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RationaleEosinophilic gastrointestinal disorders (EGID), including eosinophilic esophagitis (EoE), are inflammatory disorders of the gastrointestinal mucosa mediated by complex immune mechanisms. Although there have been initial reports of EGID in patients with inborn errors of immunity (IEI), little is known about the presentation of EGID in immunodeficient individuals.MethodsWe queried the U.S. Immunodeficiency Network (USIDNET) for patient records including the terms eosinophilic esophagitis, gastritis, enteritis, or colitis. We analyzed 74 patient records from the database, including diagnoses, demographics, infectious history, laboratory findings, genetic studies, therapeutic interventions, and clinical outcomes.ResultsWe examined 74 patient records. A total of 61 patients had isolated EoE, and 13 had distal gastrointestinal involvement consistent with EGID. The most common IEI were common variable immunodeficiency (43.2%), some form of combined immunodeficiency (21.6%), chronic granulomatous disease (8.1%), hyper-IgE syndrome (6.8%), and autoimmune lymphoproliferative syndrome (6.8%). The median age at presentation with IEI was 0.5 years (IQR 1.725, max 39 years) and 56.76% were male. Approximately 20% of the patients in the cohort received a hematopoietic stem cell transplantation for treatment of IEI, but the timing of the HSCT in relationship to the EGID diagnosis was unknown.ConclusionsHere, we report EGID in a diverse cohort of IEI patients, suggesting that both non-EoE EGID and EoE can be seen as comorbid conditions with a variety of IEI. Our data suggests that EGID may be more common in patients with IEI than would be expected based on estimates of EGID in the general population.

BackgroundInborn errors of immunity (IEI) are a group of genetic disorders that impair the immune system, with over 400 genes described so far, and hundreds more to be discovered. To facilitate the search for new genes, we need a way to prioritize among all the genes in the genome those most likely to play an important role in immunity.ResultsHere we identify a new list of genes by linking known IEI genes to new ones by using open-source databases of protein-protein interactions, post-translational modifications, and transcriptional regulation. We analyze this new set of 2,530 IEI-related genes for their tolerance of genetic variation and by their expression levels in various immune cell types.ConclusionsBy merging genes derived from protein interactions of known IEI genes with transcriptional data, we offer a new list of candidate genes that may play a role in as-yet undiscovered IEIs.

In order to maintain the polio eradication status, it has become evident that the surveillance of cases with acute flaccid paralysis and of environmental samples must be urgently supplemented with the surveillance of poliovirus excretions among individuals with inborn errors of immunity (IEI). All children with IEI were screened for the excretion of poliovirus during a collaborative study conducted by the ICMR-National Institute of Virology, Mumbai Unit, ICMR-National Institute of Immunohaematology, and World Health Organization, India. A seven-month -old male baby who presented with persistent pneumonia and lymphopenia was found to have severe combined immune deficiency (SCID) due to a missense variant in the RAG1 gene. He had received OPV at birth and at 20 weeks. Four stool samples collected at 4 weekly intervals yielded iVDPV type 1. The child’s father, an asymptomatic 32-year-old male, was also found to be excreting iVDPV. A haploidentical hematopoietic stem cell transplant was performed, but the child succumbed due to severe myocarditis and pneumonia three weeks later. We report a rare case of transmission of iVDPV from an individual with IEI to a healthy household contact, demonstrating the threat of the spread of iVDPV from persons with IEI and the necessity to develop effective antivirals.

The SARS-CoV-2 pandemic has heightened concerns about immunological protection, especially for individuals with inborn errors of immunity (IEI). While COVID-19 vaccines elicit strong immune responses in healthy individuals, their effectiveness in IEI patients remains unclear, particularly against new viral variants and vaccine formulations. This uncertainty has led to anxiety, prolonged self-isolation, and repeated vaccinations with uncertain benefits among IEI patients. Despite some level of immune response from vaccination, the definition of protective immunity in IEI individuals is still unknown. Given their susceptibility to severe COVID-19, strategies such as immunoglobulin replacement therapy (IgRT) and monoclonal antibodies have been employed to provide passive immunity, and protection against both current and emerging variants. This review examines the efficacy of COVID-19 vaccines and antibody-based therapies in IEI patients, their capacity to recognize viral variants, and the necessary advances required for the ongoing protection of people with IEIs.

Abstract Background Inherited genetic defects in immune system-related genes can result in Inborn Errors of Immunity (IEI), also known as Primary Immunodeficiencies (PID). Diagnosis of IEI disorders is challenging due to overlapping clinical manifestations. Accurate identification of disease-causing germline variants is crucial for appropriate treatment, prognosis, and genetic counseling. However, genetic sequencing is challenging in low-income countries like Brazil. This study aimed to perform genetic screening on patients treated within Brazil's public Unified Health System to identify candidate genetic variants associated with the patient’s phenotype. Methods Thirteen singleton unrelated patients from three hospitals in Rio de Janeiro were enrolled in this study. Genomic DNA was extracted from the peripheral blood lymphocytes of each patient, and whole exome sequencing (WES) analyses were conducted using Illumina NextSeq. Germline genetic variants in IEI-related genes were prioritized using a computational framework considering their molecular consequence in coding regions; minor allele frequency ≤ 0.01; pathogenicity classification based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines gathered from the VarSome clinical database; and IEI-related phenotype using the Franklin tool. The genes classification into IEI categories follows internationally recognized guidelines informed by the International Union of Immunological Societies Expert Committee. Additional methods for confirmation of the variant included Sanger sequencing, phasing analysis, and splice site prediction. Results A total of 16 disease-causing variants in nine genes, encompassing six different IEI categories, were identified. X-Linked Agammaglobulinemia, caused by BTK variations, emerged as the most prevalent IEI disorder in the cohort. However, pathogenic and likely pathogenic variants were also reported in other known IEI-related genes, namely CD40LG, CARD11, WAS, CYBB, C6, and LRBA. Interestingly, two patients with suspected IEI exhibited pathogenic variants in non-IEI-related genes, ABCA12 and SLC25A13, potentially explaining their phenotypes. Conclusions Genetic screening through WES enabled the detection of potentially harmful variants associated with IEI disorders. These findings contribute to a better understanding of patients' clinical manifestations by elucidating the genetic basis underlying their phenotypes.

Abstract Objectives Inborn error of immunity (IEI) comprises a broad group of inherited immunological disorders that usually display an overlap in many clinical manifestations challenging their diagnosis. The identification of disease-causing variants from whole-exome sequencing (WES) data comprises the gold-standard approach to ascertain IEI diagnosis. The efforts to increase the availability of clinically relevant genomic data for these disorders constitute an important improvement in the study of rare genetic disorders. This work aims to make available WES data of Brazilian patients’ suspicion of IEI without a genetic diagnosis. We foresee a broad use of this dataset by the scientific community in order to provide a more accurate diagnosis of IEI disorders. Data description Twenty singleton unrelated patients treated at four different hospitals in the state of Rio de Janeiro, Brazil were enrolled in our study. Half of the patients were male with mean ages of 9 ± 3, while females were 12 ± 10 years old. The WES was performed in the Illumina NextSeq platform with at least 90% of sequenced bases with a minimum of 30 reads depth. Each sample had an average of 20,274 variants, comprising 116 classified as rare pathogenic or likely pathogenic according to American College of Medical Genetics and Genomics and the Association (ACMG) guidelines. The genotype-phenotype association was impaired by the lack of detailed clinical and laboratory information, besides the unavailability of molecular and functional studies which, comprise the limitations of this study. Overall, the access to clinical exome sequencing data is limited, challenging exploratory analyses and the understanding of genetic mechanisms underlying disorders. Therefore, by making these data available, we aim to increase the number of WES data from Brazilian samples despite contributing to the study of monogenic IEI-disorders.

