Gut Microbiota-Host Interactions in Inborn Errors of Immunity.

ABSTRACTHuman inborn errors of immunity (IEI) represent a diverse group of genetic disorders affecting the innate and/or adaptive immune system. Some IEI entities comprise defects in DNA repair factors, resulting in (severe) combined immunodeficiencies, bone marrow failure, predisposition to malignancies, and potentially result in radiosensitivity (RS). While other IEI subcategories such as common variable immunodeficiency (CVID) and immune dysregulation disorders also associate with lymphoproliferative and malignant complications, the occurrence of RS phenotypes in the broader IEI population is not well characterized. Nonetheless, identifying RS in IEI patients through functional testing is crucial to reconsider radiation-related therapeutic protocols and to improve overall patient management. This study aimed to investigate chromosomal RS in a diverse cohort of 107 IEI patients using the G0 cytokinesis-block micronucleus (MN) assay. Our findings indicate significant variability in RS across specific genetic and phenotypical subgroups. Severe RS was detected in all ataxia-telangiectasia (AT) patients, a FANCI deficient and ERCC6L2 deficient patient, but not in any other IEI patient included in this cohort. Age emerged as the single influencing factor for both spontaneous and radiation-induced MN yields, while the manifestation of additional clinical features, including infection susceptibility, immune dysregulation, or malignancies did not associate with increased MN levels. Our extensive analysis of RS in the IEI population underscores the clinical importance of RS assessment in AT patients and supports RS testing in all IEI patients suspected of having a DNA repair disorder associated with radiosensitivity.

The aim of this study was to screen for inborn errors of immunity (IEIs) within a pediatric critical care population and further evaluate the mortality-related factors.This study included 1203 pediatric patients aged between 1 month and 18 years admitted to the pediatric intensive care unit (PICU) at Antalya Education and Research Hospital (in Turkey) between January 2020 and December 2022. Patients with chronic diseases, ongoing chronic medication regimens, other known comorbidities, traumas, postsurgical cases, poisonings, and preexisting IEI diagnoses were excluded.In this single-center prospective study, a total of 28 warning signs for IEI diagnosis were applied, including 10 per the Jeffery Modell Foundation (JMF) and 18 per literature review. Patients with severe illness requiring intensive care and at least 1 IEI warning sign were evaluated. These patients underwent standardized immunological screening, then those with abnormal findings had an extended immunologic assessment including functional analyses. Genetic analyses were conducted on those with abnormal findings concerning for IEI. Diagnoses of IEI were established using the European Society for Immunodeficiencies criteria and further categorized based on the International Union of Immunological Societies classification.Of the 1203 patients admitted to the PICU, 75 (6.2%) patients had at least 1 IEI warning sign and no exclusionary diagnoses. This study found a 4.3% confirmed IEI prevalence rate in the PICU during the 3-year study period. More than half (51.5%) of these patients presented with sepsis, 36.4% with acute respiratory failure, and 12.1% with neuroinflammatory disorders. The median age was 16 months, and there was a male predominance (60.6%). Consanguinity was present in 66.7% of the patients. History of severe viral infections was the most common IEI warning sign (61%), followed by life-threatening infections (51.7%), sibling/cousin death (25%), and a history of more than 2 episodes of pneumonia per year (22.5%). Only 31% of patients had 2 or more of the JMF warning signs. Regarding types of IEIs identified, nearly half (48.5%) were diagnosed with an immune dysregulation disorder, with the most prominent IEI diagnosis being hemophagocytic lymphohistiocytosis. Combined immunodeficiencies were also commonly identified (24.2%), followed by defects in innate immunity (15.2%) and predominant antibody deficiencies (6.1%). Genetic testing was performed on 78.8% (26/33) of patients with an IEI diagnosis. Among the 33 patients with confirmed IEI, the mortality rate was 58%.Patients with IEI can present critically ill without classic warning signs and have a high mortality rate. This highlights the need for systematic screening to reach early diagnosis and treatment, especially in critically ill children.This study highlights a significant yet underrecognized prevalence of IEI in PICUs. The identification of IEI in nearly 1 in 20 critically ill children and reported high mortality rate of 58% emphasizes the need for earlier screening and detection with targeted immunologic/genetic evaluation. The study also found that only 31% of patients exhibited 2 or more JMF warning signs, suggesting a need for wider criteria, especially in the PICU. Limitations of the study include a single-center study in a country with high consanguinity, thus limiting generalizability. There was a small sample size of only 33 patients with new IEI diagnosis, and data were limited to their hospitalization without long-term follow-up related to mortality. Despite these limitations, this study reinforces that IEIs are more common than traditionally thought and general pediatricians, as well as PICU specialists, have a critical role in early suspicion, diagnosis, and seeking immunology consultation to reduce mortality and long-term morbidity.

