Phenotypic and Immunological Characterization of Patients with Activated PI3Kδ Syndrome 1 Presenting with Autoimmunity.

PURPOSE: Autoimmunity is a significant feature of APDS1 patients. We aimed to explore the pathogenic immune phenotype and possible mechanisms of autoimmunity in APDS1 patients. METHODS: The clinical records and laboratory data of 42 APDS1 patients were reviewed. Immunophenotypes were evaluated by multiparametric flow cytometry. Autoantibodies were detected via antigen microarray analysis. RESULTS: A total of 42 children with PIK3CD gene mutations were enrolled. Immunological tests revealed increased proportions of effector memory cells (86%) and central memory cells (59%) among CD4+ T cells; increased proportions of effector memory cells (83%) and terminally differentiated effector memory T cells (38%) among CD8+ T cells. Fewer CD3+ T cells and B cells and higher IgG levels were reported in patients with autoimmunity. The proportion of Tregs was decreased, and the proportions of Th9, Tfh, and Tfr cells were increased in APDS1 patients. Among APDS1 patients, higher proportion of Th2 and Tfr cells were found in those with autoimmunity. The proportions of CD11c+ B and CD21lo B cells in patients with autoimmunity were significantly increased. Antigen microarray analysis revealed a wide range of IgG/IgM autoantibodies in patients with APDS1. In patients with autoimmunity, the proportion of Tfr might be positively correlated with autoantibodies. CONCLUSIONS: The pathogenic immune phenotype of APDS1 patients included (1) deceased CD3+ T-cell and B-cell counts and increased IgG levels in patients with autoimmunity, (2) an imbalanced T helper cell subset, (3) increased proportions of autoreactive B cells, and (4) distinct autoantibody reactivities in patients with autoimmunity.

Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria.

Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ.

Diagnosis of mixed infection and a primary immunodeficiency disease using next-generation sequencing: a case report.

Major Histocompatibility Complex Class II (MHC II) deficiency is a rare primary immunodeficiency disorder (PID) with autosomal recessive inheritance pattern. The outcome is almost fatal owing to delayed diagnosis and lacking of effective therapy. Therefore, prompt diagnosis, timely and effective treatment are critical. Here, we report a 117-day-old boy with diarrhea, cough, cyanosis and tachypnea who was failed to be cured by empiric antimicrobial therapy initially and progressed to severe pneumonia and respiratory failure. The patient was admitted to the pediatric intensive care unit (PICU) immediately and underwent a series of tests. Blood examination revealed elevated levels of inflammatory markers and cytomegalovirus DNA. Imaging findings showed signs of severe infection of lungs. Finally, the diagnosis was obtained mainly through next-generation sequencing (NGS). We found out what pathogenic microorganism he was infected via repeated conventional detection methods and metagenomic next-generation sequencing (mNGS) of sputum and bronchoalveolar lavage fluid (BALF). And his whole exome sequencing (WES) examination suggested that CIITA gene was heterozygous mutation, a kind of MHC II deficiency diseases. After aggressive respiratory support and repeated adjustment of antimicrobial regimens, the patient was weaned from ventilator on the 56th day of admission and transferred to the immunology ward on the 60th day. The patient was successful discharged after hospitalizing for 91 days, taking antimicrobials orally to prevent infections post-discharge and waiting for stem cell transplantation. This case highlights the potential importance of NGS in providing better diagnostic testing for unexplained infection and illness. Furthermore, pathogens would be identified more accurately if conventional detection techniques were combined with mNGS.

Diagnostic Performance and Clinical Impact of Metagenomic Next-Generation Sequencing for Pediatric Infectious Diseases.