Abstract Objectives Inborn errors of immunity (IEIs) are monogenic diseases of the immune system. Despite the increasing genetic advancements, the diagnosis of IEIs still lean on clinical diagnosis. Dermatological manifestations are observed in a large number of IEI patients and can lead to proper approach and prompt intervention. Methods This cross‐sectional study was carried out between 2018 and 2020 on IEIs at a Children's tertiary care center in Tehran, Iran. Demographic details and age at onset of symptoms of IEI were recorded. Results Overall, 212 patients were included. Cutaneous findings were reported in 95 (44.8%) patients, and 61 of 95 (64.2%) reported skin lesions as the first clinical presentation. Skin infection (69, 72.6%) was the most frequent cutaneous manifestation, followed by eczematous rash (24, 25%). Conclusions Skin manifestations are a common feature in IEI patients and are readily recognizable by healthcare providers. This study tried to provide information on prognostic consequences.

Abstract Background The correlation between primary immunodeficiencies (PIDs) and autoimmunity shows ethnic and geographical diversity. The aim of our study was to accumulate more data in paediatric PID population. Methods 58 children aged 1–17 and with PID (study group) and 14 age-matched immunocompetent individuals (control group) were included in the study. Serum levels of 17 different specific IgG antibodies against autoantigens were measured by means of a quantitative enzyme immunoassay. Immunoglobulin levels were analysed in relation to a detailed medical examination. Results Autoantibodies against one or more antigens were detected in the sera of 24.14% (n = 14) subjects in the study group. The most frequent were anti-thyroid peroxidase (anti-TPO) antibodies (n = 8; 13.8%). Anti-TPO antibody levels were elevated more often in PID patients with a positive family history of autoimmune diseases (p = 0.04). The screening for anti-deamidated gliadin peptide (DGP) and anti-tissue transglutaminase (tTG) antibodies in our series allowed identifying two previously undiagnosed cases of coeliac disease in PID patients. There was no statistically significant difference between the study and the control group in terms of the autoantibodies prevalence. Conclusions This study provides data on the prevalence of autoantibodies in paediatric population diagnosed with PID. Selected autoantibodies (i.e. anti-tTG, anti-DGP) might be useful for the screening of PID to avoid the delay of diagnosis of an autoimmune disease.

Tumor necrosis factor-a inhibitors can be associated with increased risk of infections, particularly reactivation of latent tuberculosis or nontuberculous mycobacterium (NTM). However, because disseminated NTM is rare, inborn errors of immunity should be considered. We present three patients with disseminated NTM after tumor necrosis factor-a inhibitor use who were found to have inborn errors of immunity.

Inborn errors of immunity (IEI) can often be misdiagnosed early in life due to their heterogenous clinical presentations. Interleukin-1 receptor-associated kinase 4 (IRAK-4) deficiency is one of the rare innate immunodeficiency disorders. We present the case of a patient who presented at the age of 15 days with meningitis and septic shock that responded to antibiotics. She was admitted again at the age of 45 days with pseudomonas aeruginosa bacteremia that was associated with increased inflammatory markers. Her third admission was at the age of 2.5 months due to left sided peri-orbital cellulitis that was again associated with elevated inflammatory markers. At 3.5 months, she experienced left orbital cellulitis, which was complicated by extensive sinus involvement, erosion, and abscess formation in the pterygopalatine fossa. Her condition progressed to septic shock and required multiple antibiotics and surgical interventions for drainage and control of the infection source. Both abscess and blood culture were positive for pseudomonas aeruginosa. An IEI was suspected but basic immunology testing was normal. Whole Exome Sequencing was performed and a novel mutation in IRAK4 was detected. In conclusion, we highlight the importance of raising awareness among pediatricians about the potentially lethal IEI and the need to consult specialists when these diseases are suspected. Among them is IRAK-4 deficiency which can be diagnosed by sophisticated functional assays and/or genetic testing.

ObjectivesThis study aims to describe clinical features, therapeutic outcomes, and safety profiles in patients affected by juvenile idiopathic arthritis (JIA) and inborn errors of immunity (IEI) treated with biological Disease-modifying antirheumatic drugs (DMARDs).MethodsWe enrolled three patients who were followed in the Pediatric Rheumatology Unit at Meyer Children's Hospital in Florence; these patients were affected by JIA, according to ILAR criteria, and IEI, according to the IUIS Phenotypical Classification for Human Inborn Errors of Immunity. Among them, two patients had 22q11.2 deletion syndrome (22q11.2DS) and one patient had X-linked agammaglobulinemia (XLA).ResultsCase 1: A 6-year and 2-month-old boy was affected by 22q11.2DS, associated with oligoarticular JIA, at the age of 2 years. He was treated with non-steroidal anti-inflammatory drugs (NSAIDs) and methotrexate, along with oral glucocorticoids but with no benefits. Treatment with etanercept allowed him to achieve remission after 10 months. Case 2: A 6-year and 2-month-old girl was affected by 22q11.2DS, associated with oligoarticular JIA, at the age of 3 years and 11 months. She was treated with NSAIDs, joint injections, and methotrexate but without clinical response. Treatment with Adalimumab allowed her to achieve remission after 6 months. Case 3: A 12-year and 2-month-old boy was affected by XLA, associated with polyarticular JIA, at the age of 9 years and 11 months. He was treated with NSAIDs, methotrexate, joint injections, and oral glucocorticoids with no benefits. He failed to respond to anti-TNF-alpha, tocilizumab, and abatacept. Currently, he is undergoing therapy with sirolimus plus abatacept, which allowed him to achieve remission after 4 months.ConclusionsResults suggest that the use of immunosuppressive biological therapies can control disease activity in these patients. No adverse drug-related reactions were observed during the follow-up.