Inborn errors of immunity (IEI), also referred to as primary immunodeficiencies (PID), are disorders that, for the most part, result from mutations in genes involved in immune host defense and immune regulation. With the increased availability of high-throughput DNA sequencing and improved genomic data interpretation, the number of newly identified genes associated with IEI has exponentially increased over the last decade. Here, we focus on the newly described IEI associated with severe COVID-19 and SASH3 deficiency, the most recently reported IEI with impaired T-cell receptor (TCR) signaling.

Objective: Inborn errors of immunity (IEI) are a diverse group of inherited diseases that affect the innate and adaptive immune systems, leading to symptoms and signs related to infections, autoimmunity, and allergies.There is a remarkable correlation between IEI and endocrinopathies.Our study aimed to retrospectively analyze the clinical, immunological, and endocrine features of our IEI patient group. Materials and Methods:We retrospectively reviewed medical records of IEI patients from our clinic.Results: Our study included 40 patients (23 men, 17 women) with a median age of 37 years (range:24-66).The predominant clinical phenotype observed was primary antibody deficiencies (92.5%).Only two patients had a genetic diagnosis: one with a pathogenic variant in the nuclear factor-kappaB2 deficiency (NFKB2) and another in Wiskott-Aldrich Syndrome (WAS) genes.At diagnosis, only one patient had endocrinopathies, but during the last visit 13 patients (32.5%) developed at least one endocrine pathology, among which thyroid disease was the most common.Thyroid disease was present in 11 patients (four with thyroid nodules, three with primary hypothyroidism, two with primary hypothyroidism and thyroid nodules, one with secondary hypothyroidism, one with Graves' disease).Additionally, adrenal insufficiency was observed in five patients and primary hypoparathyroidism was found in one patient.The patient diagnosed with NFKB2 deficiency was investigated for potential endocrine disorders that could accompany the genetic defect, despite the absence of clinical symptoms.The patient was subsequently diagnosed with central adrenal insufficiency following these investigations.Another patient in our study had primary adrenal insufficiency, primary hypoparathyroidism, thyroid nodule, and chronic mucocutaneous candidiasis.No mutations in the autoimmune regulatory and forkhead box protein P3 genes were detected in the targeted genome sequencing.Further genetic examination was planned for this patient. Conclusion:In our study, endocrinopathy was a frequent comorbidity observed in our IEI patients.We believe that establishing appropriate screening programs for endocrinopathies in IEI patients is crucial to guiding healthcare professionals.

Inborn errors of immunity (IEIs) are a heterogeneous group of germline disorders whose recognition is increasing but which remain underdiagnosed and associated with significant pediatric morbidity and mortality. This review aims to systematize the main neuroimaging manifestations of IEIs, addressing how neuroradiologists can identify characteristic patterns to support earlier diagnosis and guide clinical management. A narrative review of IEIs with neurological involvement was performed, focusing on reported primary and secondary neuroimaging features across major IEI categories. Imaging findings were correlated with underlying immune defects, typical clinical phenotypes, and their impact on diagnostic workup, risk assessment, and genetic counseling. IEIs demonstrate a broad neurological spectrum that extends beyond recurrent infections to encompass autoinflammatory, autoimmune, allergic, and malignant phenotypes with central nervous system involvement. Neuroimaging reveals both primary manifestations directly related to immune dysregulation and secondary features, allowing recognition of patterns in IEI subgroups that can provide crucial diagnostic clues in otherwise non-specific clinical scenarios. Neurological involvement in IEIs is not uncommon and may be radiologically detectable, making imaging an important ancillary tool in their evaluation. Systematic recognition of primary and secondary neuroimaging features by neuroradiologists can raise suspicion for an underlying IEI, prompting appropriate immunologic and genetic work-up. Earlier diagnosis is crucial to enable timely implementation of preventive or targeted therapies, with the potential to improve long-term outcomes.

