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1.
Microb Genom ; 7(2)2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33555243

RESUMEN

Human tuberculosis (TB) is caused by members of the Mycobacterium tuberculosis complex (MTBC). The MTBC comprises several human-adapted lineages known as M. tuberculosis sensu stricto, as well as two lineages (L5 and L6) traditionally referred to as Mycobacterium africanum. Strains of L5 and L6 are largely limited to West Africa for reasons unknown, and little is known of their genomic diversity, phylogeography and evolution. Here, we analysed the genomes of 350 L5 and 320 L6 strains, isolated from patients from 21 African countries, plus 5 related genomes that had not been classified into any of the known MTBC lineages. Our population genomic and phylogeographical analyses showed that the unclassified genomes belonged to a new group that we propose to name MTBC lineage 9 (L9). While the most likely ancestral distribution of L9 was predicted to be East Africa, the most likely ancestral distribution for both L5 and L6 was the Eastern part of West Africa. Moreover, we found important differences between L5 and L6 strains with respect to their phylogeographical substructure and genetic diversity. Finally, we could not confirm the previous association of drug-resistance markers with lineage and sublineages. Instead, our results indicate that the association of drug resistance with lineage is most likely driven by sample bias or geography. In conclusion, our study sheds new light onto the genomic diversity and evolutionary history of M. africanum, and highlights the need to consider the particularities of each MTBC lineage for understanding the ecology and epidemiology of TB in Africa and globally.

2.
J Exp Med ; 218(2)2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-33170215

RESUMEN

The identification and characterization of rare immune cell populations in humans can be facilitated by their growth advantage in the context of specific genetic diseases. Here, we use autoimmune lymphoproliferative syndrome to identify a population of FAS-controlled TCRαß+ T cells. They include CD4+, CD8+, and double-negative T cells and can be defined by a CD38+CD45RA+T-BET- expression pattern. These unconventional T cells are present in healthy individuals, are generated before birth, are enriched in lymphoid tissue, and do not expand during acute viral infection. They are characterized by a unique molecular signature that is unambiguously different from other known T cell differentiation subsets and independent of CD4 or CD8 expression. Functionally, FAS-controlled T cells represent highly proliferative, noncytotoxic T cells with an IL-10 cytokine bias. Mechanistically, regulation of this physiological population is mediated by FAS and CTLA4 signaling, and its survival is enhanced by mTOR and STAT3 signals. Genetic alterations in these pathways result in expansion of FAS-controlled T cells, which can cause significant lymphoproliferative disease.

3.
Artículo en Inglés | MEDLINE | ID: mdl-33007476

RESUMEN

OBJECTIVES: Investigation whether in depth characterization of virus variant patterns can be used for epidemiological analysis of the first SARS-CoV-2 infection clusters in Hamburg, Germany. METHODS: Metagenomic RNA- and amplicon-sequencing and subsequent variant calling in 25 respiratory samples from SARS-CoV-2 infected patients involved in the earliest infection clusters in Hamburg. RESULTS: Amplikon sequencing and cluster analyses of these SARS-CoV-2 sequences allowed the identification of the first infection cluster and five non-related infection clusters occurring at the beginning of the viral entry of SARS-CoV-2 in the Hamburg metropolitan region. Viral genomics together with epidemiological analyses revealed that the index patient acquired the infection in Northern Italy and transmitted it to two out of 134 contacts. Single nucleotide polymorphisms clearly distinguished the virus variants of the index and other clusters and allowed to track in which sequences worldwide these mutations were first described. Minor variant analyses identified the transmission of intra-host variants in the index cluster and household clusters. CONCLUSIONS: SARS-CoV-2 variant tracing allows the identification of infection clusters and the follow up of infection chains occurring in the population. Furthermore, the follow up of minor viral variants in infection cluster can provide further resolution on transmission events indistinguishable on consensus sequence level.

4.
J Allergy Clin Immunol ; 146(4): 901-911, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32278790

RESUMEN

BACKGROUND: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. OBJECTIVE: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. METHODS: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. RESULTS: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. CONCLUSIONS: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.

