BACKGROUND: CLEC16A intron 19 has been identified as a candidate locus for common variable immunodeficiency (CVID).
OBJECTIVE: This study sought to elucidate the molecular mechanism by which variants at the CLEC16A intronic locus may contribute to the pathogenesis of CVID.
METHODS: The investigators performed fine-mapping of the CLEC16A locus in a CVID cohort, then deleted the candidate functional SNP in T-cell lines by the CRISPR-Cas9 technique and conducted RNA-sequencing to identify target gene(s). The interactions between the CLEC16A locus and its target genes were identified using circular chromosome conformation capture. The transcription factor complexes mediating the chromatin interactions were determined by proteomic approach. The molecular pathways regulated by the CLEC16A locus were examined by RNA-sequencing and reverse phase protein array.
RESULTS: This study showed that the CLEC16A locus is an enhancer regulating expression of multiple target genes including a distant gene ATF7IP2 through chromatin interactions. Distinct transcription factor complexes mediate the chromatin interactions in an allele-specific manner. Disruption of the CLEC16A locus affects the AKT signaling pathway, as well as the molecular response of CD4+ T cells to immune stimulation.
CONCLUSIONS: Through multiomics and targeted experimental approaches, this study elucidated the underlying target genes and signaling pathways involved in the genetic association of CLEC16A with CVID, and highlighted plausible molecular targets for developing novel therapeutics.

The study aimed to reveal for the first time the clinical characteristics, nutritional and metabolic status and support of hospitalized patients with common variant immunodeficiency disease (CVID), and provide reference to improve the long-term nutritional management for such patients. This is a retrospective cross-sectional study. Through searching the electronic medical record system of Peking Union Medical College Hospital, the study included 33 consecutive in-patients with CVID diagnosed in Jan 2016 to Jun 2021, with the male to female ratio of 16∶17. All their medical data, nutritional assessment and intervention retrospectively summarized and analyzed. Data with normal distribution were described using (x¯±s), and analyzed with independent sample t-test. Data with non-normal distribution were compared with non-parametric test. The results showed that the median onset-age of the included patients was 22 (10.0,36.5) years old, and the median duration was 9.0 (2.0,16.0) years. All patients had recurrent infections involving various systems (33/33), with development of autoimmune diseases (8/33) and lymphoproliferative disease or malignancy (9/33) in some cases among them. The nutritional risk screening 2002 (NRS 2002) scores revealed that 85.19% of adults had an NRS 2002≥3 points, and 33.33% of children had a BMI-for-age z score<-2. Weight loss occurred in 66.67% of patients (22/33), while 87.88% (29/33), 69.70% (23/33) and 81.82% (27/33) of patients respectively had anemia, hypoalbuminemia and decreased prealbumin. Among 22 patients with micronutrients status evaluated, 77.27% (17/22), 22.73% (5/22) and 31.82% (7/22) of patients respectively had lowered serum iron, folate deficiency and vitamin B12 insufficiency. Six patients underwent 25-OH-VD3 measurement, and were all testified to have vitamin D deficiency. Among all patients with nutritional risk, 56.00% of them underwent nutritional support: oral nutritional supplements (14 cases), enteral feeding (4 cases) and parenteral nutrition (5 cases). In conclusion, the condition of malnutrition was prevalent in patients with CVID, but was under-recognized and undertreated to some degree.
探讨普通变异型免疫缺陷病（CVID）住院患者的临床特点、营养代谢状况及支持现状，为进一步改善其长期营养管理提供研究依据和参考。本研究为回顾性横断面研究，查询北京协和医院电子病历系统，连续筛选2016年1月至2021年6月符合CVID诊断标准的住院患者共33例，男、女分别为16例、17例，年龄范围2~52岁。回顾性分析其临床资料及营养状况、营养干预情况。连续性资料符合正态分布的均值比较采用两组独立样本的t检验，非正态分布的计量资料采用非参数检验进行比较。结果显示，纳入患者中位起病年龄为22（10.0，36.5）岁，中位病程9.0（2.0，16.0）年。病例均有累及不同系统的反复感染（33/33），部分合并自身免疫性疾病（8/33）、淋巴增殖性疾病与恶性肿瘤（9/33）。85.19%（23/27）的成人患者营养风险筛查（nutritional risk screening 2002，NRS 2002）评分≥3分，33.33%（2/6）的青少年儿童患者年龄别体重指数Z值<-2。66.67%（22/33）的患者在病程中有体重下降，87.88%（29/33）、69.70%（23/33）与81.82%（27/33）的患者分别存在贫血、低白蛋白血症与前白蛋白降低。22例进行了微量营养素评价，提示77.27%（17/22）、22.73%（5/22）与31.82%（7/22）的患者分别存在血清铁降低、叶酸缺乏与维生素B12不足。另有6例检测25-OH-VD3，均提示存在维生素D缺乏。存在营养风险的患者中，56.00%（14/25）在住院期间接受了营养支持：口服营养补充（14例），管饲肠内营养（4例），肠外营养支持（5例）。综上，CVID患者存在营养不良的状况突出，目前合理营养支持的管理仍存在不足。.

