Primary Immunodeficiency Diseases

原发性免疫缺陷病
  • 文章类型: Journal Article
    背景:免疫球蛋白G替代疗法(IgRT),静脉内(IV)和皮下(SC)途径,是治疗原发性免疫缺陷(PID)的关键。近年来,促进皮下免疫球蛋白(fSCIG),rHuPH20和10%IgG的组合已成为一种结合IV和SC优点的递送方法。
    方法:在观察性前瞻性队列中,我们调查了来自5个PID中心的PID患者使用fSCIG长达12个月的经历.我们使用患者/护理人员和医生报告的指标评估了这种治疗的有效性和安全性。此外,我们分析了患者治疗满意度(TSQM-9)和生活质量(QoL).
    结果:我们招募了29名患者(22名儿科患者和7名成人患者;14名女性和15名男性患者;(中位数:15,最小-最大时间:2-40.9年),这些患者作为IgRT-naive(n=1),从常规快速推送10%SCIG(n=6)或IVIG(n=22)切换。在参与者中,19(65%)表现出抗体缺乏,8(27%)联合免疫缺陷,和2(7%)免疫失调。值得注意的是,在所有以前的IgRTs和fSCIG下都达到了靶向的谷值免疫球蛋白G水平.没有严重的全身药物不良反应记录,尽管存在普遍的局部(%86.45)和轻微的全身(%26.45)不良反应,但fSCIG仍观察到.由于轻微的全身症状,2例患者从fSCIG改为10%SCIG。患者满意度调查显示,与基线相比,2-4个月(p=0.102);5-8个月(p=0.006)和9-12个月(p<0.001)显着增加。在QoL调查中没有观察到显著的趋势。
    结论:fSCIG在管理PID方面表现出可接受的耐受性和有效性,此外患者对IgRT的药物满意度也显著提高。尽管存在局部反应,但已确定的益处仍支持该疗法的继续。
    BACKGROUND: Immunoglobulin G replacement therapy (IgRT), intravenous (IV) and subcutaneous (SC) routes, is pivotal in treatment of primary immunodeficiencies (PID). In recent years, facilitated subcutaneous immunoglobulin (fSCIG), a combination of rHuPH20 and 10% IgG has emerged as a delivery method to combine advantages of both IV and SC.
    METHODS: In an observational prospective cohort, we investigated patient experience with fSCIG in PID patients from 5 PID centers for up to 12 months. We assessed the efficacy and safety of this treatment with patient/caregiver- and physician-reported indicators. Additionally, we analyzed patient treatment satisfaction (TSQM-9) and quality of life (QoL).
    RESULTS: We enrolled 29 patients (22 pediatric and 7 adults; 14 females and 15 males; (median: 15, min-max: 2-40.9 years) who initiated fSCIG as IgRT-naive (n = 1), switched from conventional rapid-push 10% SCIG (n = 6) or IVIG (n = 22). Among the participants, 19 (65%) exhibited antibody deficiencies, 8 (27%) combined immunodeficiencies, and 2 (7%) immune dysregulations. Remarkably, targeted trough immunoglobulin G levels were achieved under all previous IgRTs as well as fSCIG. No severe systemic adverse drug reactions were documented, despite prevalent local (%86.45) and mild systemic (%26.45) adverse reactions were noted with fSCIG. Due to mild systemic symptoms, 2 patients switched from fSCIG to 10% SCIG. The patient satisfaction survey revealed a notable increase at 2-4th (p = 0.102); 5-8th (p = 0.006) and 9-12th (p < 0.001) months compared to the baseline. No significant trends were observed in QoL surveys.
    CONCLUSIONS: fSCIG demonstrates admissable tolerability and efficacy in managing PIDs in addition to notable increase of patients\' drug satisfaction with IgRT. The identified benefits support the continuation of this therapy despite the local reactions.
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  • 文章类型: Journal Article
    先天性免疫错误(IEI)是一组具有广泛临床表型的遗传异质性疾病,从感染的易感性增加到免疫系统的失调,包括自身免疫现象,自身炎症性疾病,淋巴增生,和恶性肿瘤。IEI中的淋巴增殖性疾病(LPD)是指在遗传性免疫缺陷或免疫失调的临床背景下,淋巴样细胞的结节或结外和持续或复发的克隆或非克隆增殖。EB病毒(EBV)在IEI中LPD的病因中起着重要作用。在具有特定IEI的患者中,缺乏免疫监视可导致EBV感染的细胞不受抑制的增殖,这可能导致慢性活动性EBV感染,噬血细胞淋巴组织细胞增生症,还有LPD,特别是淋巴瘤.