6.
Pediatr Infect Dis J ; 38(11): e295-e300, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31626041

RESUMEN

BACKGROUND: Intravenous artesunate (ivA) is the standard treatment for severe malaria. Data systematically evaluating the use of ivA in pediatric patients outside malaria-endemic regions are limited. The aim of this case series was to summarize efficacy and safety of ivA for imported severe malaria in children in Germany. METHODS: Our retrospective case series included pediatric patients with imported severe malaria treated with at least 1 dose of ivA (Artesun, Guilin Pharmaceutical; Shanghai, China) at 4 German tertiary care centers. Severe malaria was defined according to World Health Organization criteria. RESULTS: Between 2010 and 2018, 14 children with a median [interquartile range (IQR)] age of 6 (1;9.5) years were included. All children were of African descent. All but 2 patients had Plasmodium falciparum malaria; 1 child had P. vivax malaria and 1 child had P. falciparum and P. vivax co-infection. Median (IQR) parasitemia at admission in patients with P. falciparum was 9.5% (3;16.5). Patients were treated with 1-10 [median (IQR) 3 (3;4)] doses ivA. All but one patient received a full course of oral antimalarial treatment. Parasite clearance was achieved within 2-4 days, with the exception of 1 patient with prolonged clearance of peripheral parasitemia. Three patients experienced posttreatment hemolysis but none needed blood transfusion. Otherwise ivA was safe and well tolerated. CONCLUSIONS: ivA was highly efficacious in this pediatric cohort. We observed episodes of mild to moderate posttreatment hemolysis in approximately one-third of patients. The legal status and usage of potentially lifesaving ivA should be evaluated in Europe.


Asunto(s)
Antimaláricos/uso terapéutico , Artesunato/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Malaria Vivax/tratamiento farmacológico , Enfermedad Aguda/terapia , Administración Intravenosa , Adolescente , Antimaláricos/administración & dosificación , Artesunato/administración & dosificación , Niño , Preescolar , Enfermedades Transmisibles Importadas/tratamiento farmacológico , Enfermedades Transmisibles Importadas/parasitología , Femenino , Alemania , Humanos , Lactante , Masculino , Parasitemia/tratamiento farmacológico , Estudios Retrospectivos , Centros de Atención Terciaria
7.
Infection ; 47(5): 847-852, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31190299

RESUMEN

PURPOSE: Due to early antenatal screening and treatment, HIV mother-to-child transmission (MTCT) rarely occurs in Germany. The study aimed to investigate the impact on prevalence of HIV infection in the antenatal population and the incidence of late-presenting HIV-infected mothers attributable to increased numbers of refugees. METHODS: Retrospective analysis and comparison were performed for all deliveries in HIV-infected pregnant women presenting to medical care in Munich (southern Germany) and Hamburg (northern Germany) covering two time periods, A (2010-2012) and B (2013-2015). RESULTS: In Munich, deliveries in HIV-infected pregnant women increased 1.6-fold from period A (n = 50) to B (n = 79) with late-presenting cases rising significantly from 2% (1/50) in period A to 13% (10/79) in B. In contrast, late-presenting cases in Hamburg decreased from 14% (14/100) in period A to 7% (7/107) in B, while the total number of HIV-infected women giving birth remained stable. From 2010 to 2015, one late-presenting pregnant woman transmitted HIV in Munich by presumed in utero mode of infection (case reviewed here), while no MTCT occurred in Hamburg. CONCLUSIONS: HIV infections diagnosed late in pregnancy and leading to delayed ART initiation are rising in Munich compared to Hamburg. Antenatal care of HIV-infected pregnant women in Munich appears to have been more affected by the recent refugee influx than Hamburg. Our study highlights the importance of screening all pregnant women for HIV early in pregnancy and providing timely health care access for pregnant refugees and asylum seekers to effectively prevent MTCT in Germany.


