Explore the vast range of titles available.

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.

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.

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.

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.

IntroductionCombined immunodeficiencies (CIDs) are a severe class of inborn errors of immunity characterized by defective T cell development and function, often accompanied by impaired humoral and natural killer (NK) cell responses. Despite their shared clinical classification, the immunological heterogeneity within CIDs remains incompletely understood. This study aims to characterize the immune cell landscape in CID patients caused by disease-causing mutations in different genes to identify immunophenotypic patterns.MethodsWe analyzed peripheral blood immune cells from four CID patients with disease-causing mutations in ARPC1B, EZR, BCL10, and IRF4 using mass cytometry. Unbiased computational approaches were used to profile major immune populations and their subsets, and results were compared with healthy control samples to identify differences in immune cell frequencies and phenotypes.ResultsAll patients retained major immune populations, but their relative frequencies differed significantly from those of healthy controls. Patients with EZR and ARPC1B deficiency had markedly reduced CD4+ and CD8+ T cell frequencies, whereas the BCL10-deficient patient had a near absence of NK cells, highlighting mutation-specific immune distributions. Detailed T cell subset analyses revealed increased naïve and decreased memory T cells in patients with BCL10 and IRF4 deficiencies, indicative of impaired T cell activation and memory formation. In contrast, ARPC1B deficiency was associated with elevated memory T cells and reduced naïve cells, suggesting thymic output defects. The Ezrin-deficient patient maintained a naïve-to-memory T cell ratio similar to controls despite an overall reduction in T cells. B cell abnormalities were consistent across patients, characterized by increased naïve B cells, decreased memory B cells, and severely diminished plasmablast frequencies.DiscussionOur findings reveal pronounced immunological heterogeneity among CID patients caused by different genetic defects, challenging the notion that CIDs constitute a uniform entity. Disease-causing gene-specific alterations in immune cell composition and differentiation states underscore the complexity of CID pathophysiology. Comprehensive immunophenotypic profiling offers valuable insights into distinct mechanistic pathways and may guide the development of tailored therapeutic strategies to improve clinical outcomes for CID patients.

Since the 1990s, the International Union of Immunological Societies (IUIS) PID expert committee (EC), now called Inborn Errors of Immunity Committee, has published every other year a classification of the inborn errors of immunity. This complete catalog serves as a reference for immunologists and researchers worldwide. However, it was unadapted for clinicians at the bedside. For those, the IUIS PID EC is now publishing a phenotypical classification since 2013, which proved to be more user-friendly. There are now 320 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. We herein propose the revised 2017 phenotypic classification, based on the accompanying 2017 IUIS Inborn Errors of Immunity Committee classification.

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.

BackgroundGermline monoallelic gain-of-function (GOF) variants in NFKBIA, encoding IκBα, cause a rare immunodeficiency syndrome classically described as autosomal-dominant anhidrotic ectodermal dysplasia with immunodeficiency. However, the pathogenic spectrum of variants within the N-terminal hotspot and the extent to which distinct alleles converge on shared immunologic phenotypes are not fully defined.MethodsWe studied four unrelated patients with de novo heterozygous NFKBIA variants (p.G33D, p.M37R, p.M37K, p.D31H), including two novel alleles (p.G33D and p.D31H). Clinical and immunological phenotyping, T-cell and B-cell subset analysis, and CFSE-based lymphocyte proliferation assays were performed. Functional consequences were assessed by TNF-α-induced IκBα degradation in patient PBMCs and by NF-κB dual-luciferase reporter assays in HEK293T cells expressing wild-type or mutant IκBα. A comprehensive literature review of all previously reported NFKBIA GOF cases was performed.ResultsClinical severity ranged from recurrent sinopulmonary infections onset in adolescence to severe infantile multisystem disease with bacterial, fungal, and opportunistic infections. All patients exhibited ectodermal abnormalities, and one had autoantibodies. Despite marked clinical heterogeneity, all four patients showed a qualitatively convergent lymphocyte phenotype characterized by expanded naïve T-cell and B-cell compartments and reduced memory and effector subsets. PHA-induced CD4+ and CD8+ T-cell proliferation was preserved in P1 and P3, whereas anti-CD3/CD28-induced T-cell proliferation, assessed only in P3, was impaired, while B-cell proliferation was preserved in the tested patients. Patient PBMCs exhibited markedly delayed or minimal TNF-α-induced IκBα degradation, and all four mutant proteins more strongly suppressed TNF-α-induced NF-κB reporter activity compared to wild-type IκBα. Baseline expression of the IκBα-EGFP fusion proteins was comparable across wild-type and all four mutant constructs.ConclusionThese findings broaden the clinical and genotypic spectrum of N-terminal IκBα GOF disease, identify a consistent immune phenotype characterized by expanded naïve and contracted memory lymphocyte compartments, and support defective regulated IκBα degradation and impaired lymphocyte maturation as shared features of N-terminal IκBα GOF disease.

