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Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1-3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.
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Enfermedades de Inmunodeficiencia Primaria/genética , Secuenciación Completa del Genoma , Complejo 2-3 Proteico Relacionado con la Actina/genética , Teorema de Bayes , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/inmunología , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Proteínas de Unión al ARN/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Proteína 1 Supresora de la Señalización de Citocinas/genética , Factores de Transcripción/genéticaRESUMEN
PURPOSE: A large proportion of Common variable immunodeficiency (CVID) patients has duodenal inflammation with increased intraepithelial lymphocytes (IEL) of unknown aetiology. The histologic similarities to celiac disease, lead to confusion regarding treatment (gluten-free diet) of these patients. We aimed to elucidate the role of epigenetic DNA methylation in the aetiology of duodenal inflammation in CVID and differentiate it from true celiac disease. METHODS: DNA was isolated from snap-frozen pieces of duodenal biopsies and analysed for differences in genome-wide epigenetic DNA methylation between CVID patients with increased IEL (CVID_IEL; n = 5) without IEL (CVID_N; n = 3), celiac disease (n = 3) and healthy controls (n = 3). RESULTS: The DNA methylation data of 5-methylcytosine in CpG sites separated CVID and celiac diseases from healthy controls. Differential methylation in promoters of genes were identified as potential novel mediators in CVID and celiac disease. There was limited overlap of methylation associated genes between CVID_IEL and Celiac disease. High frequency of differentially methylated CpG sites was detected in over 100 genes nearby transcription start site (TSS) in both CVID_IEL and celiac disease, compared to healthy controls. Differential methylation of genes involved in regulation of TNF/cytokine production were enriched in CVID_IEL, compared to healthy controls. CONCLUSION: This is the first study to reveal a role of epigenetic DNA methylation in the etiology of duodenal inflammation of CVID patients, distinguishing CVID_IEL from celiac disease. We identified potential biomarkers and therapeutic targets within gene promotors and in high-frequency differentially methylated CpG regions proximal to TSS in both CVID_IEL and celiac disease.
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Enfermedad Celíaca , Inmunodeficiencia Variable Común , Islas de CpG , Metilación de ADN , Duodeno , Epigénesis Genética , Humanos , Inmunodeficiencia Variable Común/genética , Duodeno/metabolismo , Duodeno/patología , Enfermedad Celíaca/genética , Femenino , Masculino , Adulto , Persona de Mediana Edad , Islas de CpG/genética , Regiones Promotoras Genéticas/genética , Linfocitos Intraepiteliales/inmunología , Adulto Joven , Estudio de Asociación del Genoma Completo , 5-Metilcitosina/metabolismoRESUMEN
BACKGROUND: A substantial proportion of common variable immunodeficiency (CVID) patients has duodenal inflammation of largely unknown etiology. However, because of its histologic similarities with celiac disease, gluten sensitivity has been proposed as a potential mechanism. OBJECTIVE: We aimed to elucidate the role of the duodenal microenvironment in the pathogenesis of duodenal inflammation in CVID by investigating the transcriptional, proteomic, and microbial signatures of duodenal biopsy samples in CVID. METHODS: DNA, total RNA, and protein were isolated from snap-frozen pieces of duodenal biopsy samples from CVID (with and without duodenal inflammation), healthy controls, and patients with celiac disease (untreated). RNA sequencing, mass spectrometry-based proteomics, and 16S ribosomal DNA sequencing (bacteria) were then performed. RESULTS: CVID separated from controls in regulation of transcriptional response to lipopolysaccharide and cellular immune responses. These differences were independent of mucosal inflammation. Instead, CVID patients with duodenal inflammation displayed alterations in transcription of genes involved in response to viral infections. Four proteins were differently regulated between CVID patients and healthy controls-DBNL, TRMT11, GCHFR, and IGHA2-independent of duodenal inflammation. Despite similar histology, there were major differences in CVID with duodenal inflammation and celiac disease both at the RNA and protein level. No significant difference was observed in the bacterial gut microbial signature between CVID, celiac, and healthy controls. CONCLUSION: Our findings suggest the existence of altered functions of the duodenal epithelium, particularly in response to lipopolysaccharide and viruses. The latter finding was related to duodenal inflammation, suggesting that viruses, not gluten sensitivity, could be related to duodenal inflammation in CVID.