BackgroundHemophagocytic Lymphohistiocytosis (HLH) is a rare and life-threatening condition characterized by a severe impairment of the immune homeostasis. While Familial-HLH (FHL) is a known cause, the involvement of other Inborn Errors of Immunity (IEI) in pediatric-HLH remains understudied.ObjectiveThis systematic review aimed to assess the clinical features, triggers, laboratory data, treatment, and outcomes of pediatric HLH patients with IEI other than FHL (IEInotFHL), emphasizing the importance of accurate identification and management.MethodsA systematic search for studies meeting inclusion criteria was conducted in PubMed, EMBASE, MEDLINE, and Cochrane Central. Quality assessment was performed through JBI criteria.ResultsA comprehensive search yielded 108 records meeting inclusion criteria, involving 178 patients. We identified 46 different IEI according to IUIS 2022 Classification. Combined immunodeficiencies, immune dysregulation disorders, and phagocyte defects were the IEI most frequently associated with HLH. In 75% of cases, HLH preceded the IEI diagnosis, often with an unrecognized history of severe infections. Triggers reflected the specific infection susceptibilities within IEI groups. Liver and central nervous system involvement were less common than in FHL cases. Treatment approaches and outcomes varied, with limited long-term follow-up data, limiting the assessment of therapeutic efficacy across IEI groups.ConclusionA comprehensive evaluation encompassing immunological, infectious, and genetic aspects is essential in pediatric-HLH. Relying solely on FHL or EBV susceptibility disorders tests is insufficient, as diverse other IEI can contribute to HLH. Early recognition of HLH as a potential warning sign can guide timely diagnostic investigations and facilitate tailored therapeutic interventions for improved outcomes.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=371425, PROSPERO, CRD42022371425.

Abstract COVID-19 pandemic represented a worldwide major challenge in different areas, and efforts undertaken by the scientific community led to the understanding of some of the genetic determinants that influence the different COVID-19 outcomes. In this paper, we review the studies about the role of human genetics in COVID-19 severity and how Brazilian studies also contributed to those findings. Rare variants in genes related to Inborn Errors of Immunity (IEI) in the type I interferons pathway, and its phenocopies, have been described as being causative of severe outcomes. IEI and its phenocopies are present in Brazil, not only in COVID-19 patients, but also in autoimmune conditions and severe reactions to yellow fever vaccine. In addition, studies focusing on common variants and GWAS studies encompassing worldwide patients have found several loci associated with COVID-19 severity. A GWAS study including only Brazilian COVID-19 patients identified a new locus 1q32.1 associated with COVID-19 severity. Thus, more comprehensive studies considering the Brazilian genomic diversity should be performed, since they can help to reveal not only what are the genetic determinants that contribute to the different outcomes for COVID-19 in the Brazilian population, but in the understanding of human genetics in different health conditions.

Lymphocytic interstitial pneumonia (LIP) in pediatric patients without human immunodeficiency virus (HIV) infection remains a poorly characterized and enigmatic disease. Immunological dysregulation, mutations in the COPA gene, and increased morbidity and mortality have been reported in these patients. We present a case of LIP in a pediatric patient without HIV infection. This patient was infected with human T-lymphotropic virus type 1 (HTLV-1) and required right lower lobectomy with pathological findings compatible with lymphocytic interstitial pneumonia. In addition, bronchiectasis, dermatological involvement, and malnutrition were documented. However, no autoimmune disease, polymyositis, myelopathy, or opportunistic infections were found. There were no abnormalities in cellular and humoral immunity. A genetic study identified heterozygous mutations in the SCNN1B, FCHO1, and IL7R genes using single exome sequencing of coding and splicing regions. Although these heterozygous variants are not reported to be aetiological for LIP or diagnostic for the patient's congenital immunodeficiency, we believe they are associated with the severe lung damage seen in the patient's case.

Abstract Background Patients with immunodeficiencies commonly experience diagnostic delays resulting in morbidity. There is an unmet need to identify patients earlier, especially those with high risk for complications. Compared to immunoglobulin quantification and flowcytometric B cell subset analysis, expanded T cell subset analysis is rarely performed in the initial evaluation of patients with suspected immunodeficiency. The simultaneous interpretation of multiple immune variables, including lymphocyte subsets, is challenging. Objective To evaluate the diagnostic value of cluster analyses of immune variables in patients with suspected immunodeficiency. Methods Retrospective analysis of 38 immune system variables, including seven B cell and sixteen T cell subpopulations, in 107 adult patients (73 with immunodeficiency, 34 without) evaluated at a tertiary outpatient immunology clinic. Correlation analyses of individual variables, k‐means cluster analysis with evaluation of the classification into “no immunodeficiency” versus “immunodeficiency” and visual analyses of hierarchical heatmaps were performed. Results Binary classification of patients into groups with and without immunodeficiency was correct in 54% of cases with the full data set and increased to 69% and 75% of cases, respectively, when only 16 variables with moderate (p

Summary: Increasing evidence suggests multilineage cytopenias (also known as Evans syndrome) may be caused by inborn errors of immunity (IEI) with immune dysregulation. We studied a patient with autoimmune haemolytic anaemia and immune thrombocytopenia and identified a germline mutation in SASH3 (c.862C>T;p.Arg288Ter), indicating a recently identified IEI. Immunohistochemistry performed after clinically indicated splenectomy revealed severe hypoplasia/absence of germinal centres. The autoimmune phenotype was associated with an increased CD21lowT‐bet+CD11c+ subset along with decreased regulatory T cells, impaired T‐cell proliferation and T‐cell exhaustion. The younger brother carries the same SASH3 mutation and shares immunophenotypic features but is currently clinical asymptomatic, indicating heterogeneity of SASH3 deficiency. [ABSTRACT FROM AUTHOR]

Background: Preventive strategies against severe COVID-19 in Inborn Errors of Immunity (IEI) include bivalent vaccines, treatment with SARS-CoV-2 monoclonal antibodies (mAbs), early antiviral therapies, and pre-exposure prophylaxis (PrEP). Objective: To assess the effectiveness of the PrEP with tixagevimab/cilgavimab (AZD7442) in IEI with primary antibody defects during the COVID-19 Omicron wave. Methods: A six-month prospective study evaluated the SARS-CoV-2 infection rate and the COVID-19 severity in the AZD7442 group, in the no-AZD7442 group, and in a group of patients with a recent SARS-CoV-2 infection (< three months). Spike-specific IgG levels were measured at regular intervals. Results: Six out of thirty-three patients (18%) and 54/170 patients (32%) became infected in the AZD7442 group and in the no-AZD7442 group, respectively. Within 90 days post-administration, the AZD7442 group was 85% less likely to be infected and 82% less likely to have a symptomatic disease than the no-AZD7442 group. This effect was lost thereafter. In the entire cohort, no mortality/hospitalisation was observed. The control group of 35 recently infected patients was 88% and 92% less likely to be infected than the AZD7442 and no-AZD7442 groups. Serum anti-Spike IgG reached the highest peak seven days post-AZD7442 PrEP then decreased, remaining over 1000 BAU/mL 180 days thereafter. Conclusion: In patients with IEI and antibody defects, AZD7442 prophylaxis had a transient protective effect, possibly lost possibly because of the appearance of new variants. However, PrEP with newer mAbs might still represent a feasible preventive strategy in the future in this population. [ABSTRACT FROM AUTHOR]

