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BackgroundDedicator of cytokinesis 8 (DOCK8) deficiency is the main cause of the autosomal recessive hyper-IgE syndrome (HIES). We previously reported the selective loss of group 3 innate lymphoid cell (ILC) number and function in a Dock8-deficient mouse model. In this study, we sought to test whether DOCK8 is required for the function and maintenance of ILC subsets in humans.MethodsPeripheral blood ILC1-3 subsets of 16 DOCK8-deficient patients recruited at the pretransplant stage, and seven patients with autosomal dominant (AD) HIES due to STAT3 mutations, were compared with those of healthy controls or post-transplant DOCK8-deficient patients (n = 12) by flow cytometry and real-time qPCR. Sorted total ILCs from DOCK8- or STAT3-mutant patients and healthy controls were assayed for survival, apoptosis, proliferation, and activation by IL-7, IL-23, and IL-12 by cell culture, flow cytometry, and phospho-flow assays.ResultsDOCK8-deficient but not STAT3-mutant patients exhibited a profound depletion of ILC3s, and to a lesser extent ILC2s, in their peripheral blood. DOCK8-deficient ILC1-3 subsets had defective proliferation, expressed lower levels of IL-7R, responded less to IL-7, IL-12, or IL-23 cytokines, and were more prone to apoptosis compared with those of healthy controls.ConclusionDOCK8 regulates human ILC3 expansion and survival, and more globally ILC cytokine signaling and proliferation. DOCK8 deficiency leads to loss of ILC3 from peripheral blood. ILC3 deficiency may contribute to the susceptibility of DOCK8-deficient patients to infections.

Aim: Primary immunodeficiencies (PIDs) are a heterogeneous disorder group characterized by an impaired immune system, leading to an increased susceptibility to infections and a wide range of clinical manifestations, including gastrointestinal (GI) complications. This study aimed to assess the GI manifestations of PID patients and highlight the significance of atypical gastrointestinal symptoms in the early diagnosis of these patients. Methods: A retrospective analysis was conducted on pediatric patients diagnosed with PIDs at Selcuk University Medical Faculty from 2011 to 2021. The study focused on demographic data, clinical presentation, genetic mutations, and GI manifestations, including endoscopic evaluation. Patients were categorized according to the International Union of Immunological Societies (IUIS) PID classifications. Statistical analyses were performed to identify significant associations between PID types and GI manifestations. Results: The cohort comprised 101 patients, with 46% presenting with GI symptoms, including malnutrition and chronic diarrhea, as the most common findings. Primary antibody deficiency (PAD) emerged as the most prevalent PID with GI involvement, followed by combined immunodeficiencies (CID) with associated or syndromic features. Endoscopic evaluations revealed inflammatory bowel disease (IBD)-like colitis in a significant subgroup of patients. The analysis showed that some GI symptoms were more common in specific PID categories, highlighting the importance of early gastroenterological assessment in PID patients. Conclusion: Recognition of common GI symptoms in pediatric patients with PIDs may facilitate early diagnosis and prompt multidisciplinary management, potentially improving patient outcomes. The study highlights the necessity of considering PIDs in diagnosing persistent or severe GI symptoms in children. [ABSTRACT FROM AUTHOR]

Purine nucleoside phosphorylase (PNP) deficiency is a rare immunodeficiency syndrome generally characterized by profound T cell deficiency and variable B cell function. More than half of PNP-deficient patients present with neurological dysfunction, with manifestations such as mental and motor retardation, spasticity, hypertonia, ataxia, and behavioral disturbances. Here, we report two siblings diagnosed with PNP deficiency in early infancy. Our patients had developmental delays, and their immunological findings indicated T-B+NK+ leaky/atypical severe combined immune deficiency. The patients are being treated with regular intravenous immunoglobulin replacement, as well as trimethoprim-sulfomethoxazole and fluconazole, for prophylaxis in preparation for transplantation. These cases draw attention to the possibility of primary immune deficiency in patients with recurrent infections and lymphopenia. In addition, PNP deficiency should be kept in mind in the presence of developmental delay, low uric acid levels, and lymphopenia. [ABSTRACT FROM AUTHOR]

BackgroundPrimary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions.ObjectiveWe sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs.MethodsPatients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping.ResultsA likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays.ConclusionThis high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.