Metagenomic next-generation sequencing (mNGS) has shown promise in the diagnosis of infectious diseases in adults, while its efficacy in pediatric infections remains uncertain. We performed a retrospective analysis of 1,493 mNGS samples from pediatric patients with blood, central nervous system, and lower respiratory tract infections. The positive percent agreement (PPA) and the negative percent agreement (NPA) of mNGS were compared to conventional microbiological tests (CMT) based on clinical diagnosis. The agreement of mNGS compared to CMT, as well as the clinical impact of mNGS, were valuated. Using the clinical diagnosis as a reference, mNGS demonstrated a significantly higher overall PPA compared to CMT (53.1% [95% CI = 49.7 to 56.6%] versus 25.8% [95% CI = 22.8 to 28.9%]), while maintaining a comparable overall NPA (93.2% [95% CI = 91.3 to 95.1%] versus 97.2% [95% CI = 95.9 to 98.4%]). In septic patients under 6 years of age or with immunosuppressive status, mNGS showed a higher PPA and a comparable NPA compared to CMT. The overall PPA and NPA of mNGS compared to CMT were 75.3 and 75.0%, respectively. The majority of cases of Streptococcus pneumoniae, Streptococcus agalactiae, Mycobacterium tuberculosis complex, and Pneumocystis jirovecii infections were identified by mNGS. A positive clinical impact of 14.0% (206/1,473), a negative impact of 0.8% (11/1,473), a nonimpact of 84.7% (1,248/1,473), and an unknown impact of 0.5% (8/1,473) were observed in the mNGS results. Notably, the positive impact was greater among immunosuppressed patients than among nonimmunosuppressed individuals (67/247, 27.1% versus 139/1,226, 11.3%; P < 0.001). mNGS is valuable for pathogen detection, diagnosis, and clinical management of infections among pediatric patients. mNGS was thus effective for the diagnosis of pediatric infections, which may guide clinical management. Patients with immunosuppressive conditions benefited more from mNGS testing.

A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency.

Interferon regulatory factor 4 (IRF4) is a transcription factor (TF) and key regulator of immune cell development and function. We report a recurrent heterozygous mutation in IRF4, p.T95R, causing an autosomal dominant combined immunodeficiency (CID) in seven patients from six unrelated families. The patients exhibited profound susceptibility to opportunistic infections, notably Pneumocystis jirovecii, and presented with agammaglobulinemia. Patients' B cells showed impaired maturation, decreased immunoglobulin isotype switching, and defective plasma cell differentiation, whereas their T cells contained reduced TH17 and TFH populations and exhibited decreased cytokine production. A knock-in mouse model of heterozygous T95R showed a severe defect in antibody production both at the steady state and after immunization with different types of antigens, consistent with the CID observed in these patients. The IRF4T95R variant maps to the TF's DNA binding domain, alters its canonical DNA binding specificities, and results in a simultaneous multimorphic combination of loss, gain, and new functions for IRF4. IRF4T95R behaved as a gain-of-function hypermorph by binding to DNA with higher affinity than IRF4WT. Despite this increased affinity for DNA, the transcriptional activity on IRF4 canonical genes was reduced, showcasing a hypomorphic activity of IRF4T95R. Simultaneously, IRF4T95R functions as a neomorph by binding to noncanonical DNA sites to alter the gene expression profile, including the transcription of genes exclusively induced by IRF4T95R but not by IRF4WT. This previously undescribed multimorphic IRF4 pathophysiology disrupts normal lymphocyte biology, causing human disease.

Severe G6PD deficiency leads to recurrent infections and defects in ROS production: Case report and literature review.

Purpose: Severe glucose-6-phosphate dehydrogenase (G6PD) deficiency can lead to reduced nicotinamide adenine dinucleotide phosphate oxidase activity in phagocytes, resulting in immunodeficiency, with a limited number of reported cases. Here, we aimed to report a child with severe G6PD deficiency in China and investigate the mechanism of his recurrent infections. Methods: The clinical manifestations and immunological phenotypes of this patient were retrospectively collected. Gene mutation was detected by whole-exome sequencing and confirmed by Sanger sequencing. Dihydrorhodamine (DHR) analysis was performed to measure the respiratory burst of neutrophils. Messenger ribonucleic acid and protein levels were detected in the patient under lipopolysaccharide stimulation by real-time quantitative reverse transcription polymerase chain reaction and Western blot. A review of the literature was performed. Results: A male child with G6PD deficiency presented with recurrent respiratory infections, Epstein‒Barr virus infection and tonsillitis from 8 months of age. Gene testing revealed that the proband had one hemizygous mutation in the G6PD gene (c.496 C>T, p. R166C), inherited from his mother. This mutation might affect hydrophobic binding, and the G6PD enzyme activity of the patient was 0. The stimulation indexes of the neutrophils in the patient and mother were 22 and 37, respectively. Compared with healthy controls, decreased reactive oxygen species (ROS) production was observed in the patient. Activation of nuclear factor kappa-B (NF-κB) signaling was found to be influenced, and the synthesis of tumor necrosis factor alpha (TNF-α) was downregulated in the patient-derived cells. In neutrophils of his mother, 74.71% of the X chromosome carrying the mutated gene was inactivated. By performing a systematic literature review, an additional 15 patients with severe G6PD deficiency and recurrent infections were identified. Four other G6PD gene mutations have been reported, including c.1157T>A, c.180_182del, c.514C>T, and c.953_976del. Conclusion: Severe G6PD deficiency, not only class I but also class II, can contribute to a chronic granulomatous disease-like phenotype. Decreased reactive oxygen species synthesis led to decreased activation of the NF-κB pathway in G6PD-deficient patients. Children with severe G6PD deficiency should be aware of immunodeficiency disease, and the DHR assay is recommended to evaluate neutrophil function for early identification.

