ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-ß are found in â¼20% of deceased patients across age groups, and in â¼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.
Subject(s)
Antibodies, Neutralizing , Autoantibodies , Autoimmunity , COVID-19 , Interferon Type I , SARS-CoV-2 , Adult , Age Factors , Aged , Aged, 80 and over , Antibodies, Neutralizing/blood , Autoantibodies/blood , COVID-19/immunology , COVID-19/mortality , Female , Humans , Interferon Type I/immunology , Male , Middle Aged , RiskABSTRACT
BACKGROUND: Cryptococcosis is a life-threatening disease caused by Cryptococcus neoformans or C. gattii. Neutralizing autoantibodies (auto-Abs) against granulocyte-macrophage colony-stimulating factor (GM-CSF) in otherwise healthy adults with cryptococcal meningitis have been described since 2013. We searched for neutralizing auto-Abs in sera collected from Colombian patients with non-HIV-associated cryptococcosis in a retrospective national cohort from 1997 to 2016. METHODS: We reviewed clinical and laboratory records and assessed the presence of neutralizing auto-Abs against GM-CSF in 30 HIV negative adults with cryptococcosis (13 caused by C. gattii and 17 caused by C. neoformans). RESULTS: We detected neutralizing auto-Abs against GM-CSF in the sera of 10 out of 13 (77%) patients infected with C. gattii and one out of 17 (6%) patients infected with C. neoformans. CONCLUSIONS: We report eleven Colombian patients diagnosed with cryptococcosis who had auto-Abs that neutralize GM-CSF. Among these patients, ten were infected with C. gattii and only one with C. neoformans.
Subject(s)
Antibodies, Neutralizing , Autoantibodies , Cryptococcosis , Cryptococcus gattii , Cryptococcus neoformans , Granulocyte-Macrophage Colony-Stimulating Factor , Humans , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Autoantibodies/blood , Autoantibodies/immunology , Male , Colombia , Female , Adult , Cryptococcus gattii/immunology , Middle Aged , Cryptococcus neoformans/immunology , Cryptococcosis/immunology , Cryptococcosis/diagnosis , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Retrospective Studies , HIV Seronegativity/immunology , Young Adult , AgedABSTRACT
This paper presents a deep learning approach for predicting rail corrugation based on on-board rolling-stock vertical acceleration and forward velocity measurements using One-Dimensional Convolutional Neural Networks (CNN-1D). The model's performance is examined in a 1:10 scale railway system at two different forward velocities. During both the training and test stages, the CNN-1D produced results with mean absolute percentage errors of less than 5% for both forward velocities, confirming its ability to reproduce the corrugation profile based on real-time acceleration and forward velocity measurements. Moreover, by using a Gradient-weighted Class Activation Mapping (Grad-CAM) technique, it is shown that the CNN-1D can distinguish various regions, including the transition from damaged to undamaged regions and one-sided or two-sided corrugated regions, while predicting corrugation. In summary, the results of this study reveal the potential of data-driven techniques such as CNN-1D in predicting rails' corrugation using online data from the dynamics of the rolling-stock, which can lead to more reliable and efficient maintenance and repair of railways.
ABSTRACT
BACKGROUND: Cryptococcosis is a potentially life-threatening fungal disease caused by encapsulated yeasts of the genus Cryptococcus, mostly C. neoformans or C. gattii. Cryptococcal meningitis is the most frequent clinical manifestation in humans. Neutralizing autoantibodies (auto-Abs) against granulocyte-macrophage colony-stimulating factor (GM-CSF) have recently been discovered in otherwise healthy adult patients with cryptococcal meningitis, mostly caused by C. gattii. We hypothesized that three Colombian patients with cryptococcal meningitis caused by C. neoformans in two of them would carry high plasma levels of neutralizing auto-Abs against GM-CSF. METHODS: We reviewed medical and laboratory records, performed immunological evaluations, and tested for anti-cytokine auto-Abs three previously healthy HIV-negative adults with disseminated cryptococcosis. RESULTS: Peripheral blood leukocyte subset levels and serum immunoglobulin concentrations were within the normal ranges. We detected high levels of neutralizing auto-Abs against GM-CSF in the plasma of all three patients. CONCLUSIONS: We report three Colombian patients with disseminated cryptococcosis associated with neutralizing auto-Abs against GM-CSF. Further studies should evaluate the genetic contribution to anti-GM-CSF autoantibody production and the role of the GM-CSF signaling pathway in the immune response to Cryptococcus spp.