Background: The determination of the prevalence and clinical relevance of allergic manifestations in individuals with human inborn errors of immunity (IEI) remains inadequately established. Here, our objective was to assess the allergic manifestations observed in patients diagnosed with IEI. Method: We evaluated allergic manifestations, including rhinitis, asthma, dermatitis, and venom, drug, and food allergies, in 220 adult patients with IEI. T and B cell subsets, the timing of allergy onset, skin test results, and drug hypersensitivity tests were assessed by using medical records and follow-up data. Results: Antibody deficiencies accounted for 85.9% of the cohort. Allergic rhinitis was the most frequent manifestation (21.8%), followed by asthma (15.9%), atopic dermatitis (12.3%), and drug hypersensitivity (10.9%). Food allergy was rare (0.9%), and no venom allergy was identified. Severe asthma was observed in two patients. Bronchiectasis was more frequent in the patients with asthma versus patients without asthma (28.6% versus 14.4%; p = 0.03). Asthma was more prevalent among patients receiving prophylactic antibiotics (34.1% in those receiving prophylactic antibiotics versus 11.7% in those not receiving prophylactic antibiotics; p = 0.001), and prophylaxis was more common in patients with asthma receiving treatment steps 3-5 than steps 1-2 (57.8% in patients at steps 3-5 versus 18.7% in patients at steps 1-2; p = 0.02). Among 28 drug hypersensitivity reactions in 24 patients (from 47 initially reported cases of patients after exclusion of predictable adverse reactions), immediate-type reactions predominated (78.6%), most commonly urticaria and anaphylaxis (each 21.4%). Among patients with allergic disease, 62% were diagnosed with allergy before IEI. The median (interquartile range) age at the IEI diagnosis was 28 years (18-38 years), and IEI diagnostic delay did not differ by allergy status. The interval between allergy and IEI diagnosis was longer when allergy preceded IEI (median 10 years; p = 0.01). Adult-onset asthma was associated with a higher age at IEI diagnosis (p = 0.004). Aeroallergen sensitization was associated with higher total, memory, and switched memory B cell counts (all p ≤ 0.01) and a higher switched memory B cell proportion (p = 0.04). Conclusion: Allergic manifestations are common in adults with IEI and often occur years before the diagnosis of immunodeficiency. Adult-onset asthma was associated with a higher age at IEI diagnosis, which suggests delayed recognition of underlying immune dysfunction in this subgroup. In addition, aeroallergen sensitization was associated with higher B cell subset counts, which highlights immunologic heterogeneity among adults with allergy and with IEI.

Introduction: Inborn errors of immunity (IEIs) are rare genetic disorders primarily identified in children due to their significant effects on immune system functionality. However, an increasing number of IEI cases are being diagnosed in adults, attributed to delayed presentation or advancements in diagnostic capabilities. This study explores the clinical and immunologic distinctions between IEIs diagnosed in adulthood versus childhood, shedding light on their differential presentations, the impact of diagnostic delays, and treatment outcomes. Methods: This study focused on 122 adult patients with IEI above 17 years old, diagnosed in adulthood or childhood. We collected comprehensive data on demographics, clinical presentations, genetic mutations, and therapeutic interventions. Results: The study revealed that 72.9% of participants were diagnosed in adulthood, facing a median diagnostic delay of 96 months. Diagnostic delays were longer in adults (132 months vs. 24 months) than in children. The most common clinical manifestations at onset were recurrent infections (46.7%) and autoimmunity (18%). Predominantly antibody deficiency was the most frequently diagnosed immunodeficiency (54.9%), followed by immunodysregulation at a rate of 26.2%. A higher incidence of immune thrombocytopenia or other complications, such as hepatomegaly and enteropathy, was observed in adult-diagnosed patients with IEI. Malignancies were more prevalent in patients with adult-onset IEI compared to those with childhood-onset (18.1% vs. 5.2%). Overall, 15 different malignancies were recorded in 13 patients (10.6%), including lymphomas and cancers of the stomach, thymus, skin, breast, and colon. Conclusions: The findings highlight a considerable diagnostic delay in recognizing IEI, especially in adults, and illustrate distinct differences in disease manifestation and progression between adult-onset and delayed-diagnosis groups.