    我们打算讨论发病机制,诊断,以及针对具有不同IEI的患者的EBV相关LPD的治疗方式。
    在IEI中EBV驱动的淋巴增殖提出了诊断和治疗问题,需要对宿主-病原体相互作用进行全面了解,免疫失调,和个性化的治疗方法。涉及免疫学家的多学科方法,血液学家,传染病专家,和遗传学家是最重要的解决诊断和治疗挑战所带来的这个有趣的但强大的临床实体。
    UNASSIGNED: Inborn errors of immunity (IEI) are a group of genetically heterogeneous disorders with a wide-ranging clinical phenotype, varying from increased predisposition to infections to dysregulation of the immune system, including autoimmune phenomena, autoinflammatory disorders, lymphoproliferation, and malignancy. Lymphoproliferative disorder (LPD) in IEI refers to the nodal or extra-nodal and persistent or recurrent clonal or non-clonal proliferation of lymphoid cells in the clinical context of an inherited immunodeficiency or immune dysregulation. The Epstein-Barr virus (EBV) plays a significant role in the etiopathogenesis of LPD in IEIs. In patients with specific IEIs, lack of immune surveillance can lead to an uninhibited proliferation of EBV-infected cells that may result in chronic active EBV infection, hemophagocytic lymphohistiocytosis, and LPD, particularly lymphomas.
    UNASSIGNED: We intend to discuss the pathogenesis, diagnosis, and treatment modalities directed toward EBV-associated LPD in patients with distinct IEIs.
    UNASSIGNED: EBV-driven lymphoproliferation in IEIs presents a diagnostic and therapeutic problem that necessitates a comprehensive understanding of host-pathogen interactions, immune dysregulation, and personalized treatment approaches. A multidisciplinary approach involving immunologists, hematologists, infectious disease specialists, and geneticists is paramount to addressing the diagnostic and therapeutic challenges posed by this intriguing yet formidable clinical entity.
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  • 文章类型: Journal Article
    免疫缺陷,着丝粒不稳定和面部异常(ICF)综合征是一种罕见的遗传性疾病,其特征是可变的免疫缺陷。超过一半的受影响个体在早期发病时表现出轻度至重度智力障碍。这种疾病是遗传异质性的,ZBTB24是亚型2的致病基因,约占ICF病例的30%。ZBTB24是一个多方面的转录因子,属于锌指和含BTB结构域的蛋白质家族,是发展过程的关键监管者。异常DNA甲基化是ICF综合征的主要分子标志。ZBTB24缺陷和DNA甲基化错误之间的功能联系仍然难以捉摸。这里,我们通过从p.Cys408Gly突变纯合的患者的外周CD34+血细胞获得诱导多能干细胞(iPSCs),产生了一种新的ICF2疾病模型,ICF2患者中最常见的错义突变,与广泛的临床谱相关。突变影响ZBTB24锌指结构域的保守半胱氨酸,扰乱其作为转录激活因子的功能。ICF2-iPSCs概括了与ZBTB24缺乏相关的甲基化缺陷,包括着丝粒低甲基化。我们验证了突变的ZBTB24蛋白失去了直接激活患者来源的iPSC中CDCA7和其他靶基因表达的能力。造血分化后,ICF2-iPSC显示出降低的活力和较低的CD34+/CD43+/CD45+祖细胞百分比。总的来说,ICF2-iPSC模型与探索ZBTB24在DNA甲基化稳态中的作用高度相关,并为研究ZBTB24缺陷与ICF2临床表型之间的早期分子事件提供了工具.