Patients with inborn errors of immunity (IEI) may develop granulomas in multiple organ systems including the skin. Vaccine strain rubella virus (RuV), part of the live attenuated measles, mumps, and rubella (MMR) vaccine, has been identified within these granulomas. RuV is typically found in macrophages; however, recently neutrophils have been identified as a novel cell type infected. Here, we present a case of RuV‐associated cutaneous granuloma with RuV localized to neutrophils. A 46‐year‐old female with common variable immunodeficiency presented with verrucous papules and crusted plaques from the right knee to the distal shin of 20 years duration, associated with prior physical trauma. Biopsy specimen showed palisaded granulomas surrounding central necrosis with scattered aggregates of neutrophils. Vaccine‐derived RuV was detected by molecular sequencing in lesional skin. Fluorescent immunohistochemistry with CD206, myeloperoxidase (MPO), and RV capsid (RVC) antibodies demonstrated that RuV localized to neutrophils but not macrophages. The clinical presentation, cutaneous findings, and likely presence of RVC‐positive granulocytes in bone marrow provide potential support to the evolving hypothesis of persistent RuV within neutrophils contributing to chronic granulomatous inflammation in a milieu of immune dysregulation. [ABSTRACT FROM AUTHOR]

Human inborn errors of immunity (IEIs) comprise pathological conditions characterized by increased susceptibility to infections and immune dysregulation. Many of these conditions result from monogenic mutations, while others lack known mutation despite similarities in clinical presentation. Epigenetic modulation has been proposed as a potential pathogenic mechanism. Mutations in many genes, including several encoding transcription factors, account for a pathogenic mechanism in common variable immunodeficiency (CVID), the most common IEI, although 80% of patients do not harbor mutation(s). Patients with CVID without mutations are characterized by extensive DNA methylation changes in the memory B cell compartment. Transcription factors with mutations in CVID, including Nuclear Factor Kappa B subunit 1 (NFKB1), interact directly or indirectly via protein partners with various epigenetic enzymes, such as histone deacetylases and DNA methylation enzymes. These interactions can mediate epigenetic changes at genomic binding sites. The identification of complete epigenetic remodeling profiles associated with mutations in various transcription factors mutated in CVID and, by extension, in IEIs, can provide insights into the whole range of dysregulated pathways in different patients. It can also offer clues to potential novel targets that might help treat patients with CVID without mutations. Transcription factors with genetic mutations that have been implicated in IEIs, such as CVID, as well as their known interactions with epigenetic enzymes, may offer a framework for better understanding certain epigenetic mechanisms underlying many of these conditions. This framework is relevant not only for patients with IEI with identified mutations, but also for those with similar clinical presentations that do not bear genetic mutations. Inborn errors of immunity (IEIs) comprise a variety of immune conditions leading to infections, autoimmunity, allergy, and cancer. Some IEIs have no identified mutation(s), while others with identical mutations can display heterogeneous presentations. These observations suggest the involvement of epigenetic mechanisms. Epigenetic alterations can arise from downstream activation of cellular pathways through both extracellular stimulation and genetic-associated changes, impacting epigenetic enzymes or their interactors. Therefore, we posit that epigenetic alterations and genetic defects do not exclude each other as a disease-causing etiology. In this opinion, encompassing both basic and clinical viewpoints, we focus on selected IEIs with mutations in transcription factors that interact with epigenetic enzymes. The intricate interplay between these factors offers insights into genetic and epigenetic mechanisms in IEIs. [ABSTRACT FROM AUTHOR]

Background: Bronchiectasis is a major respiratory complication in patients with common variable immunodeficiency (CVID) and is associated with recurrent pulmonary infections. However, it is unclear whether other infections or non-infectious respiratory conditions are related to its development. Objective: To identify respiratory comorbidities associated with bronchiectasis in patients with CVID. Methods: A total of 1470 CVID patients enrolled in the USIDNET registry were included in a cross-sectional analysis. The primary outcome of our study was to determine the clinical characteristics and other respiratory conditions associated with respiratory comorbidities and physician-reported bronchiectasis. Results: One hundred ninety-seven CVID patients were noted to have bronchiectasis (13.4%). Affected patients were significantly older than patients without bronchiectasis (median age 54 years vs. 49 years, p = 0.0004). These patients also had lower serum IgA (13 mg/dL IQR 60 mg/dL vs. 28.4 mg/dL IQR 66 mg/dL, p = 0.000). Notably, chronic rhinosinusitis (OR = 1.69 95%CI 1.05–2.75), sinusitis (OR = 2.06 95%CI 1.38–3.09), pneumonia (OR = 2.70 95%CI 1.88–3.88), COPD (OR = 2.66 95%CI 1.51–4.67), and interstitial lung disease (OR = 2.34 95%CI 1.41–3.91) were independently associated with the development of bronchiectasis in this population. Conclusion: These data suggest that lower and upper respiratory infections, chronic lower airway disease, and interstitial lung diseases are independently associated with bronchiectasis in CVID patients. Further study into predisposing conditions related to the development of bronchiectasis in CVID patients may allow prediction and early intervention strategies to prevent the development of this complication. [ABSTRACT FROM AUTHOR]

Biallelic KARS1 mutations cause KARS-related diseases, a rare syndromic condition encompassing central and peripheral nervous system impairment, heart and liver disease, and deafness. KARS1 encodes the t-RNA synthase of lysine, an aminoacyl-tRNA synthetase, involved in different physiological mechanisms (such as angiogenesis, post-translational modifications, translation initiation, autophagy and mitochondrial function). Although patients with immune-hematological abnormalities have been individually described, results have not been collectively discussed and functional studies investigating how KARS1 mutations affect B cells have not been performed. Here, we describe one patient with severe developmental delay, sensoneurinal deafness, acute disseminated encephalomyelitis, hypogammaglobulinemia and recurrent infections. Pathogenic biallelic KARS1 variants (Phe291Val/ Pro499Leu) were associated with impaired B cell metabolism (decreased mitochondrial numbers and activity). All published cases of KARS-related diseases were identified. The corresponding authors and researchers involved in the diagnosis of inborn errors of immunity or genetic syndromes were contacted to obtain up-to-date clinical and immunological information. Seventeen patients with KARS-related diseases were identified. Recurrent/severe infections (9/17) and B cell abnormalities (either B cell lymphopenia [3/9], hypogammaglobulinemia [either IgG, IgA or IgM; 6/15] or impaired vaccine responses [4/7]) were frequently reported. Immunoglobulin replacement therapy was given in five patients. Full immunological assessment is warranted in these patients, who may require detailed investigation and specific supportive treatment. [ABSTRACT FROM AUTHOR]