Asunto(s)
Infecciones por VIH/epidemiología , Transmisión Vertical de Enfermedad Infecciosa/estadística & datos numéricos , Complicaciones Infecciosas del Embarazo/epidemiología , Complicaciones Infecciosas del Embarazo/virología , Refugiados , Adulto , Fármacos Anti-VIH/uso terapéutico , Femenino , Geografía , Alemania/epidemiología , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Accesibilidad a los Servicios de Salud , Humanos , Embarazo , Prevalencia , Estudios Retrospectivos , Tiempo de Tratamiento , Adulto Joven
8.
Pediatr Infect Dis J ; 38(7): 727-730, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31033907

RESUMEN

Using retrospectively collected data from 383 infants born to HIV-1-infected mothers receiving antiretroviral therapy, we compared transmission rates and hematologic toxicity between infants receiving 2-week (short course) versus longer duration zidovudine postexposure prophylaxis. Short course resulted in lower hematologic toxicity without evidence of increased vertical transmission risk.


Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Infecciones por VIH/prevención & control , Enfermedades Hematológicas/inducido químicamente , Enfermedades Hematológicas/epidemiología , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Zidovudina/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Embarazo , Estudios Retrospectivos , Zidovudina/efectos adversos
9.
Front Immunol ; 10: 297, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30941118

RESUMEN

Non-canonical NF-κB-pathway signaling is integral in immunoregulation. Heterozygous mutations in NFKB2 have recently been established as a molecular cause of common variable immunodeficiency (CVID) and DAVID-syndrome, a rare condition combining deficiency of anterior pituitary hormone with CVID. Here, we investigate 15 previously unreported patients with primary immunodeficiency (PID) from eleven unrelated families with heterozygous NFKB2-mutations including eight patients with the common p.Arg853* nonsense mutation and five patients harboring unique novel C-terminal truncating mutations. In addition, we describe the clinical phenotype of two patients with proximal truncating mutations. Cohort analysis extended to all 35 previously published NFKB2-cases revealed occurrence of early-onset PID in 46/50 patients (mean age of onset 5.9 years, median 4.0 years). ACTH-deficiency occurred in 44%. Three mutation carriers have deceased, four developed malignancies. Only two mutation carriers were clinically asymptomatic. In contrast to typical CVID, most patients suffered from early-onset and severe disease manifestations, including clinical signs of T cell dysfunction e.g., chronic-viral or opportunistic infections. In addition, 80% of patients suffered from (predominately T cell mediated) autoimmune (AI) phenomena (alopecia > various lymphocytic organ-infiltration > diarrhea > arthritis > AI-cytopenia). Unlike in other forms of CVID, auto-antibodies or lymphoproliferation were not common hallmarks of disease. Immunophenotyping showed largely normal or even increased quantities of naïve and memory CD4+ or CD8+ T-cells and normal T-cell proliferation. NK-cell number and function were also normal. In contrast, impaired B-cell differentiation and hypogammaglobinemia were consistent features of NFKB2-associated disease. In addition, an array of lymphocyte subpopulations, such as regulatory T cell, Th17-, cTFH-, NKT-, and MAIT-cell numbers were decreased. We conclude that heterozygous damaging mutations in NFKB2 represent a distinct PID entity exceeding the usual clinical spectrum of CVID. Impairment of the non-canonical NF-κB pathways affects function and differentiation of numerous lymphocyte-subpopulations and thus causes a heterogeneous, more severe form of PID phenotype with early-onset. Further characteristic features are multifaceted, primarily T cell-mediated autoimmunity, such as alopecia, lymphocytic organ infiltration, and in addition frequently ACTH-deficiency.