Subject(s)
Cryptococcosis , Cryptococcus neoformans , Meningitis, Cryptococcal , Adult , Humans , Granulocyte-Macrophage Colony-Stimulating Factor , Meningitis, Cryptococcal/diagnosis , Autoantibodies , Colombia , Cryptococcosis/diagnosisABSTRACT
INTRODUCTION: Immunometabolic studies in mice have suggested the importance of oxidative phosphorylation (OXPHOS) in humoral immunity. However, there are important distinctions between murine and human immunity. Furthermore, translational studies on the role of OXPHOS in humoral immunity are nearly absent from the biomedical literature. Children with primary OXPHOS deficiency (i.e., mitochondrial disease, MtD), are an important patient population for demonstrating the functional effects of this bioenergetic defect on humoral immunity. METHODS: To define whether OXPHOS deficiency extended to human B cells, we performed extracellular flux analysis on lymphoblastoid B cell lines from children with MtD and controls (N = 4/group). To expand the immune phenotype of B cell OXPHOS deficiency, we conducted a cross-sectional multiplex serology study of the antibacterial antibody repertoire in children with MtD (N = 16) and controls (N = 16) using phage display and immunoprecipitation sequencing (PhIPseq). The PhIPseq library contained >3000 peptides (i.e., epitopes) covering >40 genera and > 150 species of bacteria that infect humans. RESULTS: B cell lymphoblastoid cell lines from children with MtD displayed depressed baseline oxygen consumption, ATP production and reserve capacity, indicating that OXPHOS deficiency extended to these key cells in humoral immunity. Characterization of the bacterial exposome revealed comparable bacterial species between the two groups, mostly Streptococcus and Staphylococcus. The most common species of bacteria was S. pneumoniae. By interrogating the antibacterial antibody repertoire, we found that children with MtD had less robust antibody fold changes to common epitopes. Furthermore, we also found that children with MtD failed to show a direct relationship between the number of bacterial epitopes recognized and age, unlike controls. OXPHOS deficiency extends to B cells in children with MtD, leading to limitations in the antibacterial antibody repertoire. Furthermore, the timing of bacterial exposures was asynchronous, suggesting different periods of increased exposure or susceptibility. CONCLUSIONS: Overall, the antibacterial humoral response is distinctive in children with MtD, suggesting an important role for OXPHOS in B cell function.
Subject(s)
Mitochondrial Diseases , Humans , Child , Mice , Animals , Epitopes , Cross-Sectional Studies , Mitochondrial Diseases/genetics , Oxidative Phosphorylation , Energy MetabolismABSTRACT
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.
Subject(s)
Hypersensitivity , Immunologic Deficiency Syndromes , Neoplasms , Humans , Immunologic Deficiency Syndromes/genetics , Phenotype , GenotypeABSTRACT
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.
Subject(s)
Immune System Diseases , Immunologic Deficiency Syndromes , Humans , Immunologic Deficiency Syndromes/diagnosis , Phenotype , Research ReportABSTRACT
The ability of Mycobacterium tuberculosis (Mtb) to persist inside host cells relies on metabolic adaptation, like the accumulation of lipid bodies (LBs) in the so-called foamy macrophages (FM), which are favorable to Mtb. The activation state of macrophages is tightly associated to different metabolic pathways, such as lipid metabolism, but whether differentiation towards FM differs between the macrophage activation profiles remains unclear. Here, we aimed to elucidate whether distinct macrophage activation states exposed to a tuberculosis-associated microenvironment or directly infected with Mtb can form FM. We showed that the triggering of signal transducer and activator of transcription 6 (STAT6) in interleukin (IL)-4-activated human macrophages (M(IL-4)) prevents FM formation induced by pleural effusion from patients with tuberculosis. In these cells, LBs are disrupted by lipolysis, and the released fatty acids enter the ß-oxidation (FAO) pathway fueling the generation of ATP in mitochondria. Accordingly, murine alveolar macrophages, which exhibit a predominant FAO metabolism, are less prone to become FM than bone marrow derived-macrophages. Interestingly, direct infection of M(IL-4) macrophages with Mtb results in the establishment of aerobic glycolytic pathway and FM formation, which could be prevented by FAO activation or inhibition of the hypoxia-inducible factor 1-alpha (HIF-1α)-induced glycolytic pathway. In conclusion, our results demonstrate that Mtb has a remarkable capacity to induce FM formation through the rewiring of metabolic pathways in human macrophages, including the STAT6-driven alternatively activated program. This study provides key insights into macrophage metabolism and pathogen subversion strategies.