The newborn screening program (NBS) plays a critical role in the development of the healthcare system of the Russian Federation. Since 2023, the Order No. 274n “On the approval of the Procedure for providing medical care to patients with congenital and/or hereditary diseases” has extended the scope of neonatal screening. The expanded newborn screening (ENS) includes detection of 36 nosological conditions. Among these, inborn errors of immunity (IEI) represent a significant and still extending group of genetic disorders characterized by increased susceptibility to infections due to underlying immunopathological mechanisms. At the initial stage, quantitative determination of T cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC) is performed for all newborns in order to identify individuals at risk and initiate confirmatory diagnostics. This approach enables the detection of IEI before the onset of clinical symptoms. This article presents and analyzes the results of ENS program for IEI conducted at the Northwestern Federal District (NWFD) during the period from 2023 to 2024. Over this two-year period, a total of 209,741 newborns were screened at the NWFD. Among them, 818 newborns (0.39% of those screened) were classified as high-risk IEI cases. The immunodeficiency states were identified for 45 children as based on immunophenotyping of peripheral blood lymphocytes (IFT), and genetic causes of the condition were confirmed in 49% of these cases. Statistical analysis revealed associations between gestational age and birth weight with TREC levels, and, to lesser extent, with KREC levels. The reference intervals were established for defined subgroups of neonates. These findings highlight the importance of continuous observation of newborns classified as moderate-risk cases. Notably, 9% of all screened individuals were designated as “conditionally healthy,” despite having TREC or KREC values below the lower reference limit. Based on the obtained data, the models for optimizing the screening program for IEI were proposed. These findings contribute to earlier diagnosis and more effective management of patients with immune disorders, as well as enhanced personalization of therapeutic strategies. Establishing population-based reference intervals plays a key role in standardizing methods for diagnostics and monitoring the immune system, thus representing an important step in overall advances of healthcare.

Objective: Inborn errors of immunity (IEIs) comprise a genetically heterogeneous group of disorders predisposing individuals to recurrent and severe infections, autoimmunity, and immune dysregulation. Next-generation sequencing (NGS) has greatly improved diagnostic efficiency by allowing simultaneous analysis of multiple genes. This study aimed to evaluate the molecular diagnostic yield and characterize the variant spectrum in patients with suspected IEIs using a targeted NGS panel. Methods: A total of 101 pediatric patients clinically diagnosed with IEIs and referred to the Pediatric Genetics Department Ümraniye Training and Research Hospital between 2018 and 2021 were included in the study. Genetic analysis was performed using a targeted NGS panel encompassing 260 genes associated with IEIs. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) and Clinical Genome (ClinGen) Sequence Variant Interpretation (SVI) guidelines. Single-nucleotide variants (SNVs) were confirmed by Sanger sequencing, and copy number variants (CNVs) were validated using array-based comparative genomic hybridization (array-CGH). Results: Pathogenic or likely pathogenic (P/LP) variants were identified in 25 of 101 patients (24.7%), yielding 26 distinct variants across 21 genes, including one patient with two variants in a compound heterozygous state. Among these, 18 were homozygous, 3 heterozygous, 3 hemizygous, and 1 compound heterozygous. The most frequently affected genes were RAG1, DCLRE1C, SPINK5, and STAT1. Three novel variants were identified, expanding the known mutational spectrum of IEIs. In addition, several variants initially identified in this cohort were later reported by our group, highlighting the contribution of our study to the expanding genetic spectrum of IEIs in Türkiye. Most variants exhibited autosomal recessive inheritance, consistent with the high consanguinity rate in the study population. Conclusion: In our IEI cohort, targeted NGS achieved a 24.7% molecular diagnostic yield and successfully identified both known and novel pathogenic variants across a broad spectrum of genes. These findings highlight the diagnostic value of targeted NGS in genetically and clinically heterogeneous conditions such as IEIs and underscore the importance of population-specific variant databases for improving variant interpretation and optimizing patient care.

