and expansion on H-CDR3 spectratyping, despite the many antigenic challenges provided by childhood vaccinations. This repertoire differed markedly from those of switched B cells and splenic germinal center B cells, even at the early stage of differentiation associated with μ heavy chain expression. These data provide evidence for the developmental diversification of IgM+IgD+CD27+ B cells, at least in very young children, outside of T cell–dependent and –independent immune responses

Germline genes hypomethylation and expression define a molecular signature in peripheral blood of ICF patients: implications for diagnosis and etiology.

International audienceBACKGROUND: Immunodeficiency Centromeric Instability and Facial anomalies (ICF) is a rare autosomal recessive disease characterized by reduction in serum immunoglobulins with severe recurrent infections, facial dysmorphism, and more variable symptoms including mental retardation. ICF is directly related to a genomic methylation defect that mainly affects juxtacentromeric heterochromatin regions of certain chromosomes, leading to chromosomal rearrangements that constitute a hallmark of this syndrome upon cytogenetic testing. Mutations in the de novo DNA methyltransferase DNMT3B, the protein ZBTB24 of unknown function, or loci that remain to be identified, lie at its origin. Despite unifying features, common or distinguishing molecular signatures are still missing for this disease. METHOD: We used the molecular signature that we identified in a mouse model for ICF1 to establish transcriptional biomarkers to facilitate diagnosis and understanding of etiology of the disease. We assayed the expression and methylation status of a set of genes whose expression is normally restricted to germ cells, directly in whole blood samples and epithelial cells of ICF patients. RESULTS: We report that DNA hypomethylation and expression of MAEL and SYCE1 represent robust biomarkers, easily testable directly from uncultured cells to diagnose the most prevalent sub-type of the syndrome. In addition, we identified the first unifying molecular signatures for ICF patients. Of importance, we validated the use of our biomarkers to diagnose a baby born to a family with a sick child. Finally, our analysis revealed unsuspected complex molecular signatures in two ICF patients suggestive of a novel genetic etiology for the disease. CONCLUSIONS: Early diagnosis of ICF syndrome is crucial since early immunoglobulin supplementation can improve the course of disease. However, ICF is probably underdiagnosed, especially in patients that present with incomplete phenotype or born to families with no affected relatives. The specific and robust biomarkers identified in this study could be introduced into routine clinical immunology or neurology departments to facilitate testing of patients with suspected ICF syndrome. In addition, as exemplified by two patients with a combination of molecular defects never described before, our data support the search for new types of mutations at the origin of ICF syndrome

Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee.

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

Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification.

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

Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma

Whole-exome sequencing reveals a homozygous splice-site mutation in the gene encoding STIM1 in a child with classic Kaposi sarcoma

Complementation of a pathogenic IFNGR2 misfolding mutation with modifiers of N-glycosylation

Germline mutations may cause human disease by various mechanisms. Missense and other in-frame mutations may be deleterious because the mutant proteins are not correctly targeted, do not function correctly, or both. We studied a child with mycobacterial disease caused by homozygosity for a novel in-frame microinsertion in IFNGR2. In cells transfected with the mutant allele, most of the interferon γ receptor 2 (IFN-γR2) protein was retained within the cell, and that expressed on the cell surface had an abnormally high molecular weight (MW). The misfolding mutation was not gain-of-glycosylation, as it created no new N-glycosylation site. The mutant IFNGR2 allele was null, as the patient's cells did not respond to IFN-γ. Based on the well-established relationship between protein N-glycosylation and protein quality control processes, we tested 29 compounds affecting maturation by N-glycosylation in the secretory pathway. Remarkably, up to 13 of these compounds reduced the MW of surface-expressed mutant IFN-γR2 molecules and restored cellular responsiveness to IFN-γ. Modifiers of N-glycosylation may therefore complement human cells carrying in-frame and misfolding, but not necessarily gain-of-glycosylation, mutations in genes encoding proteins subject to trafficking via the secretory pathway. Some of these compounds are available for clinical use, paving the way for clinical trials of chemical complementation for various human genetic traits

The Ever-Increasing Array of Novel Inborn Errors of Immunity : an Interim Update by the IUIS Committee

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.Peer reviewe

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. There are now a total of 485 inborn errors of immunity. These advances in discovering the genetic causes of human immune diseases continue to significantly further our understanding of molecular, cellular, and immunological mechanisms of disease pathogenesis, thereby simultaneously enhancing immunological knowledge and improving patient diagnosis and management. This report is designed to serve as a resource for immunologists and geneticists pursuing the molecular diagnosis of individuals with heritable immunological disorders and for the scientific dissection of cellular and molecular mechanisms underlying monogenic and related human immune diseases.Peer reviewe