Subject(s)
Foam Cells/microbiology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Lipid Metabolism , Macrophages/microbiology , Mycobacterium tuberculosis/pathogenicity , Animals , Lipid Droplets/metabolism , Macrophage Activation/physiology , Macrophages/metabolism , Male , Mice, Inbred BALB C , Mycobacterium tuberculosis/physiology , Tuberculosis/microbiologyABSTRACT
INTRODUCTION: The objectives of this study were to analyze and quantify molar intrusion after the use of clear aligners and to analyze the relationship with other variables such as age, duration of treatment, and a series of cephalometric osseous and dental measurements at the start of treatment. METHODS: A retrospective descriptive-analytical study was designed with a sample of 58 patients aged 18-60 years who had undergone treatment with Invisalign. The cephalometric measurements were carried out after lateral x-rays were taken of the cranium; these were compared at the start (T0) and conclusion of treatment. Parametric and nonparametric tests were used to compare means, whereas Pearson correlations and multivariate lineal regression analyses were used to establish the variables associated with molar intrusion. RESULTS: Approximately 74.2% of the patients presented some degree of molar intrusion after treatment. Furthermore, 32.8% of patients presented intrusion only at the mandibular molar, whereas 25.9% experienced intrusion at both molars, maxillary and mandibular, simultaneously. However, 15.5% presented intrusion only at the maxillary molar. The average magnitude of intrusion here was 0.98 ± 0.54 mm, whereas the mandibular molar was 0.84 ± 0.29 mm. Statistically significant reductions exist for the distance L6_MP and U6_SN between T0 and at conclusion of treatment. Maxillary molar intrusion correlates negatively with mandibular molar intrusion (r = -0.270). The number of days of treatment did not correlate with either maxillary or mandibular molar intrusion. CONCLUSIONS: Clear aligners give rise to molar intrusion in 74.2% of patients. The cephalometric variables L6_MP T0, mandibular plane angle T0, and facial axis T0 were negatively and significantly associated with maxillary molar intrusion, whereas age and facial axis T0 were negatively associated with mandibular molar intrusion allowing smaller magnitudes of intrusion to be predicted when these variables present high values at T0.
Subject(s)
Open Bite , Orthodontic Appliances, Removable , Cephalometry , Humans , Maxilla/diagnostic imaging , Molar/diagnostic imaging , Open Bite/therapy , Retrospective Studies , Tooth Movement Techniques/adverse effectsABSTRACT
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.
Subject(s)
Genetic Predisposition to Disease , Primary Immunodeficiency Diseases/epidemiology , Primary Immunodeficiency Diseases/genetics , Alleles , COVID-19/complications , COVID-19/epidemiology , COVID-19/virology , Diagnosis, Differential , Disease Management , Genetic Association Studies/methods , Genotype , Humans , Immunity/genetics , Inheritance Patterns , Phenotype , Primary Immunodeficiency Diseases/diagnosis , Public Health Surveillance , Risk FactorsABSTRACT
Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity, and immunodeficiency. We here investigated 4 patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified 4 distinct homozygous mutations in TNFRSF9 encoding the tumor necrosis factor receptor superfamily member CD137/4-1BB, leading to reduced, or loss of, protein expression. Lymphocytic responses crucial for immune surveillance, including activation, proliferation, and differentiation, were impaired. Genetic reconstitution of CD137 reversed these defects. CD137 deficiency is a novel inborn error of human immunity characterized by lymphocytic defects with early-onset Epstein-Barr virus (EBV)-associated lymphoma. Our findings elucidate a functional role and relevance of CD137 in human immune homeostasis and antitumor responses.
Subject(s)
Autoimmune Diseases/genetics , Immunologic Deficiency Syndromes/genetics , Lymphoma/genetics , Tumor Necrosis Factor Receptor Superfamily, Member 9/genetics , Autoimmune Diseases/immunology , Female , Genetic Predisposition to Disease , Humans , Immunologic Deficiency Syndromes/immunology , Lymphoma/immunology , Male , Pedigree , Tumor Necrosis Factor Receptor Superfamily, Member 9/deficiencyABSTRACT
Background and objectives: Although the main objective of any orthodontic treatment is to correct malocclusion, a range of psychosocial and/or esthetic factors drive patients to undergo orthodontic treatment. The aim of the present study was to analyze variations in oral health-related quality of life (OHRQL) levels in patients undergoing orthodontic treatment by means of four types of appliances: fixed buccal metal brackets, fixed buccal esthetic/ceramic brackets, fixed lingual brackets, and clear aligners. Material and Methods: The study sample comprised 120 patients aged 18 to 68 years who attended the Orthodontic department at the Dental Clinic of the University of Valencia. The Index of Orthodontic Treatment Need (IOTN) was used to measure orthodontic treatment need. Each patient completed three different intervals of the 14-item Oral Health Impact Profile (OHIP-14): before treatment (T0); six months after placing the orthodontic appliances (T1) and at the end of orthodontic treatment (T2). Results: All groups suffered a reduction in quality of life from T0 to T1 except the metal bracket group which presented the same level for the functional limitation domain (p = 1.000), the lingual bracket group for the psychological discomfort domain (p = 1.000) and clear aligner group for the physical disability domain (p = 0.118) and psychological disability domain (p = 1.000). Nevertheless, quality of life for most domains was similar in all groups at the end of treatment (T2). Conclusions: Patients underwent a significant reduction in quality of life during treatment in comparison with their pre-treatment condition but showed significant improvements at the end of treatment.