BackgroundAlthough splenic ultrasound (US) assessment is periodically performed in most patients with inborn error of immunity (IEI), splenic microtexture has not been specifically investigated in this setting. We describe a newly described “sponge-like” splenic microtexture pattern in patients with different IEIs and hematologic immune dysregulation, and discuss its potential implications.MethodsWe present an index case (P1) followed by a cohort analysis including 26 patients with IEIs and 20 controls with chronic immune thrombocytopenia, for whom splenic microtexture data and iconography were available.ResultsIn P1, an 11-year-old patient with an autoimmune lymphoproliferative immunodeficiency phenotype, high-frequency splenic US revealed for the first time a “sponge-like” pattern, not visible with standard assessment, characterized by multiple hypoechoic round foci that persisted during long-term follow-up. In the IEI cohort, 46.2% of patients had splenomegaly, and a persistent sponge-like pattern was observed in 30.8% in the absence of infections or malignancies. In the control group, only one of 20 patients showed similar US features, transiently, during acute EBV infection. Immunomodulation (sirolimus, mycophenolate mofetil, rituximab) resulted in a significant improvement or normalization in all cases.ConclusionWe report for the first time an association between splenic US microtexture features and IEIs. A persistent sponge-like pattern appears to be linked to IEIs/immune dysregulation, and the response to immunomodulation suggests a complex histopathological substrate. Although preliminary, our results suggest that, in patients with other signs of immune dysregulation/dysfunction, identification of this pattern could support earlier suspicion of an underlying IEI, after excluding infections and malignancies.

Background. Common variable immunodeficiency (CVID) is the most frequent clinically symptomatic primary immunodeficiency; its clinical spectrum is highly variable, ranging from isolated recurrent infections to autoimmune (AID) and inflammatory rheumatic diseases (IRD), which may even be the unique manifestation at disease onset [1]. CVID is mainly a polygenic disease, even if recent studies employing whole-genome and exome sequencing analysis have highlighted that 15–30% may display a monogenic origin [2]. Aim of the study is to describe our CVID patients (pts) cohort, highlighting AID and IRD, and to describe genetic variants possibly linked to immunodeficiency and autoimmunity and therapeutic implications.   Methods. This is a monocentric observational retrospective study considering CVID pts followed since 1985 to 2024. Diagnosis was made according to European Society for Immunodeficiency criteria [3]. A next generation sequencing (NGS) analysis of genes potentially linked to hypo-agammaglobulinemia and to antibody deficiency was executed when considered clinically appropriate.   Results. Eighty-three pts with a CVID diagnosis were included. CVID total cohort description and comparisons between CVID pts with and without AID are reported in Table 1. Autoimmune cytopenia was the most common autoimmune manifestation occurring in 22.9% of the pts, with immune thrombocytopenia being the most prevalent. Immunosuppressive treatment was necessary in 89.5% of the pts affected by autoimmune cytopenia; in 5 cases, due to refractory cytopenia, rituximab was employed, achieving persistent remission in 4 pts. A diagnosis of IRD was made in 12 pts; 75.0% suffered from inflammatory arthritis. In one pt with Adenosine Deaminase 2 deficiency, genetic analysis aided in employing a target therapy leading remission of the IRD (Table 2). Genetic analysis for variants potentially leading to CVID had been performed in 37.3% of pts; analysis resulted positive in 41.9% of the tested. Genetic variants potentially linked to inborn errors of immunity (IEI) were found in more than half of pts with AID, much more frequently than in other CVID pts (56.5% vs 0.0%; p:0.010). The identified genetic variants are reported in Table 3.   Conclusions CVID can be complicated by a wide spectrum of clinical pictures, including AID and IRD, being in our cohort inflammatory arthritis in most of the cases, categorized as a form of Spondyloarthritis in about two thirds. Notably, CVID pts affected by AID and IRD showed a higher frequency of genetic variants potentially leading to IEI; in one case genetic testing aided in orienting IS treatment, leading to remission of the IRD. Nowadays genetic analysis has still limited implications in influencing treatments in CVID, but in the future it might help in targeting precise mechanisms in patients with AID and IRD. References Thalhammer J, Kindle G, Nieters A, et al. Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations. J Allergy Clin Immunol. 2021 Nov;148(5):1332-1341.e5.  Maffucci P, Quinti I, Pulvirenti F, et al. Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency. Front Immunol. 2016 Jun 2;7:220.  Seidel MG, Kindle G, Gathmann B, et al. The European Society for Immunodeficiencies (ESID) registry clinical criteria for inborn errors of immunity diagnosis. Clin Exp Immunol. 2019;197(2):205-214.