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Enfermedad Celíaca , Inmunodeficiencia Variable Común , Virus , Humanos , Enfermedad Celíaca/genética , Lipopolisacáridos , Proteómica , Bacterias , Inflamación , Virus/genética , ARNRESUMEN
PURPOSE: Triglycerides (TG) and their major transport lipoprotein in the circulation (VLDL) appear to be related to inflammation. Patients with common variable immunodeficiency (CVID) have inflammatory complications associated with gut microbial dysbiosis. We hypothesized that CVID patients have disturbed TG/VLDL profiles associated with these clinical characteristics. METHODS: We measured plasma concentrations of TGs, inflammatory markers, and lipopolysaccharide (LPS) in 95 CVID patients and 28 healthy controls. Additionally, in 40 CVID patients, we explored plasma lipoprotein profiling, fatty acid, gut microbial dysbiosis, and diet. RESULTS: TG levels were increased in CVID patients as compared to healthy controls (1.36 ± 0.53 mmol/l versus 1.08 ± 0.56 [mean, SD], respectively, P = 0.008), particularly in the clinical subgroup "Complications," characterized by autoimmunity and organ-specific inflammation, compared to "Infection only" (1.41 mmol/l, 0.71[median, IQR] versus [1.02 mmol/l, 0.50], P = 0.021). Lipoprotein profile analyses showed increased levels of all sizes of VLDL particles in CVID patients compared to controls. TG levels correlated positively with CRP (rho = 0.256, P = 0.015), IL-6 (rho = 0.237, P = 0.021), IL-12 (rho = 0.265, P = 0.009), LPS (r = 0.654, P = 6.59 × 10-13), CVID-specific gut dysbiosis index (r = 0.315, P = 0.048), and inversely with a favorable fatty acid profile (docosahexaenoic acid [rho = - 0.369, P = 0.021] and linoleic acid [rho = - 0.375, P = 0.019]). TGs and VLDL lipids did not appear to be associated with diet and there were no differences in body mass index (BMI) between CVID patients and controls. CONCLUSION: We found increased plasma levels of TGs and all sizes of VLDL particles, which were associated with systemic inflammation, LPS, and gut dysbiosis in CVID, but not diet or BMI.
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Inmunodeficiencia Variable Común , Lipopolisacáridos , Humanos , Disbiosis , Lipoproteínas , Triglicéridos , Inflamación , Ácidos GrasosRESUMEN
BackgroundGreat efforts have been made to minimise spread and prevent outbreaks of COVID-19 in hospitals. However, there is uncertainty in identifying nosocomial vs community-acquired infections. To minimise risks and evaluate measures, timely data on infection risk in healthcare institutions are required.AimsTo design an automated nationwide surveillance system for nosocomial COVID-19 using existing data to analyse the impact of community infection rates on nosocomial infections, to explore how changes in case definitions influence incidence and to identify patients and wards at highest risk and effects of SARS-CoV-2 variants.MethodsWe used data from the Norwegian real-time emergency preparedness register (Beredt C19), which includes all patients nationwide admitted to Norwegian hospitals between March 2020 and March 2022 with a positive SARS-CoV-2 PCR test during their hospital stay or within 7 days post-discharge. COVID-19 cases were assigned to categories depending on the time between admission and testing.ResultsInfection rates for definite/probable nosocomial COVID-19 increased from 0.081% in year 1 to 0.50% in year 2 in hospital admissions 7 days or longer. Varying the definitions resulted in large changes in registered nosocomial infections. Infection rates were similar across different ward types. By 2022, 58% of patients with a definite/probable nosocomial infection had received three vaccine doses.ConclusionAutomated national surveillance for nosocomial COVID-19 is possible based on existing data sources. Beredt C19 provided detailed information with only 5% missing data on hospitals/wards. Epidemiological definitions are possible to standardise, enabling easier comparison between regions and countries.