Rapid diagnosis of Talaromyces marneffei infection by metagenomic next-generation sequencing technology in a Chinese cohort of inborn errors of immunity.

Talaromyces marneffei (T. marneffei) is an opportunistic pathogen. Patients with inborn errors of immunity (IEI) have been increasingly diagnosed with T. marneffei in recent years. The disseminated infection of T. marneffei can be life-threatening without timely and effective antifungal therapy. Rapid and accurate pathogenic microbiological diagnosis is particularly critical for these patients. A total of 505 patients with IEI were admitted to our hospital between January 2019 and June 2022, among whom T. marneffei was detected in 6 patients by metagenomic next-generation sequencing (mNGS), and their clinical and immunological characteristics were summarized. We performed a systematic literature review on T. marneffei infections with published immunodeficiency-related gene mutations. All patients in our cohort were confirmed to have genetic mutations in IL12RB1, IFNGR1, STAT1, STAT3, and CD40LG. T. marneffei was detected in both the blood and lymph nodes of P1 with IL12RB1 mutations, and the clinical manifestations were serious and included recurrent fever, weight loss, severe anemia, splenomegaly and lymphadenopathy, all requiring long-term antifungal therapy. These six patients received antifungal treatment, which relieved symptoms and improved imaging findings. Five patients survived, while one patient died of sepsis after hematopoietic stem cell transplantation. The application of mNGS methods for pathogen detection in IEI patients and comparison with traditional diagnosis methods were investigated. Traditional diagnostic methods and mNGS tests were performed simultaneously in 232 patients with IEI. Compared to the traditional methods, the sensitivity and specificity of mNGS in diagnosing T. marneffei infection were 100% and 98.7%, respectively. The reporting time for T. marneffei detection was approximately 26 hours by mNGS, 3-14 days by culture, and 6-11 days by histopathology. T. marneffei infection was first reported in IEI patients with IL12RB1 gene mutation, which expanded the IEI lineage susceptible to T. marneffei. For IEI patients with T. marneffei infection, we highlight the application of mNGS in pathogenic detection. mNGS is recommended as a front-line diagnostic test for rapidly identifying pathogens in complex and severe infections.

Chromosomal abnormalities related to fever of unknown origin in a Chinese pediatric cohort and literature review.