    Immunodeficiency, Centromeric instability and Facial anomalies (ICF) syndrome is a rare genetic disorder characterized by variable immunodeficiency. More than half of the affected individuals show mild to severe intellectual disability at early onset. This disorder is genetically heterogeneous and ZBTB24 is the causative gene of the subtype 2, accounting for about 30% of the ICF cases. ZBTB24 is a multifaceted transcription factor belonging to the Zinc-finger and BTB domain-containing protein family, which are key regulators of developmental processes. Aberrant DNA methylation is the main molecular hallmark of ICF syndrome. The functional link between ZBTB24 deficiency and DNA methylation errors is still elusive. Here, we generated a novel ICF2 disease model by deriving induced pluripotent stem cells (iPSCs) from peripheral CD34+-blood cells of a patient homozygous for the p.Cys408Gly mutation, the most frequent missense mutation in ICF2 patients and which is associated with a broad clinical spectrum. The mutation affects a conserved cysteine of the ZBTB24 zinc-finger domain, perturbing its function as transcriptional activator. ICF2-iPSCs recapitulate the methylation defects associated with ZBTB24 deficiency, including centromeric hypomethylation. We validated that the mutated ZBTB24 protein loses its ability to directly activate expression of CDCA7 and other target genes in the patient-derived iPSCs. Upon hematopoietic differentiation, ICF2-iPSCs showed decreased vitality and a lower percentage of CD34+/CD43+/CD45+ progenitors. Overall, the ICF2-iPSC model is highly relevant to explore the role of ZBTB24 in DNA methylation homeostasis and provides a tool to investigate the early molecular events linking ZBTB24 deficiency to the ICF2 clinical phenotype.
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  • 文章类型: Journal Article
    疣,低丙种球蛋白血症,感染,髓鞘综合征(WHIM)是一种罕见的,联合免疫缺陷病主要由CXCR4基因的功能获得变异体引起,该变异体通常导致C-X-C趋化因子受体4型(CXCR4)羧基末端截短,导致白细胞从骨髓向外周血的流出受损.WHIM综合征的诊断仍然具有挑战性,通常通过临床观察和/或基因检测来进行。在受影响的个体中检测致病性CXCR4变体支持WHIM综合征的诊断,但依赖于对致病变体的适当注释。了解WHIM综合征的基因型-表型相关性有可能缩短诊断时间并指导适当的临床治疗。产生了精准医学的真正例子。本文概述了WHIM综合征中CXCR4变体的频谱,并总结了可以支持新鉴定的变体解释的各种临床和功能证据。
    Warts, Hypogammaglobulinemia, Infections, Myelokathexis (WHIM) syndrome is a rare, combined immunodeficiency disease predominantly caused by gain-of-function variants in the CXCR4 gene that typically results in truncation of the carboxyl terminus of C-X-C chemokine receptor type 4 (CXCR4) leading to impaired leukocyte egress from bone marrow to peripheral blood. Diagnosis of WHIM syndrome continues to be challenging and is often made through clinical observations and/or genetic testing. Detection of a pathogenic CXCR4 variant in an affected individual supports the diagnosis of WHIM syndrome but relies on an appropriate annotation of disease-causing variants. Understanding the genotypic-phenotypic associations in WHIM syndrome has the potential to improve time to diagnosis and guide appropriate clinical management, resulting in a true example of precision medicine. This article provides an overview of the spectrum of CXCR4 variants in WHIM syndrome and summarizes the various lines of clinical and functional evidence that can support interpretation of newly identified variants.
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  • 文章类型: Journal Article
    CXCR4基因杂合子常染色体显性突变引起WHIM综合征,严重的联合免疫缺陷疾病。突变主要影响CXCR4趋化因子受体的C末端区域,特别是对激动剂(CXCL12)介导的受体内化和脱敏至关重要的几个潜在磷酸化位点。突变受体在细胞表面的停留时间延长,导致过度活跃的信号,这是WHIM综合征的一些症状的原因。最近的研究表明,情况比最初想象的要复杂,由于突变WHIM受体和CXCR4在细胞膜上表现出不同的动力学,这也影响了它们各自的细胞功能。这篇综述探讨了CXCR4的功能机制以及WHIM突变在生理和病理条件下的影响。
    Heterozygous autosomal dominant mutations in the CXCR4 gene cause WHIM syndrome, a severe combined immunodeficiency disorder. The mutations primarily affect the C-terminal region of the CXCR4 chemokine receptor, specifically several potential phosphorylation sites critical for agonist (CXCL12)-mediated receptor internalization and desensitization. Mutant receptors have a prolonged residence time on the cell surface, leading to hyperactive signaling that is responsible for some of the symptoms of WHIM syndrome. Recent studies have shown that the situation is more complex than originally thought, as mutant WHIM receptors and CXCR4 exhibit different dynamics at the cell membrane, which also influences their respective cellular functions. This review examines the functional mechanisms of CXCR4 and the impact of WHIM mutations in both physiological and pathological conditions.