Variants of uncertain significance (VUS) in CTLA4 are frequently identified in patients with antibody deficiency or immune dysregulation syndromes including, but not limited to, patients with multi-organ autoimmunity and autoinflammation. However, to ascertain the diagnosis of CTLA4 insufficiency, the functional relevance of each variant needs to be determined. Currently, various assays have been proposed to assess the functionality of CTLA4 VUS, including the analysis of transendocytosis, the biological function of CTLA4 to capture CD80 molecules from antigen presenting cells. Challenges of this assay include weak fluorescence intensity of the internalized ligand, poor reproducibility, and poor performance upon analyzing thawed cells. In addition, the distinction of pathogenic from non-pathogenic variants and from wild-type CTLA4, and the classification of the different VUS according to its level of CTLA4 dysfunction, would be desirable. We developed a novel CD80-expressing cell line for the evaluation of CD80-transendocytosis and compared it to the published transendocytosis assay. Our approach showed lower inter-assay variability and better robustness regardless the type of starting material (fresh or thawed peripheral mononuclear cells). In addition, receiver operating characteristic analysis showed 100% specificity, avoiding false positive results and allowing for a clear distinction between pathogenic and non-pathogenic variants in CTLA4-variant carriers. With our transendocytosis assay, we assessed the pathogenicity of 24 distinct CTLA4 variants from patients submitted to our diagnostic unit. Significantly impaired transendocytosis was demonstrated for 17 CTLA4 variants, whereas seven variants tested normal. In conclusion, our upgraded transendocytosis assay allows a reliable assessment of newly identified variants in CTLA4. [ABSTRACT FROM AUTHOR]

Both innate errors of immunity, such as familial Mediterranean fever (FMF) and chronic granulomatous disease (CGD), and the common inflammatory disease gout are characterized by episodes of sterile inflammatory attacks in the absence of an infection. While these disorders encompass distinct pathologies due to differentially affected metabolic pathways and inflammasome activation mechanisms, their common features are the excessive production of interleukin (IL)-1ß and innate immune cell hyperreactivity. On the other hand, the role of T cells and innate-like lymphocytes such as gamma delta (γδ) T cells in these pathologies is ill-defined. In order to widen our understanding of T cell involvement in CGD, FMF and gout pathology, we developed multicolour immunophenotyping panels for flow cytometry to characterize γδ T cells as well as CD4 and CD8 T cell populations in terms of their cytokine production, activation status, memory or naive phenotypes, exhaustion status, homing receptor expression, and cytotoxic activity. Our study is the first deep immunophenotyping analysis of T cell populations in CGD, FMF, and gout patients. We found that CGD affects the frequencies and activation status of T cells, while gout impairs the cytokine production capacity of Vδ2 T cells. FMF was characterized by decreased percentages of regulatory T cells in circulation and attenuated IFN-γ production capacity by Vδ2 T cells. Autoinflammatory syndromes and congenital defects of phagocyte differentially affect T cell compartments. Future studies are warranted to assess whether these phenotypical changes are relevant for disease pathology. [ABSTRACT FROM AUTHOR]

Mutations in CD46 predispose to atypical hemolytic uremic syndrome (aHUS) with low penetrance. Factors driving immune-dysregulatory disease in individual mutation carriers have remained ill-understood. In addition to its role as a negative regulator of the complement system, CD46 modifies T cell-intrinsic metabolic adaptation and cytokine production. Comparative immunologic analysis of diseased vs. healthy CD46 mutation carriers has not been performed in detail yet. In this study, we comprehensively analyzed clinical, molecular, immune-phenotypic, cytokine secretion, immune-metabolic, and genetic profiles in healthy vs. diseased individuals carrying a rare, heterozygous CD46 mutation identified within a large single family. Five out of six studied individuals carried a CD46 gene splice-site mutation causing an in-frame deletion of 21 base pairs. One child suffered from aHUS and his paternal uncle manifested with adult-onset systemic lupus erythematosus (SLE). Three mutation carriers had no clinical evidence of CD46-related disease to date. CD4+ T cell-intrinsic CD46 expression was uniformly 50%-reduced but was comparable in diseased vs. healthy mutation carriers. Reconstitution experiments defined the 21-base pair-deleted CD46 variant as intracellularly—but not surface-expressed and haploinsufficient. Both healthy and diseased mutation carriers displayed reduced CD46-dependent T cell mitochondrial adaptation. Diseased mutation carriers had lower peripheral regulatory T cell (Treg) frequencies and carried potentially epistatic, private rare variants in other inborn errors of immunity (IEI)-associated proinflammatory genes, not found in healthy mutation carriers. In conclusion, low Treg and rare non-CD46 immune-gene variants may contribute to clinically manifest CD46 haploinsufficiency-associated immune-dysregulation. [ABSTRACT FROM AUTHOR]

Purpose: Inborn errors of immunity (IEI) are typically monogenic. Data from the Indian subcontinent are relatively scarce. This paper evaluates IEI diagnosed in Sri Lanka. Methods: Data of patients diagnosed with IEI from 2010 to 2022 at the Department of Immunology, Medical Research Institute, Colombo, Sri Lanka, were retrospectively analyzed. Results: Two hundred and six patients were diagnosed with IEI, with a prevalence of 0.94 per 100,000. The onset of disease was below 12 years in 84.9%, whereas in 10.9%, it was after 18 years. The male: female ratio was 1.78:1. Consanguinity was identified in 26.6%. IEI were found in all but one (bone marrow failure) of the 10 IUIS categories. Predominantly antibody deficiencies were the most common category among the nine identified (30.1%), followed by combined immune deficiencies with syndromic features (21.3%), immunodeficiencies affecting cellular and humoral immunity (19.9%), congenital defects of phagocyte number or function (13.1%), and defects in intrinsic and innate immunity (8.2%). Severe combined immune deficiency (SCID) was the commonest disease (14.6%), followed by chronic granulomatous disease (CGD) (10.6%) and X linked agammaglobulinemia (8.7%). Of the patients with a known outcome (n = 184), 51 died (27.7%). Mortality rates were high in SCID (83.3%), Omenn syndrome (OS) (100%), and CGD (31.8%) patients. Conclusion: IEI in Sri Lanka are diagnosed mainly in childhood. The low diagnosis rates suggest a need for educating clinicians regarding IEI in adulthood. The high mortality rates associated with some IEI indicate the need of transplant services in the country. [ABSTRACT FROM AUTHOR]

• Our understanding of lymphoma predisposition has evolved rapidly over the last decades, accelerated by novel technologies. • Lymphoma-predisposing conditions include inborn errors of immunity, autoimmune disease and immunosuppressive treatment. • Shared characteristic features across clinically unique conditions reveal underlying mechanisms for lymphoma predisposition. • New insights in lymphomagenesis provide opportunities for early detection, prevention and tailored treatment of lymphoma. Lymphoma is a heterogeneous group of malignancies arising from lymphocytes, which poses a significant challenge in terms of diagnosis and treatment due to its diverse subtypes and underlying mechanisms. This review aims to explore the shared and distinct features of various forms of lymphoma predisposing conditions, with a focus on genetic, immunological and molecular aspects. While diseases such as autoimmune disorders, inborn errors of immunity and iatrogenic immunodeficiencies are biologically and immunologically distinct, each of these diseases results in profound immune dysregulation and a predisposition to lymphoma development. Interestingly, the increased risk is often skewed towards a particular subtype of lymphoma. Patients with inborn errors of immunity in particular present with extreme forms of lymphoma predisposition, providing a unique opportunity to study the underlying mechanisms. External factors such as chronic infections and environmental exposures further modulate the risk of lymphoma development. Common features of conditions predisposing to lymphoma include: persistent inflammation, recurrent DNA damage or malfunctioning DNA repair, impaired tumor surveillance and viral clearance, and dysregulation of fundamental cellular processes such as activation, proliferation and apoptosis. Our growing understanding of the underlying mechanisms of lymphomagenesis provides opportunities for early detection, prevention and tailored treatment of lymphoma development. [ABSTRACT FROM AUTHOR]

