ITK突变引起的原发性免疫缺陷的淋巴增殖性疾病比较罕见，及时诊断是改善原发性免疫缺陷病的结局并降低其病死率的重要因素。本文报道1例罕见的ITK杂合突变的原发性免疫缺陷的患儿，腹股沟肿块及颈部淋巴结活检提示Burkitt淋巴瘤及淋巴增殖性疾病。临床特征表现为全身淋巴结肿大、严重的EB病毒感染、CD4+T细胞持续减少、双阴性T细胞增加、IgG水平升高、血小板及中性粒细胞减少、低纤维蛋白原血症及高γ球蛋白血症。此病例具有自身免疫性淋巴细胞增生综合征样疾病的临床表现及实验室特征。.

To determine the diagnostic yield of Next-generation sequencing (NGS) in suspect Primary Immunodeficiencies Diseases (PIDs). This systematic review was conducted following PRISMA criteria. Searching Pubmed and Web of Science databases, the following keywords were used in the search: (\"Next-generation sequencing\") OR \"whole exome sequencing\" OR \"whole genome sequencing\") AND (\"primary immunodeficiency disease\" OR \"PIDs\"). We used STARD items to assess the risk of bias in the included studies. The meta-analysis included 29 studies with 5847 patients, revealing a pooled positive detection rate of 42% (95% CI 0.29-0.54, P < 0.001) for NGS in suspected PID cases. Subgroup analyses based on family history demonstrated a higher detection rate of 58% (95% CI 0.43-0.71) in patients with a family history compared to 33% (95% CI 0.21-0.46) in those without (P < 0.001). Stratification by disease types showed varied detection rates, with Severe Combined Immunodeficiency leading at 58% (P < 0.001). Among 253 PID-related genes, RAG1, ATM, BTK, and others constituted major contributors, with 34 genes not included in the 2022 IUIS gene list. The application of NGS in suspected PID patients can provide significant diagnostic results, especially in patients with a family history. Meanwhile, NGS performs excellently in accurately diagnosing disease types, and early identification of disease types can benefit patients in treatment.

OBJECTIVE: To report a case of a five-month-old Chinese infant who died of interleukin-1 receptor-associated kinase-4 (IRAK-4) deficiency presenting with rapid and progressive Pseudomonas aeruginosa sepsis.
METHODS: The genetic etiology of IRAK-4 deficiency was confirmed through trio-whole exome sequencing and Sanger sequencing. Functional consequences were invested using an in vitro minigene splicing assay.
RESULTS: Trio-whole exome sequencing of genomic DNA identified two novel compound heterozygous mutations, IRAK-4 (NM_016123.3): c.942-1G > A and c.644_651+ 6delTTGCAGCAGTAAGT in the proband, which originated from his symptom-free parents. These mutations were predicted to cause frameshifts and generate three truncated proteins without enzyme activity.
CONCLUSIONS: Our findings expand the range of IRAK-4 mutations and provide functional support for the pathogenic effects of splice-site mutations. Additionally, this case highlights the importance of considering the underlying genetic defects of immunity when dealing with unusually overwhelming infections in previously healthy children and emphasizes the necessity for timely treatment with wide-spectrum antimicrobials.

FOXP3+ regulatory T cells (Treg) are required for maintaining immune tolerance and preventing systemic autoimmunity. PI3Kδ is required for normal Treg development and function. However, the impacts of dysregulated PI3Kδ signaling on Treg function remain incompletely understood. In this study, we used a conditional mouse model of activated PI3Kδ syndrome to investigate the role of altered PI3Kδ signaling specifically within the Treg compartment. Activated mice expressing a PIK3CD gain-of-function mutation (aPIK3CD) specifically within the Treg compartment exhibited weight loss and evidence for chronic inflammation, as demonstrated by increased memory/effector CD4+ and CD8+ T cells with enhanced IFN-γ secretion, spontaneous germinal center responses, and production of broad-spectrum autoantibodies. Intriguingly, aPIK3CD facilitated Treg precursor development within the thymus and an increase in peripheral Treg numbers. Peripheral Treg, however, exhibited an altered phenotype, including increased PD-1 expression and reduced competitive fitness. Consistent with these findings, Treg-specific aPIK3CD mice mounted an elevated humoral response following immunization with a T cell-dependent Ag, which correlated with a decrease in follicular Treg. Taken together, these findings demonstrate that an optimal threshold of PI3Kδ activity is critical for Treg homeostasis and function, suggesting that PI3Kδ signaling in Treg might be therapeutically targeted to either augment or inhibit immune responses.