Background: The pathogenesis of common variable immunodeficiency disorder (CVID) is complex, especially when combined with autoimmunity. Genetic factors may be potential explanations for this complex situation, and whole genome sequencing (WGS) provide the basis for this potential. Methods: Genetic information of patients with CVID with autoimmunity, together with their first-degree relatives, was collected through WGS. The association between genetic factors and clinical phenotypes was studied using genetic analysis strategies such as sporadic and pedigree. Results: We collected 42 blood samples for WGS (16 CVID patients and 26 first-degree relatives of healthy controls). Through pedigree, sporadic screening strategies and low-frequency deleterious screening of rare diseases, we obtained 9,148 mutation sites, including 8,171 single-nucleotide variants (SNVs) and 977 Insertion-deletions (InDels). Finally, we obtained a total of 28 candidate genes (32 loci), of which the most common mutant was LRBA. The most common autoimmunity in the 16 patients was systematic lupus erythematosis. Through KEGG pathway enrichment, we identified the top ten signaling pathways, including \"primary immunodeficiency\", \"JAK-STAT signaling pathway\", and \"T-cell receptor signaling pathway\". We used PyMOL to predict and analyse the three-dimensional protein structures of the NFKB1, RAG1, TIRAP, NCF2, and MYB genes. In addition, we constructed a PPI network by combining candidate mutants with genes associated with CVID in the OMIM database via the STRING database. Conclusion: The genetic background of CVID includes not only monogenic origins but also oligogenic effects. Our study showed that immunodeficiency and autoimmunity may overlap in genetic backgrounds. Clinical Trial Registration: identifier ChiCTR2100044035.

OBJECTIVE: Common variable immunodeficiency disorder (CVID) patients may have gastrointestinal (GI) involvement and suffer from infections, which are poorly understood. This study aimed to evaluate the clinical, endoscopic, and histopathological features of CVID patients with GI symptoms and determine their correlation with infections.
METHODS: We performed a retrospective study on 21 CVID patients with GI symptoms who underwent endoscopic examination in Peking Union Medical College Hospital from 2000 to 2020. The clinical, infectious, endoscopic, and histopathological features were reassessed.
RESULTS: Chronic diarrhea was the most prevalent GI symptom, observed in 95.2% of our CVID cohort. Over 85% of patients had low body weight and malabsorption. Small bowel villous atrophy was found in 90.5% of patients under endoscopy and mostly confirmed by histopathology. GI infections were identified in 9 (42.9%) patients. Of these, 7 patients with diffuse and obvious nodular lymphoid hyperplasia (NLH) of small bowel under endoscopy had significantly higher infection rate (85.7% vs 21.4%, p < 0.05), predominantly with Giardia and bacteria. Small bowel biopsies showed 95% of patients lacked plasma cells and 60% had increased intraepithelial lymphocytes (IELs), but not significantly different between GI infection and non-infection group. Most patients improved after intravenous immunoglobulin and anti-infection therapy.
CONCLUSIONS: CVID could involve GI tract, particularly small bowel. Obvious NLH under endoscopy could be a hint for GI infection in CVID patients. Comprehensive endoscopic and histopathological evaluation may be helpful in CVID diagnosis and identification of potential co-infection, leading to proper treatment.

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We wished to summarize the clinical features of common variable immunodeficiency (CVID) complicated by non-cirrhotic portal hypertension (NCPH) and to deepen our understanding of it. The case data of CVID complicated with NCPH admitted to Peking Union Medical College Hospital from January 1983 to May 2021 were analyzed retrospectively to summarize their clinical characteristics. Six patients with CVID combined with NCPH (three of each sex; 16-45 years) were assessed. Four patients had portal hypertension. All patients had anemia, splenomegaly, a normal serum level of albumin and transaminases, and possibly increased levels of alkaline phosphatase and gamma-glutamyl transpeptidase. Two patients were diagnosed with esophagogastric fundic varices by gastroscopy. Two patients underwent splenectomy (which improved hematologic abnormalities partially). Four patients had autoimmune disease. Two cases were diagnosed with nodular regenerative hyperplasia (NRH) upon liver biopsy. Six patients were administered intravenous immunoglobulin-G (0.4-0.6 g/kg bodyweight) once every 3-4 weeks as basic therapy. Often, CVID complicated with NCPH has: (1) The manifestations of portal hypertension as the primary symptom. (2) Autoimmune-related manifestations. Imaging can provide important diagnostic clues. The etiology may be related to hepatic NRH and splenomegaly due to recurrent infections.
分析总结普通变异型免疫缺陷病（CVID）并发非肝硬化性门脉高压症（NCPH）的临床特征，提高对其的认识水平。回顾分析北京协和医院1983年1月至2021年5月收治的6例CVID合并NCPH的病例资料，总结其临床特点。结果显示，6例CVID合并NCPH患者，男女各3例，起病年龄16~45岁，4例以门脉高压表现起病，表现为贫血、脾大，2例以反复感染起病。4例患者合并自身免疫病。2例患者完善肝活检，均诊断为肝结节性再生性增生（NRH）。6例患者均予静脉注射免疫球蛋白G 0.4~0.6 g/kg、每3~4周1次作为基础治疗。2例患者行脾切除术，部分改善血液系统异常。CVID并发NCPH常以门脉高压的表现为首发症状，常有自身免疫相关表现。影像学筛查可提供重要诊断线索。究其病因，可能与肝结节性再生性增生、反复感染所致的脾大相关。.