It is widely understood that cancer is a significant cause of morbidity and mortality worldwide. Despite numerous available treatments, prognosis for many remains poor, thus, the development of novel therapies remains essential. Given the incredible success of many immunotherapies in this field, the important contribution of the immune system to the control, and elimination, of malignancy is clear. While many immunotherapies target higher‐order pathways, for example, through promoting T‐cell activation via immune checkpoint blockade, the potential to target specific immunological pathways is largely not well researched. Precisely understanding how immunity can be tailored to respond to specific challenges is an exciting idea with great potential, and may trigger the development of new therapies for cancer. Inborn Errors of Immunity (IEI) are a group of rare congenital disorders caused by gene mutations that result in immune dysregulation. This heterogeneous group, spanning widespread, multisystem immunopathology to specific immune cell defects, primarily manifest in immunodeficiency symptoms. Thus, these patients are particularly susceptible to life‐threatening infection, autoimmunity and malignancy, making IEI an especially complex group of diseases. While precise mechanisms of IEI‐induced malignancy have not yet been fully elucidated, analysis of these conditions can highlight the importance of particular genes, and downstream immune responses, in carcinogenesis and may help inform mechanisms which can be utilised in novel immunotherapies. In this review, we examine the links between IEIs and cancer, establishing potential connections between immune dysfunction and malignancy and suggesting roles for specific immunological mechanisms involved in preventing carcinogenesis, thus, guiding essential future research focused on cancer immunotherapy and providing valuable insight into the workings of the immune system in both health and disease. [ABSTRACT FROM AUTHOR]

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Background: The European Society for Immunodeficiencies recommends that all patients with inborn errors of immunity (IEI) without contraindications should receive SARS-CoV-2 vaccination. The aim of this study was to investigate the reasons that discourage IEI patients from receiving the recommended vaccination and to assess vaccination coverage among IEI patients in Latvia. Methods: In this multicenter mixed-methods study, the vaccination status of all patients with IEI within two tertiary centers in Latvia was reviewed using electronic health records. Semi-structured interviews were conducted with 16 IEI patients who did not undergo vaccination, and a thematic analysis was performed. Results: A total of 341 patients (49.3% female; median age 19.7 years (IQR:17)) were included in the quantitative part. The proportion of fully vaccinated individuals aged ≥ 12 years was 66.8%–70.9% with patients with selective IgA deficiency and 58.8% with other IEI (χ² = 14.12, p < 0.001). The proportion of fully vaccinated individuals aged 5–11 years was 11.1%. Age was associated with vaccination status: younger patients were found to have a significantly lower likelihood of receiving vaccination (U = 8585, p < 0.001). The five main themes identified were as follows: (1) fear and uncertainty; (2) risk and benefit assessment: COVID-19 vaccine—is it worth it? (3) external influences: the dark horse of the decision-making—people around us; (4) individuals against the system; and (5) beliefs about vaccination and COVID-19. Under-representation of certain IEI groups and recall bias are possible limitations of this study. Conclusions: While most reasons for hesitancy were similar to those previously described in the general population, disease-specific concerns were also identified. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell transplantation is a curative treatment for many inborn errors of immunity (IEI). Incremental improvements and advances in care have led to high rates of >85% survival and cure in many of these diseases. Improvements in HLA-classification and matching have led to increased survival using HLA-matched donors, but survival using T-lymphocyte-depleted mismatched grafts remained significantly worse until fairly recently. Advances in T-lymphocyte depletion methods and graft engineering, although not specific to IEI, have been widely adopted and instrumental in changing the landscape of donor selection, such that a donor should now be possible for every patient. A literature review focusing on T-lymphocyte depletion methodologies and treatment results was performed. The importance of early T-lymphocyte immunoreconstitution to protect against viral infection is reviewed. Two main platforms now dominate the field – immune-magnetic selection of specific cell types and post-transplant chemotherapeutic targeting of rapidly proliferating allo-reactive T-lymphocytes – the emerging literature on these reports, focusing on IEI, is explored, as well as the impact of serotherapy on early immunoreconstitution. Pharmacokinetic monitoring of serotherapy agents, and use of co-stimulatory molecule blockade are likely to become more widespread. Post-transplant cyclophosphamide or TCR depletion strategies are likely to become the dominant methods of transplantation for nonmalignant diseases. [ABSTRACT FROM AUTHOR]

The transition from pediatric to adult care is a critical milestone in managing children, especially in those with complex chronic conditions. It involves ensuring the patient and family adapt correctly to the new phase, maintaining continuity of ongoing treatments, and establishing an appropriate follow-up plan with specialists. Patients with Inborn error of immunity (IEI), formerly known as Primary Immune Disorders (PID) are part of a group of disorders characterized by alterations in the proper functioning of the immune system; as the diagnostic and treatment tools for these entities progress, life expectancy increases, and new needs emerge. These children have special needs during the transition. Particularly important in the group of children with PID and syndromic features, who often present multiple chronic medical conditions. In these cases, transition planning is a significant challenge, involving not only the patients and their families but also a wide range of specialists. To achieve this, a multidisciplinary transition team should be established between the pediatric specialists and the adult consultants, designing a circuit in which communication is essential. As few transition care guidelines in the field of PID are available, and to our knowledge, there is no specific information available regarding patients with PID associated with syndromic features, we share our experience in this issue as a Primary Immunodeficiencies Unit that is a National Reference Center for PID, and propose a guide to achieve an adequate and successful transition to adulthood in these patients, especially in those with associated syndromic features. [ABSTRACT FROM AUTHOR]

The transcription factor interferon regulatory factor 4 (IRF4) belongs to the IRF family and has several important functions for the adaptive immune response. Mutations affecting IRF family members IRF1, IRF3, IRF7, IRF8, or IRF9 have been described in patients presenting with inborn errors of immunity (IEI) highlighting the importance of these factors for the cellular host defense against mycobacterial and/or viral infections. IRF4 deficiency and haploinsufficiency have been associated with IEI. More recently, two novel IRF4 disease-causing mechanisms have been described due to the characterization of IEI patients presenting with cellular immunodeficiency associated with agammaglobulinemia. Here, we review the phenotypes and physiopathological mechanisms underlying IEI of IRF family members and, in particular, IRF4. [ABSTRACT FROM AUTHOR]

Common variable immunodeficiency (CVID) associated liver disease is an underrecognized and poorly studied non-infectious complication that lacks an established treatment. We describe a CVID patient with severe multiorgan complications, including non-cirrhotic portal hypertension secondary to nodular regenerative hyperplasia leading to diuretic-refractory ascites. Remarkably, treatment with rituximab, administered for concomitant immune thrombocytopenia, resulted in the complete and sustained resolution of portal hypertension and ascites. Our case, complemented with a literature review, suggests a beneficial effect of rituximab that warrants further research. [ABSTRACT FROM AUTHOR]