OBJECTIVE: To summarize the clinical data of 7 children with activated phosphoinositide 3-kinase delta syndrome (APDS) and enhance understanding of the disease.
METHODS: A retrospective analysis was conducted on clinical data of 7 APDS children admitted to Hunan Provincial People\'s Hospital from January 2019 to August 2023.
RESULTS: Among the 7 children (4 males, 3 females), the median age of onset was 30 months, and the median age at diagnosis was 101 months. Recurrent respiratory tract infections, hepatosplenomegaly, and multiple lymphadenopathy were observed in all 7 cases. Sepsis was observed in 5 cases, otitis media and multiple caries were observed in 3 cases, and diarrhea and joint pain were observed in 2 cases. Lymphoma and systemic lupus erythematosus were observed in 1 case each. Fiberoptic bronchoscopy was performed in 4 cases, revealing scattered nodular protrusions in the bronchial lumen. The most common respiratory pathogen was Streptococcus pneumoniae (4 cases). Six patients had a p.E1021K missense mutation, and one had a p.434-475del splice site mutation.
CONCLUSIONS: p.E1021K is the most common mutation site in APDS children. Children who present with one or more of the following symptoms: recurrent respiratory tract infections, hepatosplenomegaly, multiple lymphadenopathy, otitis media, and caries, and exhibit scattered nodular protrusions on fiberoptic bronchoscopy, should be vigilant for APDS. Citation:Chinese Journal of Contemporary Pediatrics, 2024, 26(5): 499-505.
目的: 总结7例PI3Kδ过度活化综合征（activated phosphoinositide 3-kinase delta syndrome, APDS）患儿的临床资料，提高对该病的认识。方法: 回顾性分析2019年1月—2023年8月湖南省人民医院收治的7例APDS患儿的临床资料。结果: 7例患儿（男4例，女3例）中位发病年龄为30个月，中位诊断年龄为101个月。临床表现：反复呼吸道感染、肝脾大及多部位淋巴结肿大7例，脓毒血症5例，中耳炎及多发性龋齿3例，腹泻及关节痛2例，淋巴瘤、系统性红斑狼疮各1例。4例患儿行纤维支气管镜检查，管腔内均可见大量散在的结节样突起。最常见的呼吸道病原为肺炎链球菌（4例）。6例患儿为p.E1021K位点错义突变，1例为p.434-475del位点剪切突变。结论: p.E1021K是APDS患儿最常见的突变位点。对于具有反复呼吸道感染、肝脾大、多部位淋巴结肿大、中耳炎、龋齿等表现1项或多项，且纤维支气管镜下见散在结节样突起的患儿，需警惕APDS。 ［中国当代儿科杂志，2024，26（5）：499-505］.

UNASSIGNED: CARD11 is a lymphoid lineage-specific scaffold protein regulating the NF-κB activation downstream of the antigen receptor signal pathway. Defective CARD11 function results in abnormal development and differentiation of lymphocytes, especially thymic regulatory T cells (Treg).
UNASSIGNED: In this study, we used patients\' samples together with transgenic mouse models carrying pathogenic CARD11 mutations from patients to explore their effects on Treg development. Immunoblotting and a GFP receptor assay were used to evaluate the activation effect of CARD11 mutants on NF-κB signaling. Then the suppressive function of Tregs carrying distinct CARD11 mutations was measured by in vitro suppression assay. Finally, we applied the retroviral transduced bone marrow chimeras to rescue the Treg development in an NF-κB independent manner.
UNASSIGNED: We found CARD11 mutations causing hyper-activated NF-κB signals also gave rise to compromised Treg development in the thymus, similar to the phenotype in Card11 deficient mice. This observation challenges the previous view that CARD11 regulates Treg lineage dependent on the NF-kB activation. Mechanistic investigations reveal that the noncanonical function CARD11, which negatively regulates the AKT/ FOXO1 signal pathway, is responsible for regulating Treg generation. Moreover, primary immunodeficiency patients carrying CARD11 mutation, which autonomously activates NF-κB, also represented the reduced Treg population in their peripheral blood. Our results propose a new regulatory function of CARD11 and illuminate an NF-κB independent pathway for thymic Treg lineage commitment.