Asunto(s)
Mutación/genética , Mutación/inmunología , Subunidad p52 de NF-kappa B/genética , Subunidad p52 de NF-kappa B/inmunología , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/inmunología , Adolescente , Adulto , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Proliferación Celular/genética , Niño , Femenino , Humanos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , FN-kappa B/inmunología , Fenotipo , Linfocitos T Reguladores/inmunología , Adulto Joven
10.
Brain ; 141(8): 2299-2311, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-29985992

RESUMEN

The transcription factor BCL11B is essential for development of the nervous and the immune system, and Bcl11b deficiency results in structural brain defects, reduced learning capacity, and impaired immune cell development in mice. However, the precise role of BCL11B in humans is largely unexplored, except for a single patient with a BCL11B missense mutation, affected by multisystem anomalies and profound immune deficiency. Using massively parallel sequencing we identified 13 patients bearing heterozygous germline alterations in BCL11B. Notably, all of them are affected by global developmental delay with speech impairment and intellectual disability; however, none displayed overt clinical signs of immune deficiency. Six frameshift mutations, two nonsense mutations, one missense mutation, and two chromosomal rearrangements resulting in diminished BCL11B expression, arose de novo. A further frameshift mutation was transmitted from a similarly affected mother. Interestingly, the most severely affected patient harbours a missense mutation within a zinc-finger domain of BCL11B, probably affecting the DNA-binding structural interface, similar to the recently published patient. Furthermore, the most C-terminally located premature termination codon mutation fails to rescue the progenitor cell proliferation defect in hippocampal slice cultures from Bcl11b-deficient mice. Concerning the role of BCL11B in the immune system, extensive immune phenotyping of our patients revealed alterations in the T cell compartment and lack of peripheral type 2 innate lymphoid cells (ILC2s), consistent with the findings described in Bcl11b-deficient mice. Unsupervised analysis of 102 T lymphocyte subpopulations showed that the patients clearly cluster apart from healthy children, further supporting the common aetiology of the disorder. Taken together, we show here that mutations leading either to BCL11B haploinsufficiency or to a truncated BCL11B protein clinically cause a non-syndromic neurodevelopmental delay. In addition, we suggest that missense mutations affecting specific sites within zinc-finger domains might result in distinct and more severe clinical outcomes.


Asunto(s)
Trastornos del Neurodesarrollo/genética , Proteínas Represoras/genética , Proteínas Represoras/fisiología , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/fisiología , Adolescente , Animales , Niño , Preescolar , Femenino , Regulación de la Expresión Génica/genética , Mutación de Línea Germinal , Haploinsuficiencia , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Linfocitos/patología , Linfocitos/fisiología , Masculino , Ratones , Mutación , Proteínas Represoras/metabolismo , Linfocitos T/fisiología , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/metabolismo
11.
Euro Surveill ; 23(12)2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29589578

RESUMEN

BackgroundIn Germany, the incidence of tuberculosis (TB) in children has been on the rise since 2009. High numbers of foreign-born asylum seekers have contributed considerably to the disease burden. Therefore, effective screening strategies for latent TB infection (LTBI) and active TB in asylum seeking children are needed. Aim: Our aim was to investigate the prevalence of LTBI and active TB in asylum seeking children up to 15 years of age in two geographic regions in Germany. Methods: Screening for TB was performed in children in asylum seeker reception centres by tuberculin skin test (TST) or interferon gamma release assay (IGRA). Children with positive results were evaluated for active TB. Additionally, country of origin, sex, travel time, TB symptoms, TB contact and Bacille Calmette-Guérin (BCG) vaccination status were registered. Results: Of 968 screened children 66 (6.8%) had TB infection (58 LTBI, 8 active TB). LTBI prevalence was similar in children from high (Afghanistan) and low (Syria) incidence countries (8.7% vs 6.4%). There were no differences regarding sex, age or travel time between infected and non-infected children. Children under the age of 6 years were at higher risk of progression to active TB (19% vs 2% respectively, p=0,07). Most children (7/8) with active TB were asymptomatic at the time of diagnosis. None of the children had been knowingly exposed to TB. Conclusions: Asylum seeking children from high and low incidence countries are both at risk of developing LTBI or active TB. Universal TB screening for all asylum seeking children should be considered.


Asunto(s)
Ensayos de Liberación de Interferón gamma/métodos , Tuberculosis Latente/diagnóstico , Tuberculosis Latente/epidemiología , Refugiados/estadística & datos numéricos , Prueba de Tuberculina/métodos , Tuberculosis/diagnóstico , Tuberculosis/epidemiología , Afganistán/etnología , Niño , Preescolar , Prestación de Atención de Salud , Femenino , Alemania/epidemiología , Humanos , Incidencia , Lactante , Tuberculosis Latente/etnología , Masculino , Prevalencia , Siria/etnología , Viaje , Tuberculosis/etnología
12.
J Allergy Clin Immunol ; 141(4): 1427-1438, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-28782633

RESUMEN

BACKGROUND: Primary antibody deficiencies (PADs) are the most frequent primary immunodeficiencies in human subjects. The genetic causes of PADs are largely unknown. Sec61 translocon alpha 1 subunit (SEC61A1) is the major subunit of the Sec61 complex, which is the main polypeptide-conducting channel in the endoplasmic reticulum membrane. SEC61A1 is a target gene of spliced X-box binding protein 1 and strongly induced during plasma cell (PC) differentiation. OBJECTIVE: We identified a novel genetic defect and studied its pathologic mechanism in 11 patients from 2 unrelated families with PADs. METHODS: Whole-exome and targeted sequencing were conducted to identify novel genetic mutations. Functional studies were carried out ex vivo in primary cells of patients and in vitro in different cell lines to assess the effect of SEC61A1 mutations on B-cell differentiation and survival. RESULTS: We investigated 2 families with patients with hypogammaglobulinemia, severe recurrent respiratory tract infections, and normal peripheral B- and T-cell subpopulations. On in vitro stimulation, B cells showed an intrinsic deficiency to develop into PCs. Genetic analysis and targeted sequencing identified novel heterozygous missense (c.254T>A, p.V85D) and nonsense (c.1325G>T, p.E381*) mutations in SEC61A1, segregating with the disease phenotype. SEC61A1-V85D was deficient in cotranslational protein translocation, and it disturbed the cellular calcium homeostasis in HeLa cells. Moreover, SEC61A1-V85D triggered the terminal unfolded protein response in multiple myeloma cell lines. CONCLUSION: We describe a monogenic defect leading to a specific PC deficiency in human subjects, expanding our knowledge about the pathogenesis of antibody deficiencies.


Asunto(s)
Síndromes de Inmunodeficiencia/genética , Mutación/genética , Células Plasmáticas/patología , Canales de Translocación SEC/genética , Agammaglobulinemia/genética , Agammaglobulinemia/metabolismo , Agammaglobulinemia/patología , Linfocitos B/metabolismo , Linfocitos B/patología , Calcio/metabolismo , Diferenciación Celular/genética , Línea Celular , Línea Celular Tumoral , Exoma/genética , Células HEK293 , Células HeLa , Heterocigoto , Humanos , Síndromes de Inmunodeficiencia/metabolismo , Células Plasmáticas/metabolismo , Transporte de Proteínas/genética , Infecciones del Sistema Respiratorio/genética , Infecciones del Sistema Respiratorio/metabolismo , Infecciones del Sistema Respiratorio/patología , Linfocitos T/metabolismo , Linfocitos T/patología , Respuesta de Proteína Desplegada/genética
13.
Inflamm Bowel Dis ; 23(12): 2109-2120, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28930861

RESUMEN

BACKGROUND: In contrast to adult-onset inflammatory bowel disease (IBD), where many genetic loci have been shown to be involved in complex disease etiology, early-onset IBD (eoIBD) and associated syndromes can sometimes present as monogenic conditions. As a result, the clinical phenotype and ideal disease management in these patients often differ from those in adult-onset IBD. However, due to high costs and the complexity of data analysis, high-throughput screening for genetic causes has not yet become a standard part of the diagnostic work-up of eoIBD patients. METHODS: We selected 28 genes of interest associated with monogenic IBD and performed targeted panel sequencing in 71 patients diagnosed with eoIBD or early-onset chronic diarrhea to detect causative variants. We compared these results to whole-exome sequencing (WES) data available for 25 of these patients. RESULTS: Target coverage was significantly higher in the targeted gene panel approach compared with WES, whereas the cost of the panel was considerably lower (approximately 25% of WES). Disease-causing variants affecting protein function were identified in 5 patients (7%), located in genes of the IL10 signaling pathway (3), WAS (1), and DKC1 (1). The functional effects of 8 candidate variants in 5 additional patients (7%) are under further investigation. WES did not identify additional causative mutations in 25 patients. CONCLUSIONS: Targeted gene panel sequencing is a fast and effective screening method for monogenic causes of eoIBD that should be routinely established in national referral centers.


Asunto(s)
Diarrea/etiología , Predisposición Genética a la Enfermedad , Enfermedades Inflamatorias del Intestino/genética , Edad de Inicio , Niño , Preescolar , Enfermedad Crónica , Femenino , Estudio de Asociación del Genoma Completo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Secuenciación del Exoma Completo
14.
Transplantation ; 101(5): e166-e169, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28263223

RESUMEN

Persistently elevated eosinophil granulocytes in the peripheral blood in children is challenging because of a complex diagnosis especially after solid organ transplantation and can lead to difficulties in finding an underlying causative factor.We report a 12-year-old boy who developed severe hypereosinophilia 11 years after liver transplantation due to biliary atresia. Accompanying symptoms were recurrent fever, fatigue, elevated liver enzymes, abdominal pain, and significant weight loss. After exclusion of secondary causes of eosinophilia, an idiopathic hypereosinophilic syndrome (I-HES) was diagnosed. Treatment with prednisolone resulted in an immediate response with rapid reduction of eosinophils, normalization of liver enzymes, and amelioration of any clinical symptoms. A hypereosinophilic syndrome in patients after liver transplantation is rare, and a broad differential diagnosis has to be considered. Prednisolone may lead to a prompt amelioration of eosinophilia and associated symptoms.


Asunto(s)
Síndrome Hipereosinofílico/etiología , Trasplante de Hígado , Complicaciones Posoperatorias , Niño , Humanos , Síndrome Hipereosinofílico/diagnóstico , Masculino , Complicaciones Posoperatorias/diagnóstico
15.
BMC Nephrol ; 18(1): 96, 2017 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-28320387

RESUMEN

BACKGROUND: Influenza A infections have been described to cause secondary hemolytic uremic syndrome and to trigger atypical hemolytic uremic syndrome (aHUS) in individuals with an underlying genetic complement dysregulation. To date, influenza B has not been reported to trigger aHUS. CASE PRESENTATION: A 6-month-old boy presented with hemolytic uremic syndrome triggered by influenza B infection. Initially the child recovered spontaneously. When he relapsed Eculizumab treatment was initiated, resulting in complete and sustained remission. A pathogenic mutation in membrane cofactor protein (MCP) was detected. CONCLUSION: Influenza B is a trigger for aHUS and might be underreported as such. Influenza vaccination may protect patients at risk.


Asunto(s)
Síndrome Hemolítico Urémico Atípico/diagnóstico , Síndrome Hemolítico Urémico Atípico/etiología , Virus de la Influenza B/aislamiento & purificación , Gripe Humana/complicaciones , Gripe Humana/diagnóstico , Síndrome Hemolítico Urémico Atípico/terapia , Diagnóstico Diferencial , Humanos , Lactante , Virus de la Influenza B/clasificación , Gripe Humana/terapia , Masculino , Resultado del Tratamiento
16.
Haematologica ; 102(2): e52-e56, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27789675
18.
Blood ; 128(2): 227-38, 2016 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-27099149

RESUMEN

Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas signaling, resulting in chronic benign lymphoproliferation and accumulation of TCRαß(+) CD4(-) CD8(-) double-negative T (DNT) cells. Although their phenotype resembles that of terminally differentiated or exhausted T cells, lack of KLRG1, high eomesodermin, and marginal T-bet expression point instead to a long-lived memory state with potent proliferative capacity. Here we show that despite their terminally differentiated phenotype, human ALPS DNT cells exhibit substantial mitotic activity in vivo. Notably, hyperproliferation of ALPS DNT cells is associated with increased basal and activation-induced phosphorylation of serine-threonine kinases Akt and mechanistic target of rapamycin (mTOR). The mTOR inhibitor rapamycin abrogated survival and proliferation of ALPS DNT cells, but not of CD4(+) or CD8(+) T cells in vitro. In vivo, mTOR inhibition reduced proliferation and abnormal differentiation by DNT cells. Importantly, increased mitotic activity and hyperactive mTOR signaling was also observed in recently defined CD4(+) or CD8(+) precursor DNT cells, and mTOR inhibition specifically reduced these cells in vivo, indicating abnormal programming of Fas-deficient T cells before the DNT stage. Thus, our results identify the mTOR pathway as a major regulator of lymphoproliferation and aberrant differentiation in ALPS.


Asunto(s)
Síndrome Linfoproliferativo Autoinmune/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Transducción de Señal/inmunología , Serina-Treonina Quinasas TOR/inmunología , Adolescente , Adulto , Síndrome Linfoproliferativo Autoinmune/patología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/patología , Niño , Preescolar , Femenino , Humanos , Lectinas Tipo C/inmunología , Antígenos Comunes de Leucocito/inmunología , Masculino , Proteínas Proto-Oncogénicas c-akt/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores Inmunológicos , Transactivadores/inmunología
19.
Gene ; 586(2): 234-8, 2016 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-27063510

RESUMEN

Recently, gain-of-function (GOF) mutations in the gene encoding signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis (CMC). This case report describes a 10-year-old boy presenting with signs of common variable immunodeficiency (CVID), failure to thrive, impaired neurological development, and a history of recurrent mucocutaneous Candida infections. Sequencing of the STAT1 gene identified a heterozygous missense mutation in exon 7 encoding the STAT1 coiled-coil domain (c.514T>C, p.Phe172Leu). In addition to hypogammaglobulinemia with B-cell deficiency, and a low percentage of Th17 cells, immunological analysis of the patient revealed a marked depletion of forkhead-box P3(+)-expressing regulatory T cells (Tregs). In vitro stimulation of T cells from the patient with interferon-α (IFNα) and/or IFNÉ£ resulted in a significantly increased expression of STAT1-regulated target genes such as MIG1, IRF1, MX1, MCP1/CCL2, IFI-56K, and CXCL10 as compared to IFN-treated cells from a healthy control, while no IFNα/É£-mediated up-regulation of the FOXP3 gene was found. These data demonstrate that the STAT1 GOF mutation F172L, which results in impaired stability of the antiparallel STAT1 dimer conformation, is associated with inhibited Treg cell development and neurological symptoms.


Asunto(s)
Inmunodeficiencia Variable Común/genética , Mutación Missense , Factor de Transcripción STAT1/genética , Linfocitos T Reguladores/inmunología , Candidiasis Mucocutánea Crónica/complicaciones , Candidiasis Mucocutánea Crónica/diagnóstico , Niño , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/inmunología , Expresión Génica , Humanos , Masculino , Trastornos del Neurodesarrollo/complicaciones , Trastornos del Neurodesarrollo/diagnóstico , Fenotipo
20.
J Clin Immunol ; 36(1): 73-84, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26604104

RESUMEN

PURPOSE: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients. METHODS: STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients. RESULTS: Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61%). Out of 39 familial cases from 11 families, 26 patients (67%) from 9 families and out of 18 sporadic cases, 9 patients (50%) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients. CONCLUSION: STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.


Asunto(s)
Candidiasis Mucocutánea Crónica/diagnóstico , Síndromes de Inmunodeficiencia/diagnóstico , Leucocitos Mononucleares/inmunología , Mutación/genética , Factor de Transcripción STAT1/metabolismo , Adulto , Candidiasis Mucocutánea Crónica/genética , Células Cultivadas , Citocinas/metabolismo , Análisis Mutacional de ADN , Femenino , Humanos , Síndromes de Inmunodeficiencia/genética , Masculino , Linaje , Fenotipo , Estructura Terciaria de Proteína/genética , Factor de Transcripción STAT1/genética
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