New technologies in genetic diagnostics have revolutionized the understanding and management of rare diseases. This review highlights the significant advances and latest developments in genetic diagnostics in inborn errors of immunity (IEI), which encompass a diverse group of disorders characterized by defects in the immune system, leading to increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergies, and malignancies. Various diagnostic approaches, including targeted gene sequencing panels, whole exome sequencing, whole genome sequencing, RNA sequencing, or proteomics, have enabled the identification of causative genetic variants of rare diseases. These technologies not only facilitated the accurate diagnosis of IEI but also provided valuable insights into the underlying molecular mechanisms. Emerging technologies, currently mainly used in research, such as optical genome mapping, single cell sequencing or the application of artificial intelligence will allow even more insights in the aetiology of hereditary immune defects in the near future. The integration of genetic diagnostics into clinical practice significantly impacts patient care. Genetic testing enables early diagnosis, facilitating timely interventions and personalized treatment strategies. Additionally, establishing a genetic diagnosis is necessary for genetic counselling and prognostic assessments. Identifying specific genetic variants associated with inborn errors of immunity also paved the way for the development of targeted therapies and novel therapeutic approaches. This review emphasizes the challenges related with genetic diagnosis of rare diseases and provides future directions, specifically focusing on IEI. Despite the tremendous progress achieved over the last years, several obstacles remain or have become even more important due to the increasing amount of genetic data produced for each patient. This includes, first and foremost, the interpretation of variants of unknown significance (VUS) in known IEI genes and of variants in genes of unknown significance (GUS). Although genetic diagnostics have significantly contributed to the understanding and management of IEI and other rare diseases, further research, exchange between experts from different clinical disciplines, data integration and the establishment of comprehensive guidelines are crucial to tackle the remaining challenges and maximize the potential of genetic diagnostics in the field of rare diseases, such as IEI.

In this study, we retrospectively reviewed the use of flow cytometry (FCM) in the diagnosis of inborn errors of immunity (IEIs) at a single center in Algeria. Sharing insights into our practical experience, we present FCM based diagnostic approaches adapted to different clinical scenarios. Between May 2017 and February 2024, pediatric and adult patients presenting with clinical features suggestive of immunodeficiency were subjected to FCM evaluation, including lymphocyte subset analysis, detection of specific surface or intracellular proteins, and functional analysis of immune cells. Over a nearly seven-year period, our laboratory diagnosed a total of 670 patients (372 (55.5%) males and 298 (44.5%) females), distributed into 70 different IEIs belonging to 9 different categories of the International Union of Immunological Societies classification. FCM was used to diagnose and categorize IEI in 514 patients (76.7%). It provided direct diagnostic insights for IEIs such as severe combined immunodeficiency, Omenn syndrome, MHC class II deficiency, familial hemophagocytic lymphohistiocytosis, and CD55 deficiency. For certain IEIs, including hyper-IgE syndrome, STAT1-gain of function, autoimmune lymphoproliferative syndrome, and activated PI3K delta syndrome, FCM offered suggestive evidence, necessitating subsequent genetic testing for confirmation. Protein expression and functional assays played a crucial role in establishing definitive diagnoses for various disorders. To setup such diagnostic assays at high and reproducible quality, high level of expertise is required; in house reference values need to be determined and the parallel testing of healthy controls is highly recommended. Flow cytometry has emerged as a highly valuable and cost-effective tool for diagnosing and studying most IEIs, particularly in low-income countries where access to genetic testing can be limited. FCM analysis could provide direct diagnostic insights for most common IEIs, offer clues to the underlying genetic defects, and/or aid in narrowing the list of putative genes to be analyzed.