Primary antibody deficiencies (PAD) are a group of congenital disorders caused by genetic defects that affect the development and function of the body\'s immune defence mechanisms. Patients with PAD may present with recurrent infections, lymphoproliferation, autoimmune diseases, autoinflammation, or malignancies. Respiratory system manifestations may include bronchiectasis, bronchial asthma, and interstitial lung disease, among others. A comprehensive understanding of PADs will help to distinguish these covert cases from more common respiratory diseases.
抗体免疫缺陷病是一组由遗传缺陷引起的先天性疾病，影响机体免疫防御机制的发育和功能。患者可表现为反复感染、淋巴细胞增殖、自身免疫性疾病、自身炎症或恶性肿瘤。呼吸系统可表现为支气管扩张症、支气管哮喘、间质性肺疾病等。深入了解抗体免疫缺陷病将有助于将其从呼吸系统常见疾病中甄别出来。.

We investigated two brothers who presented with repeated lung infections after 6 months of age. Lymphocytes and neutrophils were significantly decreased, and both had bronchiectasis and emphysema.
We sought to characterize the complete picture of lung injury in some types of primary immunodeficiency disease, followed by verification and analysis.
We performed immune function determination, a complete examination of the respiratory system, genetic analysis, and literature research.
The levels of lymphocytes, neutrophils, monocytes, and natural killer cells in the brothers were significantly decreased. The IgM and IgG levels of the older brother were decreased, while the IgM and IgA levels of the younger brother were decreased. Both brothers had bronchial wall erosion with a worm-eaten appearance and decreased lung function. Genetic testing revealed a hemizygous missense mutation (c.511C > T:p.R171W) in exon 5 of the MSN gene, which was inherited from the mother. A literature review showed that the primary immunodeficiency caused by MSN gene mutations is an X-linked recessive genetic disease with four known gene mutation sites, including nonsense and missense mutations. Nonsense mutations result in a higher incidence of autoimmune diseases and a lower degree of immune function impairment. Nonsense mutations closer to the front of the MSN gene may cause more severe disease. Neonatal disease screening can improve the early diagnosis rate, but hematopoietic stem cell transplantation (HSCT) treatment is controversial.
The primary immunodeficiency disease caused by MSN gene mutation is an X-linked recessive genetic disease that involves structural and functional damage to the respiratory system, and the worm-eaten appearance of the bronchial wall under endoscopy may be a relatively specific sign. The general manifestations of this disease are recurrent infections from 1 month to 6 months after birth, significantly reduced counts of lymphocytes and neutrophils, and decreased cellular and humoral immune function. Different types of MSN gene mutations and nonsense mutations at different sites have different clinical phenotypes. This study enriches the known spectrum of this disease.

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder characterized by DNA hypomethylation and antibody deficiency. It is caused by mutations in DNMT3B, ZBTB24, CDCA7, or HELLS. While progress has been made in elucidating the roles of these genes in regulating DNA methylation, little is known about the pathogenesis of the life-threatening hypogammaglobulinemia phenotype. Here, we show that mice deficient in Zbtb24 in the hematopoietic lineage recapitulate the major clinical features of patients with ICF syndrome. Specifically, Vav-Cre-mediated ablation of Zbtb24 does not affect lymphocyte development but results in reduced plasma cells and low levels of IgM, IgG1, and IgA. Zbtb24-deficient mice are hyper and hypo-responsive to T-dependent and T-independent type 2 antigens, respectively, and marginal zone B-cell activation is impaired. Mechanistically, Zbtb24-deficient B cells show severe loss of DNA methylation in the promoter region of Il5ra (interleukin-5 receptor subunit alpha), and Il5ra derepression leads to elevated CD19 phosphorylation. Heterozygous disruption of Cd19 can revert the hypogammaglobulinemia phenotype of Zbtb24-deficient mice. Our results suggest the potential role of enhanced CD19 activity in immunodeficiency in ICF syndrome.

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