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COVID-19 , Infección Hospitalaria , Humanos , COVID-19/epidemiología , SARS-CoV-2 , Infección Hospitalaria/epidemiología , Infección Hospitalaria/prevención & control , Cuidados Posteriores , Alta del Paciente , Hospitales , Atención a la SaludRESUMEN
PURPOSE: Fatty acid (FA) abnormalities are found in various inflammatory disorders and have been related to disturbed gut microbiota. Patients with common variable immunodeficiency (CVID) have inflammatory complications associated with altered gut microbial composition. We hypothesized that there is an altered FA profile in CVID patients, related to gut microbial dysbiosis. METHODS: Plasma FAs were measured in 39 CVID patients and 30 healthy controls. Gut microbial profile, a food frequency questionnaire, and the effect of the oral antibiotic rifaximin were investigated in CVID patients. RESULTS: The n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) (1.4 [1.0-1.8] vs. 1.9 [1.2-2.5], median (IQR), P < 0.05), and docosahexaenoic acid (DHA) (3.2 [2.4-3.9] vs. 3.5 [2.9-4.3], P < 0.05), all values expressed as weight percent of total plasma FAs, were reduced in CVID compared to controls. Also, n-6 PUFAs (34.3 ± 3.4 vs. 37.1 ± 2.8, mean ± SD, P < 0.001) and linoleic acid (LA) (24.5 ± 3.3 vs. 28.1 ± 2.7, P < 0.0001) and the FA anti-inflammatory index (98.9 [82.1-119.4] vs. 117.0 [88.7-153.1], median (IQR), P < 0.05) were reduced in CVID. The microbial alpha diversity was positively associated with plasma n-6 PUFAs (r = 0.41, P < 0.001) and LA (r = 0.51, P < 0.001), but not n-3 PUFAs (P = 0.78). Moreover, a 2-week course of rifaximin significantly reduced the proportion of n-6 PUFAs (P = 0.04, UNIANOVA). Serum immunoglobulin G (IgG) levels correlated with plasma n-3 PUFAs (rho = 0.36, P = 0.03) and DHA (rho = 0.41, P = 0.009). CONCLUSION: We found a potentially unfavorable FA profile in CVID, related to low IgG levels. High plasma n-6 PUFAs were related to increased gut microbial diversity and altered by rifaximin therapy.
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Inmunodeficiencia Variable Común , Ácidos Grasos Omega-3 , Microbioma Gastrointestinal , Inmunodeficiencia Variable Común/tratamiento farmacológico , Ácidos Grasos/farmacología , Ácidos Grasos Omega-3/farmacología , Ácidos Grasos Omega-6/farmacología , HumanosRESUMEN
PURPOSE: About 20-30% of patients with common variable immunodeficiency (CVID) develop granulomatous-lymphocytic interstitial lung disease (GLILD) as one of several non-infectious complications to their immunodeficiency. The purpose of this study was to identify biomarkers that could distinguish GLILD from other non-infectious complications in CVID. METHODS: We analyzed serum biomarkers related to inflammation, pulmonary epithelium injury, fibrogenesis, and extracellular matrix (ECM) remodeling, and compared three subgroups of CVID: GLILD patients (n = 16), patients with other non-infectious complications (n = 37), and patients with infections only (n = 20). RESULTS: We found that GLILD patients had higher levels of sCD25, sTIM-3, IFN-γ, and TNF, reflecting T cell activation and exhaustion, compared to both CVID patients with other inflammatory complications and CVID with infections only. GLILD patients also had higher levels of SP-D and CC16, proteins related to pulmonary epithelium injury, as well as the ECM remodeling marker MMP-7, than patients with other non-infectious complications. CONCLUSION: GLILD patients have elevated serum markers of T cell activation and exhaustion, pulmonary epithelium injury, and ECM remodeling, pointing to potentially important pathways in GLILD pathogenesis, novel targets for therapy, and promising biomarkers for clinical evaluation of these patients.