Inborn errors of immunity (IEIs) are genetic disorders that impair immune defense and regulation, increasing susceptibility to infections, including those in the oral cavity. The oral microbiota plays a vital role in maintaining oral health, and in pediatric patients with IEIs, disruptions in this balance can lead to dental caries and other oral diseases. This chapter provides a comprehensive analysis of the relationship between immune deficiencies and oral microbiota dysbiosis, focusing on dental caries in children with IEIs. Omics technologies, particularly metagenomics, have enhanced understanding of the microbial diversity and metabolic activities within the oral microbiota of the patients. Key findings reveal that compromised immune responses in children with IEIs disrupt the balance of oral bacteria, making them more prone to dental caries. The chapter highlights the importance of an interdisciplinary approach, integrating microbiology, immunology, dentistry, and bioinformatics, to uncover the complex interactions between the oral microbiome and the immune system. The insights gained from this research will contribute to the development of personalized therapeutic strategies, improving the dental and overall health of pediatric patients with IEIs.

Keeping up with recent developments in immunodeficiency.

Inborn errors of immunity (IEIs) are a frequently underdiagnosed group of disorders, with infectious complications posing significant clinical challenges. Recognizing atypical presentations of common infections and the presence of rare opportunistic pathogens can be critical in suspecting an underlying IEI. Among the infectious complications, chronic viral infections are particularly difficult to manage due to limited evidence-based guidelines. Intra-host viral evolution in these patients can lead to treatment resistance and the emergence of novel viral strains, raising concerns about their potential role as reservoirs for mutant viruses. Novel pathogens such as Aichivirus have been identified as significant causes of infection in individuals with IEIs. Furthermore, infections such as talaromycosis, tuberculosis, BCG-related disease, leishmaniasis, and melioidosis may be underrecognized in certain groups of patients with IEIs, largely due to differences in geographic exposure and environmental risk factors. The effects of emerging infections, such as mpox and Middle East respiratory syndrome coronavirus, on individuals with IEIs remain largely unknown. Management strategies for infections in this population include vaccinations, immunoglobulin replacement, and antimicrobial prophylaxis. However, newer higher valency conjugate pneumococcal vaccines may limit the utility of traditional pneumococcal polysaccharide vaccines in assessing immune function. While immunoglobulin replacement is cost-effective, it can interfere with serological diagnostics. Additionally, antimicrobial resistance is a growing issue, emphasizing the need for improved empiric antibiotic strategies and research into optimal treatment durations. This review highlights the key challenges faced by infectious disease clinicians in the care of patients with IEIs.

Inborn Errors of Immunity (IEIs) are rare genetic disorders that cause immunodeficiency. Diagnosis and classification of these disorders are challenging due to the heterogeneous clinical manifestations and genetic mutations. This is the first study to fully describe the spectrum of gene mutations and genetic diversity of IEIs in Vietnamese pediatric patients. A cross-sectional study was conducted on pediatric patients diagnosed with IEIs at Children’s Hospital 1, Vietnam, from 2014 to 2024. Ninety-two patients with identified mutations were enrolled. Genetic testing was performed using Sanger, fluorescence in situ hybridization, and whole exome sequencing to identify pathogenic variants. Clinical and epidemiological data were collected from medical records and mutations were classified according to the IUIS 2024 classification. The study identified 99 mutations in 33 different genes, with X-linked inheritance being predominant (53.2%). The antibody deficiency and immune dysregulation groups were the most common (22.8% for each mutation). Nineteen novel mutations were identified, all of which were predictively classified as pathogenic or likely pathogenic. The majority of mutations caused protein truncations, leading to loss of function, especially in the immunodeficiencies affecting cellular and humoral immunity and the phagocyte disorder groups. Clinical manifestations differed markedly between the different gene groups, highlighting the complexity of diagnosing IEIs. The number of cases with mutations causing X-linked inheritance was dominant, which was similar to studies from Asian countries, though different from studies from Africa due to the rates of consanguineous marriage. In addition, the variability between clinical phenotype and genotype in IEIs noted from our study has been a significant obstacle to the classification of diseases and their efficient treatment. This is the largest single center cohort to date in Vietnam to describe gene mutations in children with IEIs. The results of the study emphasize the importance of genetic testing in the diagnosis and treatment of IEIs, and open possible directions for further research for novel mutations.