Background: X‐linked agammaglobulinemia (XLA) is the most common form of agammaglobulinemia and is caused by mutations in Btk, which encodes Bruton tyrosine kinase (BTK). Case Description: We describe a 36‐year‐old male who presented as an infant with hypogammaglobulinemia and sinopulmonary infections and was initially diagnosed with common variable immunodeficiency. Genetic testing showed he was hemizygous for Btk c.240G > A. This synonymous variant affecting the last nucleotide of exon 3 leads to aberrant splicing of most but not all mRNA transcripts. Conclusion: We demonstrated reduced BTK protein expression confirming the pathogenicity of the variant and related our findings to genotype‐phenotype relationship studies ina XLA caused by synonymous mutations. [ABSTRACT FROM AUTHOR]

Patients with autosomal dominant (AD) hyper-IgE syndrome (HIES) suffer from a constellation of manifestations including recurrent bacterial and fungal infections, severe atopy, and skeletal abnormalities. This condition is typically caused by monoallelic dominant-negative (DN) STAT3 variants. In 2020, we described 12 patients from eight kindreds with DN IL6ST variants resulting in a new form of AD HIES. These variants encoded truncated GP130 receptors, with intact extracellular and transmembrane domains, but lacking the intracellular recycling motif and the four STAT3-binding residues, resulting in an inability to recycle and activate STAT3. We report here two new DN variants of IL6ST in three unrelated families with HIES-AD. The biochemical and clinical impacts of these variants are different from those of the previously reported variants. The p.(Ser731Valfs*8) variant, identified in seven patients from two families, lacks the recycling motif and all the STAT3-binding residues, but its levels on the cell surface are only slightly increased and it underlies mild biological phenotypes with variable clinical expressivity. The p.(Arg768*) variant, identified in a single patient, lacks the recycling motif and the three most distal STAT3-binding residues. This variant accumulates at the cell surface and underlies severe biological and clinical phenotypes. The p.(Ser731Valfs*8) variant shows that a DN GP130 expressed at near normal levels on the cell surface can underlie heterogeneous clinical presentations, ranging from mild to severe. The p.(Arg768*) variant demonstrates that a truncated GP130 protein retaining one STAT3-binding residue can underlie severe HIES. [ABSTRACT FROM AUTHOR]

Primary immunodeficiency disease (PIDD) comprises a group of disorders of immune function. Some of the most severe PIDD can be treated with hematopoietic cell transplant (HCT). Hizentra® is a 20% liquid IgG product approved for subcutaneous administration in adults and children greater than 2 years of age with PIDD-associated antibody deficiency. Limited information is available on the use of Hizentra® in children following HCT for PIDD. A multicenter retrospective chart review demonstrated 37 infants and children (median age 70.1 [range 12.0 to 176.4] months) with PIDD treated by HCT who received Hizentra® infusions over a median duration of 31 (range 4–96) months post-transplant. The most common indication for HCT was IL2RG SCID (n = 16). Thirty-two patients switched from IVIG to SCIG administration, due to one or more of the following reasons: patient/caregiver (n = 17) or physician (n = 12) preference, discontinuation of central venous catheter (n = 16), desire for home infusion (n = 12), improved IgG serum levels following lower levels on IVIG (n = 10), and loss of venous access (n = 8). Serious bacterial infections occurred at a rate of 0.041 per patient-year while on therapy. Weight percentile increased by a mean of 16% during the observation period, with females demonstrating the largest gains. Mild local reactions were observed in 24%; 76% had no local reactions. One serious adverse event (death from sepsis) was reported. Hizentra® was discontinued in 15 (41%) patients, most commonly due to recovery of B cell function (n = 11). These data demonstrate that Hizentra® is a safe and effective option in children who have received HCT for PIDD. [ABSTRACT FROM AUTHOR]

[Display omitted] Gain-of-function variants of JAK1 drive a rare immune dysregulation syndrome associated with atopic dermatitis, allergy, and eosinophilia. This study sought to describe the clinical and immunological characteristics associated with a new gain-of-function variant of JAK1 and report the therapeutic efficacy of Janus kinase (JAK) inhibition. The investigators identified a family affected by JAK1 -associated autoinflammatory disease and performed clinical assessment and immunological monitoring on 9 patients. JAK1 signaling was studied by flow and mass cytometry in patients' cells at basal state or after immune stimulation. A molecular disease signature in the blood was studied at the transcriptomic level. Patients were treated with 1 of 2 JAK inhibitors: either baricitinib or upadacitinib. Clinical, cellular, and molecular response were evaluated over a 2-year period. Affected individuals displayed a syndromic disease with prominent allergy including atopic dermatitis, ichthyosis, arthralgia, chronic diarrhea, disseminated calcifying fibrous tumors, and elevated whole blood histamine levels. A variant of JAK1 localized in the pseudokinase domain was identified in all 9 affected, tested patients. Hyper-phosphorylation of STAT3 was found in 5 of 6 patients tested. Treatment of patients' cells with baricitinib controlled most of the atypical hyper-phosphorylation of STAT3. Administration of baricitinib to patients led to rapid improvement of the disease in all adults and was associated with reduction of systemic inflammation. Patients with this new JAK1 gain-of-function pathogenic variant displayed very high levels of blood histamine and showed a variable combination of atopy with articular and gastrointestinal manifestations as well as calcifying fibrous tumors. The disease, which appears to be linked to STAT3 hyperactivation, was well controlled under treatment by JAK inhibitors in adult patients. [ABSTRACT FROM AUTHOR]

An improved recognition of inborn errors of immunity (IEI) is associated with an increase in life expectancy and a higher incidence of complications and related conditions. The aim of the study was to analyze factors enabling the primary prevention: BMI, smoking and selected laboratory tests (morphology with smear, creatinine, eGFR, total protein, albumin, ferritin, folic acid, vitamin B12, vitamin D3) included in the protocols of standard of care for adult patients with primary antibody deficiencies (PADs). The study included 94 participants ≥ 18 years old, diagnosed with PADs. Overweight was found in 17%, obesity in 14% and underweight in 15% of patients; 11.5% of patients smoked. Leukopenia was diagnosed in 16%, neutropenia in 8.5%, lymphopenia in 22.5% and thrombocytopenia in 14% of patients. A decreased concentration of hemoglobin was found in 32%, total protein in 19%, albumin in 17%, vitamin D3 in 52%, vitamin B12 in 6.5%, folic acid in 34% and ferritin in 26% of patients. Creatinine concentrations were elevated in 16% of patients, while in 20%, eGFR was reduced. Only a holistic assessment of comorbidities and complications of deficiency, as well as regular follow-up and lifestyle changes, can yield the best results in the long-term care of patients. [ABSTRACT FROM AUTHOR]