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Inmunodeficiencia Variable Común , Enfermedades Pulmonares Intersticiales , Humanos , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/patología , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Biomarcadores , Linfocitos T/patologíaRESUMEN
PURPOSE: GATA2 deficiency is a rare primary immunodeficiency that has become increasingly recognized due to improved molecular diagnostics and clinical awareness. The only cure for GATA2 deficiency is allogeneic hematopoietic stem cell transplantation (allo-HSCT). The inconsistency of genotype-phenotype correlations makes the decision regarding "who and when" to transplant challenging. Despite considerable morbidity and mortality, the reported proportion of patients with GATA2 deficiency that has undergone allo-HSCT is low (~ 35%). The purpose of this study was to explore if detailed clinical, genetic, and bone marrow characteristics could predict end-point outcome, i.e., death and allo-HSCT. METHODS: All medical genetics departments in Norway were contacted to identify GATA2 deficient individuals. Clinical information, genetic variants, treatment, and outcome were subsequently retrieved from the patients' medical records. RESULTS: Between 2013 and 2020, we identified 10 index cases or probands, four additional symptomatic patients, and no asymptomatic patients with germline GATA2 variants. These patients had a diverse clinical phenotype dominated by cytopenia (13/14), myeloid neoplasia (10/14), warts (8/14), and hearing loss (7/14). No valid genotype-phenotype correlations were found in our data set, and the phenotypes varied also within families. We found that 11/14 patients (79%), with known GATA2 deficiency, had already undergone allo-HSCT. In addition, one patient is awaiting allo-HSCT. The indications to perform allo-HSCT were myeloid neoplasia, disseminated viral infection, severe obliterating bronchiolitis, and/or HPV-associated in situ carcinoma. Two patients died, 8 months and 7 years after allo-HSCT, respectively. CONCLUSION: Our main conclusion is that the majority of patients with symptomatic GATA2 deficiency will need allo-HSCT, and a close surveillance of these patients is important to find the "optimal window" for allo-HSCT. We advocate a more offensive approach to allo-HSCT than previously described.
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Deficiencia GATA2 , Trasplante de Células Madre Hematopoyéticas , Médula Ósea , Deficiencia GATA2/diagnóstico , Deficiencia GATA2/genética , Deficiencia GATA2/terapia , Factor de Transcripción GATA2/genética , Humanos , Noruega/epidemiologíaRESUMEN
To characterize the family index case for detected SARS-CoV-2 and describe testing and secondary attack rates in the family, we used individual-level administrative data of all families and all PCR tests for SARS-CoV-2 in Norway in 2020. All families with at least one parent and one child below the age of 20 who lived at the same address (N = 662,582), where at least one member, i.e. the index case, tested positive for SARS-CoV-2 in 2020, were included. Secondary attack rates (SAR7) were defined as the share of non-index family members with a positive PCR test within 7 days after the date when the index case tested positive. SARs were calculated separately for parent- and child-index cases, and for parent- and child-secondary cases. We identified 7548 families with an index case, comprising 26,991 individuals (12,184 parents, 14,808 children). The index was a parent in 66% of the cases. Among index children, 42% were in the age group 17-20 and only 8% in the age group 0-6. When the index was a parent, SAR7 was 24% (95% CI 24-25), whilst SAR7 was 14% (95% CI 13-15) when the index was a child. However, SAR7 was 24% (95% CI 20-28) when the index was a child aged 0-6 years and declined with increasing age of the index child. SAR7 from index parent to other parent was 35% (95% CI 33-36), and from index child to other children 12% (95% CI 11-13). SAR7 from index child aged 0-6 to parents was 27% (95% CI 22-33). The percent of non-index family members tested within 7 days after the index case, increased from about 20% in April to 80% in December, however, SAR7 stabilized at about 20% from May. We conclude that parents and older children are most often index cases for SARS-CoV-2 in families in Norway, while parents and young children more often transmit the virus within the family. This study suggests that whilst the absolute infection numbers are low for young children because of their low introduction rate, when infected, young children and parents transmit the virus to the same extent within the family.