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  • 文章类型: Journal Article
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  • 文章类型: Journal Article
    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。.
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  • 文章类型: Journal Article
    体液原发性免疫缺陷是原发性免疫缺陷(PID)的最普遍形式。目前,没有方便的方法来定量新形成的B细胞。这项概念验证研究的目的是定量体液原发性免疫缺陷患者的编码关节(CJs)与Kappa缺失重组切除环(KRECs)和血清B细胞活化因子(BAFF)的比率,并评估它们是否与疾病严重程度相关。这项IRB批准的研究是在一家学术儿童医院进行的。包括患有体液PID的患者和健康对照。通过qPCR测量CJ和KREC水平。使用中尺度测量血清BAFF水平。包括16例体液PID患者和5例健康对照。CVID中的平均CJ:KREC比率,抗体缺乏综合征,和控制组,分别为13.04±9.5、5.25±4.1和4.38±2.5(p=0.059)。CVID中的平均血清BAFF水平,抗体缺乏综合征和对照为216.3±290pg/mL,107.9±94pg/mL和50.9±12pg/mL,分别(p=0.271)。当CVID患者被细分为具有或不具有淋巴增生特征的CVID时,在具有淋巴增生的CVID队列中,BAFF水平明显更高(平均372.4±361pg/mL,p=0.031)。在CVID中观察到CJ:KREC比率升高,尽管没有达到统计学意义,可能是由于样本量小。具有淋巴增生特征的CVID患者的血清BAFF水平显着升高。我们推测,CJ:KREC比值和血清BAFF水平可用于患者的体液PID,更广泛的研究证实了这一探索性调查。
    Humoral primary immunodeficiencies are the most prevalent form of primary immunodeficiency (PID). Currently, there is no convenient method to quantify newly formed B cells. The aim of this proof-of-concept study was to quantitate the ratio of coding joints (CJs) to Kappa-deleting recombination excision circles (KRECs) and serum B cell activating factor (BAFF) in patients with humoral primary immunodeficiency and assess if they correlate with disease severity. This IRB-approved study was conducted at one academic children\'s hospital. Patients with humoral PIDs and healthy controls were included. CJ and KREC levels were measured via qPCR. Serum BAFF levels were measured using Mesoscale. 16 patients with humoral PID and 5 healthy controls were included. The mean CJ:KREC ratio in the CVID, antibody deficiency syndromes, and controls groups, respectively were 13.04 ± 9.5, 5.25 ± 4.1, and 4.38 ± 2.5 (p = 0.059). The mean serum BAFF levels in CVID, antibody deficiency syndromes and controls were 216.3 ± 290 pg/mL, 107.9 ± 94 pg/mL and 50.9 ± 12 pg/mL, respectively (p = 0.271). When the CVID patients were subdivided into CVID with or without lymphoproliferative features, the BAFF level was substantially higher in the CVID with lymphoproliferation cohort (mean 372.4 ± 361 pg/mL, p = 0.031). Elevated CJ:KREC ratio was observed in CVID, although statistical significance was not achieved, likely due to the small sample size. Serum BAFF levels were significantly higher in CVID patients with lymphoproliferative features. We speculate that the CJ:KREC ratio and serum BAFF levels can be utilized in patients with humoral PID, once more extensive studies confirm this exploratory investigation.