Objective: Although there has been increased attention in recent years to the relationship between allergic disease and obesity, there is limited information about allergic rhinitis (AR) and central obesity. The aim of this study is to investigate the relationship between central obesity and rhinitis severity in patients with rhinitis and controls. Materials and Methods: A total of 164 children, aged 7-17 years, were included in the study between 2020 and 2021. Three groups were formed: AR, non-allergic rhinitis (NAR), and the control group. The height, weight, waist, hip, neck, and arm circumference of the groups were measured. The BMI, waist-to-hip ratio, waist-to-height ratio, and conicity index were calculated. Eosinophil and neutrophil counts, IgE levels, and allergic sensitization were recorded. Anthropometric measurements, rhinitis severity, and persistence were compared among the groups. Results: The study included a total of 164 children: 63 with AR, 51 with NAR, and 50 in the control groups of the children included in the study, 71 (43.3%) were boys, and 93 (56.7%) were girls. Approximately 30% of children with normal BMI were evaluated as centrally obese despite having a normal weight. Rhinitis patients had a higher prevalence of central obesity compared to the control group. When comparing both persistence and disease severity, central obesity was higher in AR patients than in NAR patients. The AR group had higher BMI, arm circumference, waist circumference, and neck circumference than the control group (p=0.003, p=0.01, 0.001, 0.004, respectively), while the waist-to-height ratio was higher in both the AR and NAR groups compared to the control group (p=0.001, p=0.026). Conclusion: In this study, central obesity was significantly higher in patients with AR and NAR than in the control group although there was no significant difference in obesity between the groups according to BMI. Additionally, centrally obese AR patients exhibited higher persistence and disease severity compared to NAR patients. In conclusion, other obesity indicators such as waist circumference should be measured in addition to height and body weight in children with AR and NAR. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 3-month-old patient with congenital non-bullous ichthyosiform erythroderma, initially misdiagnosed as Omenn syndrome but later identified with Desmoglein-1 (DSG1) deficiency. Topics discussed include the diagnostic process, the clinical features distinguishing DSG1 deficiency from Omenn syndrome, and the treatment approach including immunoglobulin replacement therapy and retinoid treatment.

The aim of this study was to evaluate the role of T- and B-regulatory cells (Tregs and Bregs) in the pathogenesis of idiopathic granulomatous mastitis (IGM). This study includes 47 patients with pathologically proven IGM (Group P) and 26 healthy subjects (Group C). The patients in Group P were divided into two groups according to whether their lesions were active (Group PA, n: 21) or in remission (Group PR, n: 26). By using flow-cytometry, the frequencies of CD3+CD4+CD45RA−Foxp3high activated Tregs (aTregs), CD3+CD4+CD45RA−Foxp3low non-suppressive Tregs, CD3+CD4+CD45RA+Foxp3low resting Tregs (rTregs), CD3+CD4+CD25+Foxp3− T-effector cells (Teff), total Tregs and Bregs were analyzed in all subjects. The frequency of the Teff cells was statistically higher in Group P when compared with Group C (p =.004). The Foxp3 expression of Treg cells and the frequency of non-suppressive Tregs in Group P were statistically lower than Group C (p =.032 and p =.02, respectively). In addition, Group PR's Foxp3 expressions were statistically lower than Group C (p =.027); Group PR's aTregs ratio was statistically lower than Group PA (p =.021); and the non-suppressive Tregs ratio of Group PR was lower than both Group PA and Group C (p =.006 and p <.0001). No significant differences were seen Bregs and B cell subsets. Significant changes in Foxp3 expression and Treg subsets were seen in patients with active IGM lesion and in remission. This study shows an intrinsic defect of Tregs in patients with IGM. [ABSTRACT FROM AUTHOR]