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COVID-19/transmisión , Trazado de Contacto , Familia , Adolescente , Adulto , Factores de Edad , COVID-19/diagnóstico , COVID-19/epidemiología , Prueba de COVID-19 , Niño , Preescolar , Femenino , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Sistema de Registros , Adulto JovenRESUMEN
Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency among adults and is characterized by a B cell dysfunction and increased risk of respiratory tract infections with encapsulated bacteria. However, a large proportion of patients also has inflammatory and autoimmune complications. It may seem like a paradox that immunodeficiency and inflammation/autoimmunity coexist within the same individuals. In this commentary, we propose that CVID immunopathogenesis involves an interplay of genes, environmental factors, and dysregulation of immune cells, where gut microbiota and gastrointestinal inflammation can both be important contributors or endpoints to the systemic immune activation seen in CVID, and where epigenetic mechanism may be the undiscovered link between these contributors. In our opinion, these pathways could represent novel targets for therapy in CVID directed against autoimmune and inflammatory manifestations that represent the most severe complications in these patients. Considering the heterogeneous nature of CVID, these mechanisms may not be present in all patients, and different complications may be triggered by different risk factors. CVID is really a variable disease and in the future there is clearly a need for a more personalized medicine based on both genotypic and phenotypic findings.
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Autoinmunidad/inmunología , Inmunodeficiencia Variable Común/inmunología , Epigénesis Genética/inmunología , Microbioma Gastrointestinal/inmunología , Inflamación/inmunología , Animales , Cinamatos , Reacciones Cruzadas/inmunología , Genotipo , Humanos , Imidazoles , FenotipoRESUMEN
The dynamics related to the loss of stx genes from Shiga toxin-producing Escherichia coli remain unclear. Current diagnostic procedures have shortcomings in the detection and identification of STEC. This is partly owing to the fact that stx genes may be lost during an infection or in the laboratory. The aim of the present study was to provide new insight into in vivo and in vitro stx loss in order to improve diagnostic procedures. Results from the study support the theory that loss of stx is a strain-related phenomenon and not induced by patient factors. It was observed that one strain could lose stx both in vivo and in vitro. Whole genome comparison of stx-positive and stx-negative isolates from the same patient revealed that different genomic rearrangements, such as complete or partial loss of the parent prophage, may be factors in the loss of stx. Of diagnostic interest, it was shown that patients can be co-infected with different E. coli pathotypes. Therefore, identification of eae-positive, but stx-negative isolates should not be interpreted as "Shiga toxin-lost" E. coli without further testing. Growth and recovery of STEC were supported by different selective agar media for different strains, arguing for inclusion of several media in STEC diagnostics.
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Infecciones por Escherichia coli/diagnóstico , Toxina Shiga/genética , Escherichia coli Shiga-Toxigénica/genética , Adulto , Anciano , Niño , Preescolar , Medios de Cultivo/química , Diarrea/microbiología , Heces/microbiología , Femenino , Humanos , Lactante , Masculino , Técnicas Microbiológicas , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Escherichia coli Shiga-Toxigénica/aislamiento & purificación , Factores de Virulencia , Adulto JovenRESUMEN
OBJECTIVE: Activating mutations in the GUCY2C gene, which encodes the epithelial receptor guanylate cyclase C, cause diarrhea due to increased loss of sodium chloride to the intestinal lumen. Patients with familial GUCY2C diarrhea syndrome (FGDS) are predisposed to inflammatory bowel disease (IBD). We investigated whether genes in the guanylate cyclase C pathway are enriched for association with IBD and reversely whether genetic or transcriptional changes associated with IBD are found in FGDS patients. METHODS: (1) A set of 27 genes from the guanylate cyclase C pathway was tested for enrichment of association with IBD by Gene Set Enrichment Analysis, using genome-wide association summary statistics from 12,882 IBD patients and 21,770 controls. (2) We genotyped 163 known IBD risk loci and sequenced NOD2 in 22 patients with FGDS. Eight of them had concomitant Crohn's disease. (3) Global gene expression analysis was performed in ileal tissue from patients with FGDS, Crohn's disease and healthy individuals. RESULTS: The guanylate cyclase C gene set showed a significant enrichment of association in IBD genome-wide association data. Risk variants in NOD2 were found in 7/8 FGDS patients with concomitant Crohn's disease and in 2/14 FDGS patients without Crohn's disease. In ileal tissue, downregulation of metallothioneins characterized FGDS patients compared to healthy controls. CONCLUSIONS: Our results support a role of guanylate cyclase C signaling and disturbed electrolyte homeostasis in development of IBD. Furthermore, downregulation of metallothioneins in the ileal mucosa of FGDS patients may contribute to IBD development, possibly alongside effects from NOD2 risk variants.