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  • 文章类型: Journal Article
    背景:胸腺上皮肿瘤(TET)是罕见的肿瘤,通常与免疫相关疾病有关。患有良好综合征(GS)的患者,成人获得性TET相关免疫缺陷,因传染病而死亡的风险很高。这项研究旨在检查TET患者的COVID-19发生率和严重程度,有或没有GS
    方法:回顾性收集转诊到坎帕尼亚地区罕见肿瘤区域协调中心的TET患者的临床记录。在观察期间,从2020年3月到2023年4月,收集了以下数据:SARS-CoV-2感染的发生;COVID-19的严重程度,根据美国国立卫生研究院(NIH)的疾病类别;COVID-19治疗。在总体人群中评估了COVID-19的发生和严重程度,并与GS和/或其他免疫相关失调的存在相关。
    结果:总体而言,47名TET患者被纳入研究;其中27名(57.4%)患有GS。所有参与者都接受了SARS-CoV2的mRNA疫苗的完整周期。,31例患者(66.0%)经历了COVID-19,其中18例(58.0%)以前曾被诊断为GS。未检测到GS和/或其他免疫相关失调与SARS-CoV-2感染发生的显着关联(分别为Fisher精确检验p=1和p=0.3587)。GS患者中,8人(45.0%)报告COVID-19严重程度评分≥3;而,无GS的13例患者中只有1例(7.7%)的严重程度评分≥3.GS的存在与COVID-19严重程度之间的相关性(评分1或2与≥3)有统计学意义(p=0.0448)。在COVID-19的严重程度和其他免疫相关综合征之间没有发现统计学上的显著关联(p=1)。值得注意的是,所有NIH4和5COVID-19的住院患者均患有GS。
    结论:我们的数据表明TET患者,尤其是那些有GS的,需要对SARS-CoV-2感染进行仔细的多学科监测,以建立量身定制的治疗和预防方案。
    BACKGROUND: Thymic epithelial tumors (TETs) are rare neoplasms often associated with immune-related disorders. Patients with Good\'s syndrome (GS), an adult-acquired TET-related immunodeficiency, are at a high risk of mortality due to infectious diseases. This study aims to examine COVID-19 occurrence and severity in TET patients, with or without GS.
    METHODS: Clinical records of TET patients referred to the Regional Coordinating Center for Rare Tumors of Campania Region were retrospectively collected. During the observation period, elapsing from March 2020 to April 2023, the following data were collected: occurrence of SARS-CoV-2 infection; COVID-19 severity, according to the National Institute of Health (NIH) illness categories; COVID-19 treatment. COVID-19 occurrence and severity were assessed in the overall population and correlated with the presence of GS and/or other immune-related dysregulations.
    RESULTS: Overall, 47 TET patients were included in the study; 27 of these (57.4%) had GS. All participants had received a full cycle of mRNA vaccine for SARS-CoV2., Thirty-one patients (66.0%) experienced COVID-19, of whom 18 (58.0%) had previously received a diagnosis of GS. No significant association of GS and/or other immune-related dysregulations with SARS-CoV-2 infection occurrence was detected (Fisher\'s exact test p = 1 and p = 0.3587, respectively). Among patients with GS, 8 (45.0%) reported a COVID-19 severity score of ≥ 3; whereas, only 1 of the 13 patients without GS (7.7%) had a severity score of ≥ 3. The correlation between presence of GS and COVID-19 severity (score 1 or 2 vs. ≥ 3) was statistically significant (p = 0.0448). No statistically significant association between COVID-19 severity and other immune-related syndromes were found (p = 1). Of note, all the hospitalized patients for NIH 4 and 5 COVID-19 had GS.
    CONCLUSIONS: Our data suggest that TET patients, especially those with GS, require a careful multidisciplinary monitoring for SARS-CoV-2 infection, in order to establish tailored treatments and prophylactic protocols.
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  • 文章类型: Systematic Review
    确定下一代测序(NGS)在可疑原发性免疫缺陷疾病(PID)中的诊断产量。本系统评价是按照PRISMA标准进行的。搜索Pubmed和WebofScience数据库,搜索中使用了以下关键词:(\"下一代测序\")或\"全外显子组测序\"或\"全基因组测序\")和(\"原发性免疫缺陷病\"或\"PID\").我们使用STARD项目来评估纳入研究中的偏倚风险。荟萃分析包括29项研究,共5847例患者,在可疑的PID病例中,NGS的合并阳性检出率为42%(95%CI0.29-0.54,P<0.001)。基于家族史的亚组分析显示,有家族史患者的检出率为58%(95%CI0.43-0.71),无家族史患者的检出率为33%(95%CI0.21-0.46)(P<0.001)。按疾病类型分层显示出不同的检出率,严重联合免疫缺陷发生率为58%(P<0.001)。在253个PID相关基因中,RAG1,ATM,BTK,其他人构成了主要贡献者,有34个基因未列入2022年IUIS基因列表。NGS在疑似PID患者中的应用可以提供显著的诊断结果,尤其是有家族史的患者。同时,NGS在准确诊断疾病类型方面表现出色,早期识别疾病类型可以使患者在治疗中受益。
    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.
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