BACKGROUND: Fever of unknown origin (FUO) has been difficult to diagnose in pediatric clinical practice. With the gradual change in the disease spectrum, genetic factors have received increasing attention. Limited studies have shown an association between FUO and chromosomal abnormalities. In this study, we investigated the clinical and genetic characteristics of patients with FUO presenting with chromosomal abnormalities in a Chinese pediatric cohort. RESULTS: Chromosomal abnormalities were detected in 5.5% (8/145) of the patients with FUO. Six patients with inflammatory fever presented with pharyngitis/amygdalitis (4/6), oral aphthous ulcer (2/6), digestive symptoms (3/6), developmental delay (4/6) and elevated C-reactive protein levels (6/6) during fever. These patients were often considered to have systemic inflammatory diseases, such as Behcet's disease or systemic juvenile idiopathic arthritis. Trisomy 8, 7q11.23 dup, 3p26.3-p26.1 del/17q12 dup, 22q11.21 del, and 6q23.3-q24.1 del were identified in patients with inflammatory fever. The TNFAIP3 gene was included in the 6q23.3-q24.1 deletion fragment. Two patients with central fever were characterized by facial anomalies, developmental delay, seizures and no response to antipyretic drugs and were identified as carrying the de novo 18q22.3-q23 del. By performing a literature review, an additional 19 patients who had FUO and chromosomal abnormalities were identified. Trisomy 8, 6q23.2-q24.3 del and 18q22.3-q23 del were reported to present as fever, similar to the findings of our study. CONCLUSIONS: We emphasized the important role of detecting chromosomal abnormalities in patients with FUO, especially in patients with systemic inflammatory manifestations or developmental delay. Identifying chromosomal abnormalities may change the diagnosis and management of patients with FUO.

Cellular Mechanisms Underlying B Cell Abnormalities in Patients With Gain-of-Function Mutations in the PIK3CD Gene.

Background: Activated phosphoinositide 3 kinase (PI3K) -delta syndrome (APDS) is an inborn error of immunity with variable clinical phenotype of immunodeficiency and immune dysregulation and caused by gain-of-function mutations in PIK3CD. The hallmark of immune phenotype is increased proportions of transitional B cells and plasmablasts (PB), progressive B cell loss, and elevated levels of serum IgM. Objective: To explore unique B cell subsets and the pathomechanisms driving B cell dysregulation beyond the transitional B cell stage in APDS. Methods: Clinical and immunological data was collected from 24 patients with APDS. In five cases, we performed an in-depth analysis of B cell phenotypes and cultured purified naïve B cells to evaluate their survival, activation, Ig gene class switch recombination (CSR), PB differentiation and antibody secretion. We also analyzed PB differentiation capacity of sorted CD27-IgD- double-negative B (DNB) cells. Results: The patients had increased B cell sizes and higher proportions of IgM+ DNB cells than healthy controls (HC). Their naïve B cells exhibited increased death, impaired CSR but relatively normal PB differentiation. Upon stimulation, patient's DNB cells secreted a similar level of IgG but a higher level of IgM than DNB cells from HC. Targeted therapy of PI3K inhibition partially restored B cell phenotypes. Conclusions: The present study suggests additional mechanistic insight into B cell pathology of APDS: (1) decreased peripheral B cell numbers may be due to the increased death of naïve B cells; (2) larger B cell sizes and expanded DNB population suggest enhanced activation and differentiation of naïve B cells into DNB cells; (3) the impaired CSR yet normal PB differentiation can predominantly generate IgM-secreting cells, resulting in elevated IgM levels.

Variant Type X91+ Chronic Granulomatous Disease: Clinical and Molecular Characterization in a Chinese Cohort.

PURPOSE: We aimed to report the clinical and immunological characteristics of variant type X91+ chronic granulomatous disease (CGD) in a Chinese cohort. METHODS: The clinical manifestations and immunological phenotypes of patients with X91+ CGD were collected. A dihydrorhodamine (DHR) analysis was performed to evaluate neutrophil function. Gp91phox protein expression was determined using extracellular staining with the monoclonal antibody (mAb) 7D5 and flow cytometry. RESULTS: Patients with X91+ CGD accounted for 8% (7/85) of all patients with CGD. The median age of onset in the seven patients with X91+ CGD was 4 months. Six patients received the BCG vaccine, and 50% (3/6) had probable BCG infections. Mycobacterium tuberculosis infection was prominent. The most common sites of infection were the lung (6/7), lymph nodes (5/7), and soft tissue (3/7). Two patients experienced recurrent oral ulcers. The stimulation index (SI) of the patients with X91+ CGD ranged widely from 1.9 to 67.3. The difference in the SI among the three groups of patients (X91+ CGD, X91- CGD, and X910 CGD) was statistically significant (P = 0.0071). The three groups showed no significant differences in onset age, diagnosis age, or severe infection frequency. CYBB mutations associated with X91+ CGD were commonly located in the second transmembrane or intracellular regions. Three novel X91+ CGD-related mutations (c.1462-2 A > T, c.1243C > T, and c.925G > A) were identified. CONCLUSIONS: Variant type X91+ CGD may result in varied clinical manifestations. Moreover, the laboratory findings might indicate a moderate neutrophil SI. We should deepen our understanding of variant X91+ CGD to prevent missed diagnoses.

Imaging characteristics of pulmonary BCG/TB infection in patients with chronic granulomatous disease.

In China, tuberculosis (TB) is endemic and the Bacillus Callmette-Güerin (BCG) vaccine is administered to all the newborns, which may lead to BCG infection in patients with chronic granulomatous disease (CGD). Infection of BCG/TB in CGD patients can be fatal and pulmonary is the most affected organ. Our objective was to assess the imaging of pulmonary BCG/TB infection in CGD. We screened 169 CGD patients and identified the patients with pulmonary BCG/TB infection. BCG infection was diagnosis according to the vaccination history, local infection manifestation, acid-fast bacilli staining, specific polymerase chain reaction, and/or spoligotyping. PPD, T-SPOT and acid-fast bacilli staining were used for diagnosis of TB. Totally 58 patients were identified, including TB (n = 7), solely BCG (n = 18), BCG + bacterial (n = 20), and BCG + fungi (n = 13). The onset of BCG disease was much earlier than TB. For those patients only with BCG, lymphadenopathy was the first and most prevalent feature. The most found location was the left axilla, followed by the ipsilateral cervical areas and mediastinal or hilar area. On chest CT, ground-glass opacities, multiple nodules and pulmonary scarring were the most common findings. For TB patients, the pulmonary infections were more serious, including large masses, severe lymphadenopathy, and extensive pulmonary fibrosis. Pulmonary infection of BCG were more common than TB in CGD patients, but much less severe.

RAG1 splicing mutation causes enhanced B cell differentiation and autoantibody production.

Hypomorphic RAG1 or RAG2 mutations cause primary immunodeficiencies and can lead to autoimmunity, but the underlying mechanisms are elusive. We report here a patient carrying a c.116+2T>G homozygous splice site mutation in the first intron of RAG1, which led to aberrant splicing and greatly reduced RAG1 protein expression. B cell development was blocked at both the pro-B to pre-B transition and the pre-B to immature B cell differentiation step. The patient B cells had reduced B cell receptor repertoire diversity and decreased complementarity determining region 3 lengths. Despite B cell lymphopenia, the patient had abundant plasma cells in the BM and produced large quantities of IgM and IgG Abs, including autoantibodies. The proportion of naive B cells was reduced while the frequency of IgD-CD27- double-negative (DN) B cells, which quickly differentiated into Ab-secreting plasma cells upon stimulation, was greatly increased. Immune phenotype analysis of 52 patients with primary immunodeficiency revealed a strong association of the increased proportion of DN B and memory B cells with decreased number and proportion of naive B cells. These results suggest that the lymphopenic environment triggered naive B cell differentiation into DN B and memory B cells, leading to increased Ab production.

High-Frequency Exon Deletion of DNA Cross-Link Repair 1C Accounting for Severe Combined Immunodeficiency May Be Missed by Whole-Exome Sequencing.

Next-generation sequencing (NGS) has been used to detect severe combined immunodeficiency (SCID) in patients, and some patients with DNA cross-link repair 1C (DCLRE1C) variants have been identified. Moreover, some compound variants, such as copy number variants (CNV) and single nucleotide variants (SNV), have been reported. The purpose of this study was to expand the genetic data related to patients with SCID carrying the compound DCLRE1C variant. Whole-exome sequencing (WES) was performed for genetic analysis, and variants were verified by performing Sanger sequencing or quantitative PCR. Moreover, we searched PubMed and summarized the data of the reported variants. Four SCID patients with DCLRE1C variants were identified in this study. WES revealed a homozygous deletion in the DCLRE1C gene from exons 1-5 in patient 1, exons 1-3 deletion and a novel rare variant (c.92T>C, p.L31P) in patient 2, exons 1-3 deletion and a novel rare variant (c.328C>G, p.L110V) in patient 3, and exons 1-4 deletion and a novel frameshift variant (c.449dup, p.His151Alafs*20) in patient 4. Based on literature review, exons 1-3 was recognized as a hotspot region for deletion variation. Moreover, we found that compound variations (CNV + SNV) accounted for approximately 7% variations in all variants. When patients are screened for T-cell receptor excision circles (TRECs), NGS can be used to expand genetic testing. Deletion of the DCLRE1C gene should not be ignored when a variant has been found in patients with SCID.

Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation.

BACKGROUND: We aimed to report the clinical characteristics, immunological features, and treatment of one patient with a de novo STAT3 gain-of-function mutation identified by next generation sequencing. We investigated the efficacy of tocilizumab therapy in immune dysregulation diseases caused by STAT3 mutation. RESULTS: The patient was a 16-year-old girl. She presented with recurrent respiratory infections and chronic diarrhea after birth. She had life-threatening autoimmune pancytopenia at 14 years old. After receiving glucocorticoid therapy, she developed diabetes. However, her pancytopenia relapsed when the glucocorticoid was tapered. Next-generation sequencing showed a de novo heterozygous mutation in the STAT3 gene, c.1261G > A (p. G421R), which was previously described as a gain-of-function mutation. After tocilizumab therapy, her pancytopenia fully resolved, and insulin and glucocorticoid therapies were gradually discontinued within 12 months. She had lymphopenia and an inverted CD4/CD8 ratio before therapy. Lymphocyte subpopulation analysis indicated an expansion of effector memory CD4+, effector memory CD8+ and central memory CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased. None of the abnormal lymphocytic changes improved significantly. STAT3 GOF mutations were identified by next gene sequencing in those with early-onset multi-organ autoimmunity. Including our patient, 13 patients with STAT3 GOF mutations received targeted treatment. Twelve of them were treated with tocilizumab alone or combination tocilizumab with JAK inhibitor, and ten patients improved. CONCLUSIONS: Gene sequencing should be performed for patients with early-onset refractory or multiorgan immune dysregulation diseases. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.

Imaging findings of pulmonary manifestations of chronic granulomatous disease in a large single center from Shanghai, China (1999-2018).

Chronic granulomatous disease (CGD) is characterized by recurrent infections and granuloma formation in multiple organs, especially the lung. We aimed to investigate pulmonary manifestations by computed tomography (CT). In total, 100 patients with 117 episodes of pulmonary infection were included. Chest CT scans of every episode were analyzed. Random nodules were the most common findings (79.49%), followed by ground-grass opacities (74.36%), focal consolidations (62.39%), and masses (59.83%). Cavities (12.82%) and multiple small abscesses (17.09%) could be found in the consolidations and masses. CT revealed interstitial pneumonia with tree-in-bud opacities (17.09%), interlobular septal thickening (23.08%) and emphysema (35.04%), which were more severe in the bilateral upper lobes. Mediastinal and hilar lymphadenopathy (78.63%) and axillary lymphadenopathy (65.81%) were common. Fungal infection (n = 27) was the most common and presented with multiple nodules and masses. Approximately 1/4 of fungal infections had interstitial pneumonia. In Staphylococcus aureus (n = 6) and Klebsiella pneumoniae (n = 3) infections, large areas of consolidation were common. In tuberculosis infection, the pulmonary infections were more severe and complex. For Bacillus Calmette-Guérin disease, left-sided axillary lymphadenopathy was a characteristic manifestation. CT images of CGD demonstrated variable pulmonary abnormalities. The main infectious organisms have unique imaging features.

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

The clinical, immunological and genetic features of 12 Chinese patients with STAT3 mutations.