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Diarrea/genética , Enfermedades Inflamatorias del Intestino/genética , Receptores de Enterotoxina/genética , Adulto , Anciano , Estudios de Casos y Controles , Diarrea/metabolismo , Regulación hacia Abajo , Salud de la Familia , Femenino , Expresión Génica , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Íleon/patología , Enfermedades Inflamatorias del Intestino/complicaciones , Masculino , Persona de Mediana Edad , Proteína Adaptadora de Señalización NOD2/genética , Noruega , Plasma/química , Medición de Riesgo , Síndrome , Adulto JovenRESUMEN
BACKGROUND: Primary 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. OBJECTIVE: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. METHODS: Patients 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. RESULTS: A 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. CONCLUSION: This 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.
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Síndromes de Inmunodeficiencia/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Variaciones en el Número de Copia de ADN , Femenino , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BAKGRUNN: I norsk helsevesen gjennomføres omfattende tiltak for å hindre spredning av meticillinresistente Staphylococcus aureus (MRSA). Vi ønsket å undersøke hvor mange smitteoppsporinger som gjøres rundt nyoppdagede MRSA-tilfeller hos pasienter og ansatte i sykehus, og hvor ofte smitteoppsporingene fører til ytterligere funn hos helsepersonell. MATERIALE OG METODE: I denne retrospektive observasjonsstudien bidro smittevernenhetene ved åtte helseforetak i landets fire helseregioner med opplysninger om MRSA-funn hos helsepersonell etter gjennomførte MRSA-smitteoppsporinger. Data ble innhentet fra 14 ulike somatiske sykehus i årene 2012-15. RESULTATER: 10 142 ansatte i helsevesenet ble testet for MRSA, med positivt funn hos 31 ansatte (0,31 %). Hos 19 ansatte (0,19 %) ble det påvist samme MRSA-stamme som hos indekskasus. I kun to av 351 smitteoppsporinger (0,57 %) ble samme MRSA-stamme funnet hos mer enn én ansatt. FORTOLKNING: MRSA-smitteoppsporing i norske sykehus har et betydelig omfang, men det er sjelden det påvises MRSA hos helsepersonell i forbindelse med smitteoppsporing.
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Portador Sano/epidemiología , Trazado de Contacto/estadística & datos numéricos , Personal de Salud/estadística & datos numéricos , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Infección Hospitalaria/epidemiología , Infección Hospitalaria/prevención & control , Infección Hospitalaria/transmisión , Hospitales , Humanos , Control de Infecciones , Noruega/epidemiología , Estudios Retrospectivos , Infecciones Estafilocócicas/epidemiología , Infecciones Estafilocócicas/prevención & control , Infecciones Estafilocócicas/transmisiónRESUMEN
Patients with common variable immunodeficiency (CVID) constitute a clinically and immunologically heterogeneous group characterized by B-cell dysfunction with hypogammaglobulinemia and defective immunoglobulin class switch of unknown etiology. Current classification systems are insufficient to achieve precise disease management. Characterization of signaling pathways essential for B-cell differentiation and class switch could provide new means to stratify patients. We evaluated constitutive and induced signaling by phospho-specific flow cytometry in 26 CVID patients and 18 healthy blood donors. Strong responses were induced both in CVID and healthy donor B cells upon activation. In contrast, constitutive phosphorylation levels of STAT3,-5,-6, Erk, PLC-γ and Syk were significantly increased in CVID B cells only. Hierarchical clustering revealed a subgroup of CVID patients with elevated constitutive phosphorylation of Syk and PLC-γ. All these patients had non-infectious complications, indicating that a distinct phosphorylation pattern of kinases in B cells identifies a clinically important subgroup of CVID patients.