The novel coronavirus disease 2019 (COVID‐19) remains a global health emergency, and understanding the interactions between the virus and host immune responses is crucial to preventing its lethal effects. The expansion of myeloid‐derived suppressor cells (MDSCs) in COVID‐19, thereby suppressing immune responses, has been described as responsible for the severity of the disease, but the correlation between MDSC subsets and COVID‐19 severity remains elusive. Therefore, we classified patients according to clinical and laboratory findings—aiming to investigate the relationship between MDSC subsets and laboratory findings such as high C‐reactive protein, ferritin and lactate dehydrogenase levels, which indicate the severity of the disease. Forty‐one patients with COVID‐19 (26 mild and 15 severe; mean age of 49.7 ± 15 years) and 26 healthy controls were included in this study. MDSCs were grouped into two major subsets—polymorphonuclear MDSCs (PMN‐MDSCs) and monocytic MDSCs—by flow cytometric immunophenotyping, and PMN‐MDSCs were defined as mature and immature, according to CD16 expressions, for the first time in COVID‐19. Total MDSCs, PMN‐MDSCs, mature PMN‐MDSCs and monocytic MDSCs were significantly higher in patients with COVID‐19 compared with the healthy controls (P <.05). Only PMN‐MDSCs and their immature PMN‐MDSC subsets were higher in the severe subgroup than in the mild subgroup. In addition, a significant correlation was found between C‐reactive protein, ferritin and lactate dehydrogenase levels and MDSCs in patients with COVID‐19. These findings suggest that MDSCs play a role in the pathogenesis of COVID‐19, while PMN‐MDSCs, especially immature PMN‐MDSCs, are associated with the severity of the disease. [ABSTRACT FROM AUTHOR]

Background: Genetic deficiencies of immune system, referred to as inborn errors of immunity (IEI), serve as a valuable model to study human immune responses. In a multicenter prospective cohort, we evaluated the outcome of SARS‐CoV‐2 infection among IEI subjects and analyzed genetic and immune characteristics that determine adverse COVID‐19 outcomes. Methods: We studied 34 IEI patients (19M/15F, 12 [min: 0.6‐max: 43] years) from six centers. We diagnosed COVID‐19 infection by finding a positive SARS‐CoV‐2 PCR test (n = 25) and/or a lung tomography scoring (CORADS) ≥4 (n = 9). We recorded clinical and laboratory findings prospectively, fitted survival curves, and calculated fatality rates for the entire group and each IEI subclass. Results: Nineteen patients had combined immune deficiency (CID), six with predominantly antibody deficiency (PAD), six immune dysregulation (ID), two innate immune defects, and one in the autoinflammatory class. Overall, 23.5% of cases died, with disproportionate fatality rates among different IEI categories. PAD group had a relatively favorable outcome at any age, but CIDs and IDs were particularly vulnerable. At admission, presence of dyspnea was an independent risk for COVID‐related death (OR: 2.630, 95% CI; 1.198–5.776, p <.001). Concerning predictive roles of laboratory markers at admission, deceased subjects compared to survived had significantly higher CRP, procalcitonin, Troponin‐T, ferritin, and total‐lung‐score (p =.020, p =.003, p =.014, p =.013, p =.020; respectively), and lower absolute lymphocyte count, albumin, and trough IgG (p =.012, p =.022, p =.011; respectively). Conclusion: Our data disclose a highly vulnerable IEI subgroup particularly disadvantaged for COVID‐19 despite their youth. Future studies should address this vulnerability and consider giving priority to these subjects in SARS‐Cov‐2 therapy trials. [ABSTRACT FROM AUTHOR]