BACKGROUND: Loss-of-function (LOF) mutations in signal transducer and activator of transcription 3 (STAT3) is one of the causes of STAT3 hyperimmunoglobulin E (IgE) syndrome (STAT3-HIES), while gain-of-function (GOF) mutations in STAT3 lead to immune dysregulation diseases. We retrospectively analyzed the age, common clinical symptoms, immunologic and molecular manifestations in 11 patients with LOF STAT3 mutations and 1 patient with a GOF STAT3 mutation. METHODS: Twelve patients were enrolled in our study. Serum immunoglobulin measurements, lymphocyte subset detection and whole-exome sequencing were performed. RESULTS: The median age at diagnosis of STAT3-HIES patients was 4.74 years. Eczema, recurrent respiratory infections, fevers, abscesses and Staphylococcus aureus infections were the classic manifestations. Elevated serum IgE levels are not always observed in conjunction with high eosinophil counts. A moderate viral DNA load was also measured in peripheral blood mononuclear cells. We noticed that c. 1144C>T was the most common mutation site, followed by c.1311C>A. Additionally, c.1311C>A and c. 1826G>C are two novel mutations. Eight patients achieved notable improvement after receiving intravenous immunoglobulin. CONCLUSION: We updated the current knowledge of this topic. We found an earlier median age at diagnosis, a higher survival rate, and a general lack of nonimmunological abnormalities; we also described the treatment details and novel mutations involve in STAT3-HIES and compared STAT3 LOF and GOF mutations.

LIG4 syndrome: clinical and molecular characterization in a Chinese cohort.

BACKGROUND: DNA Ligase IV (LIG4) syndrome is a rare disease with few reports to date. Patients suffer from a broad spectrum of clinical features, including microcephaly, growth retardation, developmental delay, dysmorphic facial features, combined immunodeficiency, and malignancy predisposition. There may be a potential association between genotypes and phenotypes. We investigated the characteristics of LIG4 syndrome in a Chinese cohort. RESULTS: All seven patients had growth restriction. Most patients (6/7) had significant microcephaly (< - 3 SD). Recurrent bacterial infections of the lungs and intestines were the most common symptoms. One patient had myelodysplastic syndromes. One patient presented with an inflammatory bowel disease (IBD)-like phenotype. Patients presented with combined immunodeficiency. The proportions of naïve CD4+ and naïve CD8+ T cells decreased notably in five patients. All patients harbored compound heterozygous mutations in the LIG4 gene, which consisted of a missense mutation (c.833G > T, p.R278L) and a deletion shift mutation, primarily c.1271_1275delAAAGA (p.K424Rfs*20). Two other deletion mutations, c.1144_1145delCT and c.1277_1278delAA, were novel. Patients with p.K424Rfs*20/p.R278 may have milder dysmorphism but more significant IgA/IgM deficiency compared to the frequently reported genotype p.R814X/p.K424Rfs*20. One patient underwent umbilical cord blood stem cell transplantation (UCBSCT) but died. CONCLUSIONS: The present study reported the clinical and molecular characteristics of a Chinese cohort with LIG4 syndrome, and the results further expand the phenotypic and genotypic spectrum and our understanding of genotype-to-phenotype correlations in LIG4 syndrome.

Dexamethasone sodium phosphate attenuates lipopolysaccharide-induced neuroinflammation in microglia BV2 cells.

Abnormal neuroinflammation ignited by overproduction of chemokines and cytokines via microglial cells can induce the occurrence and development of neurodegenerative disorders. The aim of this study is to investigate the effects of dexamethasone sodium phosphate (Dex-SP) on chemokine and cytokine secretion in lipopolysaccharide (LPS)-activated microglial cells. LPS markedly enhanced the secretion of pro-inflammatory factors such as regulated on activation, normal T cell expressed and secreted (RANTES), transforming growth factor beta-ß1 (TGF-ß1) and nitric oxide (NO), but decreased the production of macrophage inflammatory protein-1α (MIP-1α) and interleukin 10 (IL-10) in BV-2 microglial cells. Furthermore, LPS increased BV-2 microglial cell migration. However, Dex-SP treatment had the opposite effect, dampening the secretion of RANTES, TGF-ß1, and NO, while increasing the production of MIP-1α and IL-10 and blocking migration of LPS-stimulated BV-2 microglial cells. Furthermore, Dex-SP markedly suppressed the LPS-induced degradation of IRAK-1 and IRAK-4, and blocked the activation in TRAF6, p-TAK1, and p-JNK in BV-2 microglial cells. These results showed that Dex-SP inhibited the neuroinflammatory response and migration in LPS-activated BV-2 microglia by inhibiting the secretion of RANTES, TGF-ß1, and NO and increasing the production of MIP-1α and IL-10. The molecular mechanism of Dex-SP may be associated with inhibition of TRAF6/TAK-1/JNK signaling pathways mediated by IRAK-1 and IRAK-4.