Common variable immunodeficiency (CVID) is a \'late-onset\' primary immunodeficiency characterized by variable manifestations and genetic heterogeneity. A monogenic cause of CVID has been reported in 10% of patients. In this study, we identified two novel pathogenic variants implicated in monogenic CVID by whole exome sequencing (WES) analysis: a heterozygous nuclear factor κB subunit 1 (NFKB1) p.G686fs mutation and a homozygous inducible T-cell co-stimulator (ICOS) p.L96Sfs mutation. The predicted crystal models indicated premature truncation of the two mutated proteins. Both variants were demonstrated as loss-of-function mutations and were associated with overlapped manifestations of respiratory fungal infection and splenomegaly. We further performed a detailed assessment of immunologic phenotypes and impaired lymphocyte functions in patients. Moreover, we discovered an association between monoclonal T-large granular lymphocyte proliferation and ICOS-deficient CVID for the first time. These observations lead to a new perspective on the underlying genetic heterogeneity of CVID.

UNASSIGNED: LPS-responsive beige-like anchor (LRBA) deficiency is one of the most common monogenic disorders causing common variable immunodeficiency (CVID) and CVID-like disorders. However, the clinical spectrum of compound heterozygous (CHZ) LRBA variation should be extended. In this study, we presented five cases of compound heterozygous LRBA with various refractory cytopenias.
UNASSIGNED: Retrospective analysis of the clinical manifestations, management, and outcomes of five cases (from five pedigrees) with LRBA gene CHZ variants which initially manifested as single/multilineage immune cytopenias was performed.
UNASSIGNED: 1. Gene variations: All five patients inherited the compound heterozygous LRBA variations from their parents which were thought to be pathogenic. BEACH, DUF4704, and LamG were the main affected domains of LRBA gene in this case series. 2. Immune dysregulation of clinic: (1) Hypogammaglobulinemia were recorded in four patients, and the proportion of Treg was decreased in two patients. Only one patient had been with increased TCRαβ+CD4/CD8 double-negative T cells (DNT). (2) Lymphoproliferative manifestations were seen in three patients. (3) All five patients were complained with cytopenia, although they showed different clinical manifestations. None of the parents was asymptomatic. (4) Other immune disorders: P5 also had relapsed infections and autoimmune endocrinopathy. 3. Management and outcomes: P1 and P5 responded well to immunomodulatory therapy and P3 was effectively treated with hemophagocytic lymphohistiocytosis (HLH) first-line regimen chemotherapy. P4 showed no responses to steroids and IVIG. However, TPO-R agonist was effective.
UNASSIGNED: Unlike homozygous mutations, compound heterozygous LRBA variation should always be kept in mind for the various phenotypes and different treatment responses.

BACKGROUND: Common variable immunodeficiency (CVID) is a rare disease that affects children and adults and is often difficult to diagnose. Despite being one of the most frequent causes of immunodeficiency, involving gastrointestinal (GI), respiratory, and hematological systems, the disease onset can have heterogeneous and intermittent symptoms, frequently leading to diagnostic delay. GI symptoms are common and can include diarrhea, but the asymptomatic periods lead to overlooking the recurrent pattern. The same can occur with respiratory infections, thus delaying CVID suspicion. The starting point for CVID diagnosis is the decreased gamma globulin levels in serum protein electrophoresis (SPE), also observed through direct immunoglobulin\'s dosage.
METHODS: The patient is a 38 years-old man who had intermittent diarrhea and recurrent airway infections for 19 years, but the CVID diagnosis was achieved only after SPE was carried out. At that time, he was already malnourished, and developed other complications related to CVID in a short period.
CONCLUSIONS: SPE is readily available and inexpensive, but is not part of the laboratory approach in diarrhea. According to the case presented herein, it can be useful for patients with recurrent infections or other clues of the disease.