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Subgrupos de Linfocitos B/inmunología , Inmunodeficiencia Variable Común/inmunología , Fosforilación/inmunología , Fosfotransferasas/inmunología , Adulto , Anciano , Femenino , Humanos , Cambio de Clase de Inmunoglobulina/inmunología , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Receptores de Antígenos de Linfocitos B/inmunología , Transducción de Señal/inmunología , Adulto JovenRESUMEN
Common variable immunodeficiency (CVID) is defined by hypogammaglobulinemia and B-cell dysfunction, with significant clinical and immunological heterogeneity. Severe non-infectious complications, such as autoimmunity, granulomatous disease and splenomegaly, constitute a major cause of morbidity in CVID patients. T cells are generally regarded important for development of these clinical features. However, while T-cell abnormalities have been found in CVID patients, functional characteristics of T cells corresponding to well-defined clinical subtypes have not been identified. As common γ-chain cytokines play important roles in survival and differentiation of T cells, characterization of their signaling pathways could reveal functional differences of clinical relevance. We characterized CVID T cells functionally by studies of cytokine-induced signaling, and correlated the findings to defined clinical subtypes. Peripheral blood T cells from 29 CVID patients and 19 healthy donors were analyzed for i) phenotype, ii) cytokine-induced (interleukin (IL)-2, IL-4, IL-7 and IL-21) phosphorylation of signal transducer and activator of transcription (STAT) 3, STAT5 and STAT6, and iii) T-helper (Th)1/Th2 polarization. Expression of IL-4 receptor and downstream signaling molecules was measured. A subgroup of CVID patients (n = 7) was identified by impaired IL-4-induced p-STAT6 in naive and memory CD4 and CD8 T cells. This corresponded to patients with the largest accumulation of severe (non-infectious) complications. The signaling defect persisted over years and was not due to constitutively activated p-STAT6. The CD4 T cells were strongly Th1-skewed, but IL-4 signaling was impaired independently of Th status. However, IL-4Rα and Janus kinase (JAK) 1 mRNA levels were significantly lower than in normal donors, providing a likely mechanism for the defective IL-4-induced p-STAT6 and Th1-bias. In conclusion, we identified a subgroup of CVID patients with defective IL-4 signaling in T cells, with severe clinical features of inflammation and autoimmunity.
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Inmunodeficiencia Variable Común/inmunología , Inmunodeficiencia Variable Común/metabolismo , Interleucina-4/metabolismo , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/metabolismo , Adulto , Biomarcadores , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/diagnóstico , Femenino , Expresión Génica , Humanos , Inmunofenotipificación , Janus Quinasa 1/metabolismo , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Factor de Transcripción STAT6/metabolismo , Índice de Severidad de la Enfermedad , Células TH1/inmunología , Células TH1/metabolismo , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
In the present study, we aimed at identifying the mechanisms whereby the vitamin A metabolite all-trans retinoic acid (RA) promotes the formation of plasma cells upon stimulation of B cells via the innate immunity receptors TLR9 and RP105. Most often, differentiation of B cells involves the sequential events of class switch recombination and somatic hypermutations characteristic of germinal center reactions, followed by plasma cell formation. By studying the regulatory networks known to drive these reactions, we revealed that RA enhances the expression of the plasma cell-generating transcription factors IFN regulatory factor (IRF)4 and Blimp1, and paradoxically also activation-induced deaminase (AID) involved in somatic hypermutations/class switch recombination, in primary human B cells. IRF4 was identified as a particularly important protein involved in the RA-mediated production of IgG in TLR9/RP105-stimulated B cells. Based on kinetic studies, we present a model suggesting that the initial induction of IRF4 by RA favors AID expression. According to this model, the higher level of IRF4 that eventually arises results in sustained elevated levels of Blimp1. Regarded as a master regulator of plasma cell development, Blimp1 will in turn suppress AID expression and drive the formation of IgG-secreting plasma cells. Notably, we demonstrated IRF4 to be deregulated in B cells from common variable immunodeficiency patients, contributing to the observed aberrant expression of AID in these patients. Taken together, the present study both provides new insight into the mechanisms whereby RA induces differentiation of B cells and identifies IRF4 as a key to understand the defective functions of B cells in common variable immunodeficiency patients.