Ataxia telangiectasia (AT) is a rare disease characterized by the early onset and slow progression of neurodegenerative defects, mainly affecting the cerebellum, associated with immunodeficiency and teleangiectasias. Ataxia is the hallmark of the disease and usually its first manifestation. Overt cerebellar ataxia usually becomes evident between 16 and 18 months of age, after the onset of walking, and is characterized by frequent falls and an ataxic gait with an enlarged base. We report the case of a child who first presented with serious recurrent infectious, without exhibiting neurological symptoms. The patient was initially diagnosed with combined immunodeficiency (CID) of unknown etiology for nearly 3 years, before he was definitively diagnosed with ataxia telangiectasia. [ABSTRACT FROM AUTHOR]

Many inborn errors of immunity (IEI) manifest with hallmarks of both immunodeficiency and immune dysregulation due to uncontrolled immune responses and impaired immune homeostasis. A subgroup of these disorders frequently presents with autoimmunity and lymphoproliferation (ALPID phenotype). After the initial description of the genetic basis of autoimmune lymphoproliferative syndrome (ALPS) more than 20 years ago, progress in genetics has helped to identify many more genetic conditions underlying this ALPID phenotype. Among these, the majority is caused by a group of autosomal-dominant conditions including CTLA-4 haploinsufficiency, STAT3 gain-of-function disease, activated PI3 kinase syndrome, and NF-κB1 haploinsufficiency. Even within a defined genetic condition, ALPID patients may present with staggering clinical heterogeneity, which makes diagnosis and management a challenge. In this review, we discuss the pathophysiology, clinical presentation, approaches to diagnosis, and conventional as well as targeted therapy of the most common ALPID conditions. [ABSTRACT FROM AUTHOR]

MBL is critical in activating the lectin pathway of the complement system. MBL deficiency remains a contentious issue in clinical practice, mainly because low MBL levels may present in completely asymptomatic individuals. However, in some cases, symptomatic patients may present with susceptibility to infections and even immune dysregulation. Infections may range from mild to severe, and may even be life-threatening and fatal. A significant number of patients may remain undiagnosed, merely because interrogating complement function is often postponed until after presumably more common immune problems have been excluded in patients with severe, recurrent or unusual infections. In addition, clinicians are less familiar with the clinical recognition and appropriate choice of special investigations necessary to diagnose MBL and other complement deficiencies. Our case report describes a young girl with a serious underlying inborn error of immunity. She initially presented with recurrent 'innocent' and mild infections. We illustrate that clinically relevant MBL deficiency, if undiagnosed, may have disastrous consequences. We also stress the importance of careful interpretation of MBL quantitative laboratory values and the urgent need for access to more specialised complement-component and genetic testing, especially for patients attending state healthcare facilities. [ABSTRACT FROM AUTHOR]

Introduction: In children with inborn errors of immunity (IEI) who will receive a hematopoietic stem cell transplant (HSCT) treosulfan‐based conditioning is currently preferred. The aim of this study was to investigate early and late outcomes in pediatric IEI patients receiving pre‐HSCT treosulfan and to examine the effect of treosulfan dose monitoring on outcomes. Methods: Seventy‐three pediatric patients receiving this management between 2015 and 2022 were included. Results: Overall survival rate was 80%, and event‐free survival was 67.8%. A larger treosulfan dose AUC after first application increased the rate of early toxicity (p =.034) and slowed lymphocyte engraftment (r =.290; p =.030). Underlying disease, treosulfan AUC, donor type, stem cell type, number of immunosuppressive agents, the dose of anti‐thymocyte globulin, and post‐transplantation cyclophosphamide did not to increase risk of acute graft‐versus‐host disease. The risk of mixed chimerism (MC) in patients with autoimmune lymphoproliferative syndrome and leukocyte adhesion deficiency were higher than those with severe combined immunodeficiency (p =.021 and p =.014, respectively). The risk of MC was lower in those receiving peripheral blood stem cells (SC) compared with bone marrow derived SC (OR =.204, p =.022). Conclusion: The AUC of the treosulfan dose was not associated with poorer late outcomes. Treosulfan is an agent that can be used safely in the IEI patient group, level measurement appears essential to identify early toxicities. Prospective studies with more extended follow‐up periods are needed. [ABSTRACT FROM AUTHOR]

Background: A few studies assessed the clinical and immunological features of selective IgM deficiency (SIgMD), especially in the pediatric age. We aimed to characterize the clinical and immunological phenotypes of a cohort of pediatric patients with SIgMD according to the different diagnostic criteria available. Methods: In this multicenter study, we evaluated pediatric SIgMD patients diagnosed at the Pediatric Clinic in Pavia, Italy, or through the Italian Primary Immunodeficiency NETwork (IPINET) and monitored changes in their diagnosis over a time frame that ranges from several months to several years. Results: Forty‐eight patients with SIgMD were included (mean serum IgM: 33 mg/dL). The most common clinical manifestations were recurrent infections (67%) and allergies (48%). Subgroup analysis according to SIgMD definition criteria of the European Society for Immunodeficiencies (ESID) showed no significant difference in clinical manifestations, also considering the group with additional immunological abnormalities. Sixteen patients had long‐term follow‐up, during which 87% preserved their SIgMD diagnosis, while two patients showed a reduction in IgA in addition to low IgM. Conclusions: Our data suggest that the identification of a reduction in serum IgM in children should lead to a complete immunological work‐up to obtain a comprehensive clinical and immunological characterization of the patient. The follow‐up of these patients is fundamental to define the disease evolution and appropriate management. [ABSTRACT FROM AUTHOR]

Selective Immunoglobulin M deficiency (SIgMD) has been recently included in the inborn errors of immunity (IEI) classification by the International Union of Immunological Societies Expert Committee. The understanding of SIgMD is still extremely limited, especially so in cases of SIgMD in the pediatric population. The epidemiology of SIgMD in the pediatric population is still unknown. The pathogenesis of SIgMD remains elusive, and thus far no genetic nor molecular basis has been clearly established as a definitive cause of this primary immunodeficiency. Recurrent respiratory infections represent the main clinical manifestations in children, followed by allergic and autoimmune diseases. No conclusive data on the correct therapeutic management of SIgMD are available. Although, for most SIgMD patients, Ig replacement therapy is not required, it may be recommended for patients with significantly associated antibody deficiency and recurrent or severe infections. Prophylactic antibiotics and the prompt treatment of febrile illness are crucial. There is insufficient evidence on the prognosis of this condition. Therefore, further studies are required to define the disease trajectories and to increase our understanding of the molecular mechanisms underlying SIgMD in order to facilitate a better clinical, immunological, and prognostic characterization of the condition and develop tailored therapeutic management strategies. [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription 3 (STAT3) is a key transcription factor involved in regulation of immune cell activation and differentiation. Recent discoveries highlight the role of germline activating STAT3 mutations in inborn errors of immunity characterized by early-onset multi-organ autoimmunity and lymphoproliferation. Much progress has been made in defining the clinical spectrum of STAT3 GOF disease and unraveling the molecular and cellular mechanisms underlying this disease. In this review, we summarize our current understanding of the disease and discuss the clinical phenotype, diagnostic approach, cellular and molecular effects of STAT3 GOF mutations and therapeutic concepts for these patients.