Subject(s)
Malocclusion , Quality of Life , Humans , Index of Orthodontic Treatment Need , Malocclusion/therapy , Orthodontic Appliances , Surveys and QuestionnairesABSTRACT
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.
Subject(s)
Immunity/genetics , Immunologic Deficiency Syndromes/genetics , Autoimmunity/genetics , Genotype , Hereditary Autoinflammatory Diseases/genetics , Humans , Hypersensitivity , PhenotypeABSTRACT
The noncanonical NF-κB pathway is implicated in diverse biological and immunological processes. Monoallelic C-terminus loss-of-function and gain-of-function mutations of NFKB2 have been recently identified as a cause of immunodeficiency manifesting with common variable immunodeficiency (CVID) or combined immunodeficiency (CID) phenotypes. Herein we report a family carrying a heterozygous nonsense mutation in NFKB2 (c.809G > A, p.W270*). This variant is associated with increased mRNA decay and no mutant NFKB2 protein expression, leading to NFKB2 haploinsufficiency. Our findings demonstrate that bona fide NFKB2 haploinsufficiency, likely caused by mutant mRNA decay and protein instability leading to the transcription and expression of only the wild-type allele, is associated with clinical immunodeficiency, although with incomplete clinical penetrance. Abnormal B cell development, hypogammaglobulinemia, poor antibody response, and abnormal noncanonical (but normal canonical) NF-κB pathway signaling are the immunologic hallmarks of this disease. This adds a third allelic variant to the pathophysiology of NFKB2-mediated immunodeficiency disorders.
Subject(s)
Agammaglobulinemia/diagnosis , Agammaglobulinemia/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Haploinsufficiency , Mutation , NF-kappa B p52 Subunit/genetics , Adolescent , Adult , Alleles , Female , Genetic Association Studies/methods , Genotype , Humans , Immunophenotyping , Lymphocytes/metabolism , Male , Middle Aged , Pedigree , Phenotype , Exome Sequencing , Young AdultABSTRACT
Due to typesetting mistake, the caption of Figure 2 was mistakenly replaced with the caption of Figure 3.
ABSTRACT
The original version of this article unfortunately contained mistakes in reference numbers. The in-text citations and the references were mismatched. The original article has been corrected.
ABSTRACT
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.
ABSTRACT
ARPC1B is a key factor for the assembly and maintenance of the ARP2/3 complex that is involved in actin branching from an existing filament. Germline biallelic mutations in ARPC1B have been recently described in 6 patients with clinical features of combined immunodeficiency (CID), whose neutrophils and platelets but not T lymphocytes were studied. We hypothesized that ARPC1B deficiency may also lead to cytoskeleton and functional defects in T cells. We have identified biallelic mutations in ARPC1B in 6 unrelated patients with early onset disease characterized by severe infections, autoimmune manifestations, and thrombocytopenia. Immunological features included T-cell lymphopenia, low numbers of naïve T cells, and hyper-immunoglobulin E. Alteration in ARPC1B protein structure led to absent/low expression by flow cytometry and confocal microscopy. This molecular defect was associated with the inability of patient-derived T cells to extend an actin-rich lamellipodia upon T-cell receptor (TCR) stimulation and to assemble an immunological synapse. ARPC1B-deficient T cells additionally displayed impaired TCR-mediated proliferation and SDF1-α-directed migration. Gene transfer of ARPC1B in patients' T cells using a lentiviral vector restored both ARPC1B expression and T-cell proliferation in vitro. In 2 of the patients, in vivo somatic reversion restored ARPC1B expression in a fraction of lymphocytes and was associated with a skewed TCR repertoire. In 1 revertant patient, memory CD8+ T cells expressing normal levels of ARPC1B displayed improved T-cell migration. Inherited ARPC1B deficiency therefore alters T-cell cytoskeletal dynamics and functions, contributing to the clinical features of CID.
Subject(s)
Actin-Related Protein 2-3 Complex/genetics , Germ-Line Mutation , Immunologic Deficiency Syndromes/genetics , T-Lymphocytes/pathology , Actin-Related Protein 2-3 Complex/chemistry , Female , Homozygote , Humans , Immunologic Deficiency Syndromes/pathology , Male , Models, Molecular , Pedigree , Protein Conformation , Severe Combined Immunodeficiency/genetics , Severe Combined Immunodeficiency/pathology , T-Lymphocytes/metabolismABSTRACT
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.
Subject(s)
Allergy and Immunology , Immunity/genetics , Immunologic Deficiency Syndromes/immunology , Humans , Immunologic Deficiency Syndromes/genetics , International Cooperation , PhenotypeABSTRACT
Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide.