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1.
Hepatology ; 75(1): 13-27, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34473365

RESUMEN

BACKGROUND AND AIMS: Detection of autoantibodies is a mainstay of diagnosing autoimmune hepatitis (AIH). However, conventional autoantibodies for the workup of AIH lack either sensitivity or specificity, leading to substantial diagnostic uncertainty. We aimed to identify more accurate serological markers of AIH with a protein macroarray. APPROACH AND RESULTS: During the search for more-precise autoantibodies to distinguish AIH from non-AIH liver diseases (non-AIH-LD), IgG antibodies with binding capacities to many human and foreign proteins were identified with a protein macroarray and confirmed with solid-phase ELISAs in AIH patients. Subsequently, polyreactive IgG (pIgG) was exemplarily quantified by reactivity against human huntingtin-interacting protein 1-related protein in bovine serum albumin blocked ELISA (HIP1R/BSA). The diagnostic fidelity of HIP1R/BSA binding pIgG to diagnose AIH was assessed in a retrospective training, a retrospective multicenter validation, and a prospective validation cohort in cryoconserved samples from 1,568 adults from 10 centers from eight countries. Reactivity against HIP1R/BSA had a 25% and 14% higher specificity to diagnose AIH than conventional antinuclear and antismooth muscle antibodies, a significantly higher sensitivity than liver kidney microsomal antibodies and antisoluble liver antigen/liver pancreas antigen, and a 12%-20% higher accuracy than conventional autoantibodies. Importantly, HIP1R/BSA reactivity was present in up to 88% of patients with seronegative AIH and in up to 71% of AIH patients with normal IgG levels. Under therapy, pIgG returns to background levels of non-AIH-LD. CONCLUSIONS: pIgG could be used as a promising marker to improve the diagnostic workup of liver diseases with a higher specificity for AIH compared to conventional autoantibodies and a utility in autoantibody-negative AIH. Likewise, pIgG could be a major source of assay interference in untreated AIH.


Asunto(s)
Autoanticuerpos/sangre , Hepatitis Autoinmune/diagnóstico , Inmunoglobulina G/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Diagnóstico Diferencial , Femenino , Hepatitis Autoinmune/sangre , Hepatitis Autoinmune/inmunología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto Joven
2.
Blood ; 125(3): 457-64, 2015 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-25411428

RESUMEN

The origins of dendritic cells (DCs) and other myeloid cells in the thymus have remained controversial. In this study, we assessed developmental relationships between thymic dendritic cells and thymocytes, employing retrovirus-based cellular barcoding and reporter mice, as well as intrathymic transfers coupled with DC depletion. We demonstrated that a subset of early T-lineage progenitors expressed CX3CR1, a bona fide marker for DC progenitors. However, intrathymic transfers into nonmanipulated mice, as well as retroviral barcoding, indicated that thymic dendritic cells and thymocytes were largely of distinct developmental origin. In contrast, intrathymic transfers after in vivo depletion of DCs resulted in intrathymic development of non-T-lineage cells. In conclusion, our data support a model in which the adoption of T-lineage fate by noncommitted progenitors at steady state is enforced by signals from the thymic microenvironment unless niches promoting alternative lineage fates become available.


Asunto(s)
Células Dendríticas/inmunología , Células Mieloides/inmunología , Nicho de Células Madre/inmunología , Células Madre/inmunología , Linfocitos T/inmunología , Timo/inmunología , Animales , Diferenciación Celular , Linaje de la Célula , Células Cultivadas , Células Dendríticas/citología , Citometría de Flujo , Ratones , Ratones Endogámicos C57BL , Células Mieloides/citología , Células Madre/citología , Linfocitos T/citología , Timo/citología
3.
Blood ; 121(15): 2943-51, 2013 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-23403622

RESUMEN

Genetic disorders of lymphocyte cytotoxicity predispose patients to hemophagocytic lymphohistiocytosis (HLH). Reduced lymphocyte cytotoxicity has been demonstrated in Hermansky-Pudlak syndrome type 2 (HPS2), but only a single patient was reported who developed HLH. Because that patient also carried a potentially contributing heterozygous RAB27A mutation, the risk for HLH in HPS2 remains unclear. We analyzed susceptibility to HLH in the pearl mouse model of HPS2. After infection with lymphocytic choriomeningitis virus, pearl mice developed all key features of HLH, linked to impaired virus control caused by a moderate defect in CTL cytotoxicity in vivo. However, in contrast to perforin-deficient mice, the disease was transient, and all mice fully recovered and controlled the infection. An additional heterozygous Rab27a mutation did not aggravate the cytotoxicity defect or disease parameters. In the largest survey of 22 HPS2 patients covering 234 patient years, we identified only 1 additional patient with HLH and 2 with incomplete transient HLH-like episodes, although cytotoxicity or degranulation was impaired in all 16 patients tested. HPS2 confers a risk for HLH that is lower than in Griscelli or Chediak-Higashi syndrome, probably because of a milder defect in cytotoxicity. Preemptive hematopoietic stem cell transplantation does not appear justified in HPS2.


Asunto(s)
Citotoxicidad Inmunológica/inmunología , Síndrome de Hermanski-Pudlak/inmunología , Linfohistiocitosis Hemofagocítica/inmunología , Linfocitos T Citotóxicos/inmunología , Complejo 3 de Proteína Adaptadora/deficiencia , Complejo 3 de Proteína Adaptadora/genética , Complejo 3 de Proteína Adaptadora/inmunología , Subunidades beta de Complejo de Proteína Adaptadora/deficiencia , Subunidades beta de Complejo de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/inmunología , Adolescente , Adulto , Animales , Niño , Preescolar , Citotoxicidad Inmunológica/genética , Citometría de Flujo , Síndrome de Hermanski-Pudlak/complicaciones , Síndrome de Hermanski-Pudlak/genética , Humanos , Linfohistiocitosis Hemofagocítica/etiología , Linfohistiocitosis Hemofagocítica/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Factores de Riesgo , Linfocitos T Citotóxicos/metabolismo , Adulto Joven , Proteínas de Unión al GTP rab/deficiencia , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab/inmunología , Proteínas rab27 de Unión a GTP
4.
J Clin Immunol ; 34(3): 331-9, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24519095

RESUMEN

PURPOSE: Loss-of-function mutations in IL10 and IL10R cause very early onset inflammatory bowel disease (VEO-IBD). Here, we investigated the molecular pathomechanism of a novel intronic IL10RA mutation and describe a new therapeutic approach of T cell replete haploidentical hematopoietic stem cell transplantation (HSCT). METHODS: Clinical data were collected by chart review. Genotypes of IL10 and IL10R genes were determined by Sanger sequencing. Expression and function of mutated IL-10R1 were assessed by quantitative PCR, Western blot analysis, enzyme-linked immunosorbent assays, confocal microscopy, and flow cytometry. RESULTS: We identified a novel homozygous point mutation in intron 3 of the IL10RA (c.368-10C > G) in three related children with VEO-IBD. Bioinformatical analysis predicted an additional 3' splice site created by the mutation. Quantitative PCR analysis showed normal mRNA expression of mutated IL10RA. Sequencing of the patient's cDNA revealed an insertion of the last nine nucleotides of intron 3 as a result of aberrant splicing. Structure-based modeling suggested misfolding of mutated IL-10R1. Western blot analysis demonstrated a different N-linked glycosylation pattern of mutated protein. Immunofluorescence and FACS analysis revealed impaired expression of mutated IL-10R1 at the plasma membrane. In the absence of HLA-identical donors, T cell replete haploidentical HSCT was successfully performed in two patients. CONCLUSIONS: Our findings expand the spectrum of IL10R mutations in VEO-IBD and emphasize the need for genetic diagnosis of mutations in conserved non-coding sequences of candidate genes. Transplantation of haploidentical stem cells represents a curative therapy in IL-10R-deficient patients, but may be complicated by non-engraftment.


Asunto(s)
Trasplante de Médula Ósea , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/terapia , Subunidad alfa del Receptor de Interleucina-10/metabolismo , Edad de Inicio , Empalme Alternativo , Secuencia de Aminoácidos , Línea Celular , Membrana Celular/metabolismo , Niño , Preescolar , Consanguinidad , Análisis Mutacional de ADN , Femenino , Genotipo , Glicosilación , Trasplante de Células Madre Hematopoyéticas , Humanos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Subunidad alfa del Receptor de Interleucina-10/química , Subunidad alfa del Receptor de Interleucina-10/genética , Intrones , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Mutación , Linaje , Fenotipo , Conformación Proteica , Transporte de Proteínas , Alineación de Secuencia , Transducción de Señal , Linfocitos T/inmunología , Resultado del Tratamiento
5.
Blood ; 119(15): 3450-7, 2012 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-22294732

RESUMEN

We describe a novel clinical phenotype associating T- and B-cell lymphopenia, intermittent neutropenia, and atrial septal defects in 3 members of a consanguineous kindred. Their clinical histories included recurrent bacterial infections, viral infections, mucocutaneous candidiasis, cutaneous warts, and skin abscesses. Homozygosity mapping and candidate gene sequencing revealed a homozygous premature termination mutation in the gene STK4 (serine threonine kinase 4, formerly having the symbol MST1). STK4 is the human ortholog of Drosophila Hippo, the central constituent of a highly conserved pathway controlling cell growth and apoptosis. STK4-deficient lymphocytes and neutrophils exhibit enhanced loss of mitochondrial membrane potential and increased susceptibility to apoptosis. STK4 deficiency is a novel human primary immunodeficiency syndrome.


Asunto(s)
Síndromes de Inmunodeficiencia/genética , Neutropenia/genética , Proteínas Serina-Treonina Quinasas/genética , Secuencia de Bases , Estudios de Casos y Controles , Preescolar , Consanguinidad , Análisis Mutacional de ADN , Femenino , Humanos , Síndromes de Inmunodeficiencia/sangre , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/inmunología , Péptidos y Proteínas de Señalización Intracelular , Irán/epidemiología , Masculino , Neutropenia/sangre , Neutropenia/etiología , Neutropenia/inmunología , Linaje , Fenotipo , Proteínas Serina-Treonina Quinasas/deficiencia
6.
Hepatol Int ; 18(4): 1214-1226, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38976227

RESUMEN

OBJECTIVE: The detection of autoantibodies is essential to diagnose autoimmune hepatitis (AIH). Particularly in children, specificity of autoantibodies decreases due to lower titers being diagnostic and being present not only in AIH but also in other liver diseases. Recently, quantification of polyreactive IgG (pIgG) for detection of adult AIH showed the highest overall accuracy compared to antinuclear antibodies (ANA), anti-smooth muscle antibodies (anti-SMA), anti-liver kidney microsomal antibodies (anti-LKM) and anti-soluble liver antigen/liver pancreas antibodies (anti-SLA/LP). We aimed to evaluate the diagnostic value of pIgG for pediatric AIH. DESIGN: pIgG, quantified using HIP1R/BSA coated ELISA, and immunofluorescence on rodent tissue sections were performed centrally. The diagnostic fidelity to diagnose AIH was compared to conventional autoantibodies of AIH in training and validation cohorts from a retrospective, European multi-center cohort from nine centers from eight European countries composed of existing biorepositories from expert centers (n = 285). RESULTS: IgG from pediatric AIH patients exhibited increased polyreactivity to multiple protein and non-protein substrates compared to non-AIH liver diseases and healthy children. pIgG had an AUC of 0.900 to distinguish AIH from non-AIH liver diseases. pIgG had a 31-73% higher specificity than ANA and anti-SMA and comparable sensitivity that was 6-20 times higher than of anti-SLA/LP, anti-LC1 and anti-LKM. pIgG had a 21-34% higher accuracy than conventional autoantibodies, was positive in 43-75% of children with AIH and normal IgG and independent from treatment response. CONCLUSION: Detecting pIgG improves the diagnostic evaluation of pediatric AIH compared to conventional autoantibodies, primarily owing to higher accuracy and specificity.


Asunto(s)
Autoanticuerpos , Hepatitis Autoinmune , Inmunoglobulina G , Hepatitis Autoinmune/diagnóstico , Hepatitis Autoinmune/inmunología , Hepatitis Autoinmune/sangre , Humanos , Niño , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Masculino , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Femenino , Adolescente , Estudios Retrospectivos , Preescolar , Sensibilidad y Especificidad , Ensayo de Inmunoadsorción Enzimática/métodos , Animales
7.
Gastroenterology ; 143(2): 347-55, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22549091

RESUMEN

BACKGROUND & AIMS: Homozygous loss of function mutations in interleukin-10 (IL10) and interleukin-10 receptors (IL10R) cause severe infantile (very early onset) inflammatory bowel disease (IBD). Allogeneic hematopoietic stem cell transplantation (HSCT) was reported to induce sustained remission in 1 patient with IL-10R deficiency. We investigated heterogeneity among patients with very early onset IBD, its mechanisms, and the use of allogeneic HSCT to treat this disorder. METHODS: We analyzed 66 patients with early onset IBD (younger than 5 years of age) for mutations in the genes encoding IL-10, IL-10R1, and IL-10R2. IL-10R deficiency was confirmed by functional assays on patients' peripheral blood mononuclear cells (immunoblot and enzyme-linked immunosorbent assay analyses). We assessed the therapeutic effects of standardized allogeneic HSCT. RESULTS: Using a candidate gene sequencing approach, we identified 16 patients with IL-10 or IL-10R deficiency: 3 patients had mutations in IL-10, 5 had mutations in IL-10R1, and 8 had mutations in IL-10R2. Refractory colitis became manifest in all patients within the first 3 months of life and was associated with perianal disease (16 of 16 patients). Extraintestinal symptoms included folliculitis (11 of 16) and arthritis (4 of 16). Allogeneic HSCT was performed in 5 patients and induced sustained clinical remission with a median follow-up time of 2 years. In vitro experiments confirmed reconstitution of IL-10R-mediated signaling in all patients who received the transplant. CONCLUSIONS: We identified loss of function mutations in IL-10 and IL-10R in patients with very early onset IBD. These findings indicate that infantile IBD patients with perianal disease should be screened for IL-10 and IL-10R deficiency and that allogeneic HSCT can induce remission in those with IL-10R deficiency.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Enfermedades Inflamatorias del Intestino , Subunidad alfa del Receptor de Interleucina-10/genética , Subunidad beta del Receptor de Interleucina-10/genética , Interleucina-10/genética , Western Blotting , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Femenino , Marcadores Genéticos , Humanos , Lactante , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/cirugía , Interleucina-10/deficiencia , Subunidad alfa del Receptor de Interleucina-10/deficiencia , Subunidad beta del Receptor de Interleucina-10/deficiencia , Masculino , Mutación , Análisis de Secuencia de ADN , Resultado del Tratamiento
8.
N Engl J Med ; 361(21): 2033-45, 2009 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-19890111

RESUMEN

BACKGROUND: The molecular cause of inflammatory bowel disease is largely unknown. METHODS: We performed genetic-linkage analysis and candidate-gene sequencing on samples from two unrelated consanguineous families with children who were affected by early-onset inflammatory bowel disease. We screened six additional patients with early-onset colitis for mutations in two candidate genes and carried out functional assays in patients' peripheral-blood mononuclear cells. We performed an allogeneic hematopoietic stem-cell transplantation in one patient. RESULTS: In four of nine patients with early-onset colitis, we identified three distinct homozygous mutations in genes IL10RA and IL10RB, encoding the IL10R1 and IL10R2 proteins, respectively, which form a heterotetramer to make up the interleukin-10 receptor. The mutations abrogate interleukin-10-induced signaling, as shown by deficient STAT3 (signal transducer and activator of transcription 3) phosphorylation on stimulation with interleukin-10. Consistent with this observation was the increased secretion of tumor necrosis factor alpha and other proinflammatory cytokines from peripheral-blood mononuclear cells from patients who were deficient in IL10R subunit proteins, suggesting that interleukin-10-dependent "negative feedback" regulation is disrupted in these cells. The allogeneic stem-cell transplantation performed in one patient was successful. CONCLUSIONS: Mutations in genes encoding the IL10R subunit proteins were found in patients with early-onset enterocolitis, involving hyperinflammatory immune responses in the intestine. Allogeneic stem-cell transplantation resulted in disease remission in one patient.


Asunto(s)
Enfermedades Inflamatorias del Intestino/genética , Subunidad alfa del Receptor de Interleucina-10/genética , Subunidad beta del Receptor de Interleucina-10/genética , Mutación Missense , Edad de Inicio , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 21 , Femenino , Ligamiento Genético , Humanos , Lactante , Enfermedades Inflamatorias del Intestino/terapia , Interleucina-10/metabolismo , Subunidad alfa del Receptor de Interleucina-10/química , Subunidad beta del Receptor de Interleucina-10/química , Masculino , Linaje , Polimorfismo de Nucleótido Simple , Inducción de Remisión , Análisis de Secuencia de ADN , Trasplante de Células Madre , Factor de Necrosis Tumoral alfa/metabolismo
9.
N Engl J Med ; 360(1): 32-43, 2009 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-19118303

RESUMEN

BACKGROUND: The main features of severe congenital neutropenia are the onset of severe bacterial infections early in life, a paucity of mature neutrophils, and an increased risk of leukemia. In many patients, the genetic causes of severe congenital neutropenia are unknown. METHODS: We performed genomewide genotyping and linkage analysis on two consanguineous pedigrees with a total of five children affected with severe congenital neutropenia. Candidate genes from the linkage interval were sequenced. Functional assays and reconstitution experiments were carried out. RESULTS: All index patients were susceptible to bacterial infections and had very few mature neutrophils in the bone marrow; structural heart defects, urogenital abnormalities, and venous angiectasia on the trunk and extremities were additional features. Linkage analysis of the two index families yielded a combined multipoint lod score of 5.74 on a linkage interval on chromosome 17q21. Sequencing of G6PC3, the candidate gene encoding glucose-6-phosphatase, catalytic subunit 3, revealed a homozygous missense mutation in exon 6 that abolished the enzymatic activity of glucose-6-phosphatase in all affected children in the two families. The patients' neutrophils and fibroblasts had increased susceptibility to apoptosis. The myeloid cells showed evidence of increased endoplasmic reticulum stress and increased activity of glycogen synthase kinase 3beta (GSK-3beta). We identified seven additional, unrelated patients who had severe congenital neutropenia with syndromic features and distinct biallelic mutations in G6PC3. CONCLUSIONS: Defective function of glucose-6-phosphatase, catalytic subunit 3, underlies a severe congenital neutropenia syndrome associated with cardiac and urogenital malformations.


Asunto(s)
Anomalías Múltiples/genética , Glucosa-6-Fosfatasa/genética , Cardiopatías Congénitas/genética , Mutación Missense , Neutropenia/genética , Anomalías Urogenitales/genética , Adolescente , Apoptosis/genética , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Estudio de Asociación del Genoma Completo , Glucosa-6-Fosfatasa/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo I/genética , Humanos , Lactante , Escala de Lod , Masculino , Neutropenia/congénito , Neutropenia/fisiopatología , Neutrófilos/fisiología , Linaje , Síndrome , Telangiectasia/genética
10.
Am J Med Genet A ; 152A(12): 3157-63, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21108402

RESUMEN

Biallelic mutations in the gene encoding HCLS-associated protein X-1 (HAX1) cause autosomal recessive severe congenital neutropenia (SCN). Some of these patients have neurological abnormalities including developmental delay, cognitive impairment, and/or epilepsy. Recent genotype-phenotype studies have shown that mutations in HAX1 affecting transcripts A (NM_006118.3) and B (NM_001018837.1) cause the phenotype of SCN with neurological impairment, while mutations affecting isoform A but not B lead to SCN without neurological aberrations. In this study, we identified a consanguineous family with two patients suffering from SCN and neurological disease caused by a novel, homozygous genomic deletion including exons 4-7 of the HAX1 gene. Quantitative MRI analyses showed generalized alterations in cerebral proton density in both of the patients, as well as in an additional unrelated patient with another HAX1 mutation (Arg86X) known to be associated with neurological manifestations. This study provides first in vivo evidence of aberrant neuroimaging findings associated with HAX1 deficiency in SCN patients.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Encéfalo/anomalías , Mutación , Enfermedades del Sistema Nervioso/genética , Neutropenia/congénito , Neutropenia/genética , Adulto , Estudios de Casos y Controles , Niño , Consanguinidad , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/genética , Epilepsia/complicaciones , Epilepsia/congénito , Epilepsia/genética , Femenino , Genes Recesivos , Homocigoto , Humanos , Imagen por Resonancia Magnética/métodos , Enfermedades del Sistema Nervioso/complicaciones , Enfermedades del Sistema Nervioso/congénito , Enfermedades del Sistema Nervioso/patología , Neutropenia/complicaciones , Linaje , Fenotipo , Isoformas de Proteínas/genética , Índice de Severidad de la Enfermedad
11.
Front Immunol ; 10: 497, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30936881

RESUMEN

B-cell development and function depend on stage-specific signaling through the B-cell antigen receptor (BCR). Signaling and intracellular trafficking of the BCR are connected, but the molecular mechanisms of this link are incompletely understood. Here, we investigated the role of the endosomal adaptor protein and member of the LAMTOR/Ragulator complex LAMTOR2 (p14) in B-cell development. Efficient conditional deletion of LAMTOR2 at the pre-B1 stage using mb1-Cre mice resulted in complete developmental arrest. Deletion of LAMTOR2 using Cd19-Cre mice permitted analysis of residual B cells at later developmental stages, revealing that LAMTOR2 was critical for the generation and activation of mature B lymphocytes. Loss of LAMTOR2 resulted in aberrant BCR signaling due to delayed receptor internalization and endosomal trafficking. In conclusion, we identify LAMTOR2 as critical regulator of BCR trafficking and signaling that is essential for early B-cell development in mice.


Asunto(s)
Linfocitos B/inmunología , Endosomas/metabolismo , Proteínas/inmunología , Receptores de Antígenos de Linfocitos B/inmunología , Animales , Linfocitos B/ultraestructura , Señalización del Calcio , División Celular , Proteínas de Unión al ADN/deficiencia , Activación de Linfocitos , Linfopoyesis , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Electrónica de Transmisión , Transporte de Proteínas , Transducción de Señal , Organismos Libres de Patógenos Específicos , Recombinación V(D)J
12.
Sci Rep ; 8(1): 17452, 2018 11 28.
Artículo en Inglés | MEDLINE | ID: mdl-30487523

RESUMEN

Preceding viral infections have mostly been described in autoimmune hepatitis (AIH) in single cases. We aimed to identify viral infections that potentially trigger AIH, as suggested for hepatitis E virus (HEV) infections. Therefore, antibodies against hepatitis A (HAV), B, C and E viruses; hepatotropic herpesviruses; and parvovirus B19 (PVB19) were analyzed retrospectively in 219 AIH patients at diagnosis, 356 patients with other liver diseases and 89 children from our center. Untreated adult AIH (aAIH) patients showed higher anti-HEV seroprevalences at diagnosis than patients with other liver diseases. Untreated aAIH patients had no increased incidence of previous hepatitis A, B or C. Antibodies against hepatotropic herpesviruses in untreated AIH were in the range published for the normal population. Untreated pediatric AIH (pAIH) patients had evidence of more previous HAV and PVB19 infections than local age-matched controls. The genetic AIH risk factor HLA DRB1*03:01 was more frequent in younger patients, and DRB1*04:01 was more frequent in middle-aged patients without an obvious link to virus seropositivities. Pediatric and adult AIH seem to be distinct in terms of genetic risk factors and preceding viral infections. While associations cannot prove causal relations, the results suggest that hepatotropic virus infections could be involved in AIH pathogenesis.


Asunto(s)
Virus de la Hepatitis A Humana/inmunología , Hepatitis A/complicaciones , Virus de la Hepatitis E/inmunología , Hepatitis E/complicaciones , Hepatitis Autoinmune/epidemiología , Hepatitis Autoinmune/etiología , Infecciones por Parvoviridae/complicaciones , Parvovirus B19 Humano/inmunología , Adolescente , Adulto , Distribución por Edad , Anciano , Anticuerpos Antivirales/inmunología , Autoanticuerpos/inmunología , Biomarcadores , Niño , Preescolar , Susceptibilidad a Enfermedades , Femenino , Predisposición Genética a la Enfermedad , Hepatitis A/epidemiología , Hepatitis E/diagnóstico , Hepatitis E/epidemiología , Hepatitis Autoinmune/diagnóstico , Humanos , Inmunoglobulina G/inmunología , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Infecciones por Parvoviridae/epidemiología , Prevalencia , Factores de Riesgo , Estudios Seroepidemiológicos , Adulto Joven
13.
Sci Rep ; 8(1): 419, 2018 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-29323192

RESUMEN

Although autoimmune hepatitis (AIH) can be treated with corticosteroid-based first-line therapy, incomplete remission is associated with progressive liver fibrosis. So far accepted predictors of the subsequent treatment response of AIH patients are lacking. Therefore, we analysed baseline parameters, including iron homeostasis and cytokine levels, in 60 children with paediatric AIH (pAIH). In contrast to adults, elevated serum markers indicating iron overload were not commonly found in children. Therefore, ferritin was not predictive of the treatment response in pAIH. Although baseline immunoglobulins were lower in pAIH children with subsequent complete biochemical remission (BR) upon standard first-line therapy, only lower AIH scores (≤16 points) could predict BR upon standard therapy in our training and validation cohorts. Additionally, higher baseline IL-2 and MCP-1/CCL2 levels were associated with BR in a sub-cohort. A combined score of IL-2 level and a simplified AIH score predicted treatment response more precisely than both parameter alone in this sub-cohort. In conclusion, the baseline AIH score could be validated as a predictor of treatment response in pAIH. Additionally, low baseline IL-2 may help identify children who need salvage therapy. This could be important because the use of low-dose IL-2 therapies is being tested in various autoimmune diseases.


Asunto(s)
Corticoesteroides/uso terapéutico , Hepatitis Autoinmune/tratamiento farmacológico , Interleucina-2/sangre , Adolescente , Adulto , Quimiocina CCL2/sangre , Niño , Estudios de Cohortes , Femenino , Hepatitis Autoinmune/inmunología , Humanos , Hierro/metabolismo , Masculino , Estudios Retrospectivos , Resultado del Tratamiento
14.
PLoS One ; 12(7): e0181107, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28700730

RESUMEN

BACKGROUND & AIMS: The autoimmune hepatitis (AIH) is a chronic hepatitis driven by the adaptive immunity that affects all age groups. A functional and numerical regulatory T cell (Treg) defect has been reported in pediatric AIH (pAIH), while an intrahepatic increase in adult AIH (aAIH) patients has been detected in current research findings. METHODS: Therefore, we quantified the intrahepatic numbers of Treg, T and B cells, as well as serum cytokine levels before and during therapy in pAIH. RESULTS: We found a disproportional intrahepatic enrichment of Tregs in untreated pAIH compared to pediatric non-alcoholic fatty liver disease. The increase of Treg/total T cells was even more pronounced than in aAIH due to fewer infiltrating T and B cells. Portal densities of Treg, as well as total T and B cells, declined significantly during therapy. However, portal Treg densities decreased disproportionately, leading to even decreasing ratios of Treg to T and B cells during therapy. Out of 28 serum cytokines IL-2 showed the strongest (10fold) decrease under therapy. This decline of IL-2 was associated with decreasing intrahepatic Treg numbers under therapy. None of the baseline T and B cell infiltration parameters were associated with the subsequent treatment response in pAIH. CONCLUSIONS: Intrahepatic Tregs are rather enriched in untreated pAIH. The disproportional decrease of Tregs during therapy may be caused by a decrease of IL-2 levels. New therapies should, therefore, aim in strengthening intrahepatic immune regulation.


Asunto(s)
Hepatitis Autoinmune/inmunología , Hepatitis Autoinmune/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Adolescente , Adulto , Linfocitos B/inmunología , Linfocitos B/metabolismo , Niño , Citocinas/sangre , Femenino , Hepatitis Autoinmune/sangre , Humanos , Interleucina-2/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Estudios Retrospectivos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Adulto Joven
15.
Nat Genet ; 46(9): 1021-7, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25129144

RESUMEN

The analysis of individuals with severe congenital neutropenia (SCN) may shed light on the delicate balance of factors controlling the differentiation, maintenance and decay of neutrophils. We identify 9 distinct homozygous mutations in the JAGN1 gene encoding Jagunal homolog 1 in 14 individuals with SCN. JAGN1-mutant granulocytes are characterized by ultrastructural defects, a paucity of granules, aberrant N-glycosylation of multiple proteins and increased incidence of apoptosis. JAGN1 participates in the secretory pathway and is required for granulocyte colony-stimulating factor receptor-mediated signaling. JAGN1 emerges as a factor that is necessary in the differentiation and survival of neutrophils.


Asunto(s)
Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Células Mieloides/metabolismo , Neutropenia/congénito , Adolescente , Adulto , Apoptosis/genética , Diferenciación Celular/genética , Supervivencia Celular/genética , Niño , Preescolar , Síndromes Congénitos de Insuficiencia de la Médula Ósea , Femenino , Glicosilación , Homeostasis/genética , Humanos , Lactante , Recién Nacido , Masculino , Proteínas de la Membrana/metabolismo , Mutación , Neutropenia/genética , Neutropenia/metabolismo , Neutropenia/patología , Neutrófilos/metabolismo , Receptores de Factor Estimulante de Colonias de Granulocito/genética , Receptores de Factor Estimulante de Colonias de Granulocito/metabolismo , Transducción de Señal , Adulto Joven
16.
Transplantation ; 95(1): 247-55, 2013 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-23222899

RESUMEN

BACKGROUND: Posttransplantation lymphoproliferative disease (PTLD) is an often Epstein-Barr virus (EBV)-associated mainly malignant complication after transplantation. We present data on EBV-specific T cells in children treated with rituximab with or without chemotherapy on the pediatric PTLD Pilot 2005 protocol. METHODS: Peripheral blood mononuclear cells were isolated from 16 pediatric patients with PTLD, 4 transplanted children with EBV reactivation, and 18 healthy controls. EBV-specific T cells were quantified by flow cytometric detection of intracellular interferon-γ after stimulation with autologous EBV-transformed lymphoblastoid cell lines and correlated with EBV load in peripheral blood. RESULTS: At diagnosis, PTLD patients had similar numbers of EBV-specific CD4 and CD8 T cells as healthy EBV-positive controls. EBV-specific T cells tended to be lower in early PTLD compared with late PTLD. During treatment with rituximab, CD4 and/or CD8 EBV-specific T cells increased in most patients, possibly reflecting restored immunocompetence due to a reduction of immunosuppression as well as antigenic stimulation by cross-presentation of EBV antigen from destroyed B cells. However, this increase did not predict response to rituximab or chemotherapy. EBV load and circulating B cells became undetectable in most patients during rituximab therapy. B-cell recovery after treatment was accompanied by redetection of EBV in peripheral blood, which was controlled by T-cell responses in 11 of 11 evaluable cases. CONCLUSIONS: In pediatric PTLD patients, pretreatment EBV-specific T-cell numbers are in the range of healthy controls. These cells increased on reduction of immunosuppression and treatment with rituximab. Recurrence of EBV viremia during complete remission is matched by strong T-cell responses.


Asunto(s)
Herpesvirus Humano 4/inmunología , Trastornos Linfoproliferativos/inmunología , Trasplante de Órganos/efectos adversos , Linfocitos T/inmunología , Adolescente , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Niño , Preescolar , Femenino , Humanos , Lactante , Trastornos Linfoproliferativos/etiología , Masculino , Rituximab
17.
J Exp Med ; 210(3): 433-43, 2013 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-23440042

RESUMEN

Primary immunodeficiencies (PIDs) represent exquisite models for studying mechanisms of human host defense. In this study, we report on two unrelated kindreds, with two patients each, who had cryptosporidial infections associated with chronic cholangitis and liver disease. Using exome and candidate gene sequencing, we identified two distinct homozygous loss-of-function mutations in the interleukin-21 receptor gene (IL21R; c.G602T, p.Arg201Leu and c.240_245delCTGCCA, p.C81_H82del). The IL-21R(Arg201Leu) mutation causes aberrant trafficking of the IL-21R to the plasma membrane, abrogates IL-21 ligand binding, and leads to defective phosphorylation of signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5. We observed impaired IL-21-induced proliferation and immunoglobulin class-switching in B cells, cytokine production in T cells, and NK cell cytotoxicity. Our study indicates that human IL-21R deficiency causes an immunodeficiency and highlights the need for early diagnosis and allogeneic hematopoietic stem cell transplantation in affected children.


Asunto(s)
Síndromes de Inmunodeficiencia/genética , Subunidad alfa del Receptor de Interleucina-21/genética , Mutación , Niño , Preescolar , Femenino , Humanos , Síndromes de Inmunodeficiencia/etiología , Síndromes de Inmunodeficiencia/inmunología , Subunidad alfa del Receptor de Interleucina-21/química , Subunidad alfa del Receptor de Interleucina-21/fisiología , Células Asesinas Naturales/inmunología , Masculino , Fosforilación , Factor de Transcripción STAT3/metabolismo , Transducción de Señal
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