RESUMEN
Narcolepsy type 1 (NT1) is a chronic neurological disorder having a strong association with HLA-DQB1*0602, thereby suggesting an immunological origin. Increased risk of NT1 has been reported among children or adolescents vaccinated with AS03 adjuvant-supplemented pandemic H1N1 influenza A vaccine, Pandemrix. Here we show that pediatric Pandemrix-associated NT1 patients have enhanced T-cell immunity against the viral epitopes, neuraminidase 175-189 (NA175-189) and nucleoprotein 214-228 (NP214-228), but also respond to a NA175-189-mimic, brain self-epitope, protein-O-mannosyltransferase 1 (POMT1675-689). A pathogenic role of influenza virus-specific T-cells and T-cell cross-reactivity in NT1 are supported by the up-regulation of IFN-γ, perforin 1 and granzyme B, and by the converging selection of T-cell receptor TRAV10/TRAJ17 and TRAV10/TRAJ24 clonotypes, in response to stimulation either with peptide NA175-189 or POMT1675-689. Moreover, anti-POMT1 serum autoantibodies are increased in Pandemrix-vaccinated children or adolescents. These results thus identify POMT1 as a potential autoantigen recognized by T- and B-cells in NT1.
Asunto(s)
Subtipo H1N1 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/efectos adversos , Gripe Humana/prevención & control , Manosiltransferasas/inmunología , Narcolepsia/inmunología , Adolescente , Animales , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Linfocitos B/inmunología , Antígenos CD4/genética , Estudios de Casos y Controles , Niño , Preescolar , Reacciones Cruzadas/inmunología , Modelos Animales de Enfermedad , Epítopos de Linfocito T/inmunología , Femenino , Cadenas beta de HLA-DQ/inmunología , Humanos , Lactante , Vacunas contra la Influenza/inmunología , Gripe Humana/inmunología , Gripe Humana/virología , Masculino , Ratones Transgénicos , Narcolepsia/sangre , Narcolepsia/inducido químicamente , Neuraminidasa/inmunología , Linfocitos T/inmunología , Proteínas Virales/inmunología , Adulto JovenRESUMEN
Homozygosity for a nonsense mutation in the fucosyltransferase 2 (FUT2) gene (rs601338G>A) leads to the absence of ABH blood groups (FUT2 non-secretor status) in body fluids. As the secretor status has been shown to be a major determinant for the gut microbial spectrum, assumed to be important in the gut immune homeostasis, we studied the association of rs601338-FUT2 with celiac disease (CelD) and inflammatory bowel disease (IBD) in the Finnish population. Rs601338 was genotyped in CelD (n = 909), dermatitis herpetiformis (DH) (n = 116), ulcerative colitis (UC) (n = 496) and Crohn's disease (CD) (n = 280) patients and healthy controls (n = 2738). CelD showed significant genotypic [P = 0.0074, odds ratio (OR): 1.28] and recessive (P = 0.015, OR: 1.28) association with the rs601338-AA genotype. This was also found in the combined CelD+DH dataset (genotype association: P = 0.0060, OR: 1.28; recessive association: P < 0.011, OR: 1.28). The A allele of rs601338 showed nominal association with dominant protection from UC (P = 0.044, OR: 0.82) and UC+CD (P = 0.035, OR: 0.84). The frequency of non-secretors (rs601338-GG) in controls, CelD, DH, UC and CD datasets was 14.7%, 18%, 18.1%, 14.3% and 16.1%, respectively. No association was evident in the DH or CD datasets alone. In conclusion, FUT2 non-secretor status is associated with CelD susceptibility and FUT2 secretor status may also play a role in IBD in the Finnish population.
Asunto(s)
Enfermedad Celíaca/enzimología , Enfermedad Celíaca/genética , Fucosiltransferasas/genética , Enfermedades Inflamatorias del Intestino/enzimología , Enfermedades Inflamatorias del Intestino/genética , Alelos , Secuencia de Bases , Estudios de Casos y Controles , Colitis Ulcerosa/enzimología , Colitis Ulcerosa/genética , Enfermedad de Crohn/enzimología , Enfermedad de Crohn/genética , Cartilla de ADN/genética , Dermatitis Herpetiforme/enzimología , Dermatitis Herpetiforme/genética , Finlandia , Genes Recesivos , Estudios de Asociación Genética , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Galactósido 2-alfa-L-FucosiltransferasaRESUMEN
Some genetic loci may affect susceptibility to multiple immune system-related diseases. In the current study, we investigated whether the known susceptibility loci for celiac disease (CelD) also associate with Crohn's disease (CD) and/or ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), in Finnish patients. A total of 45 genetic markers were genotyped in a Finnish data set comprising 699 IBD patients and 2482 controls. Single-marker association with IBD and its subphenotypes was tested. A meta-analysis with a Swedish UC data set was also performed. A total of 12 single-nucleotide polymorphisms associated with CD and/or UC (P<0.05). In the subphenotype analysis, rs6974491-ELMO1 (P=0.0002, odds ratio (OR): 2.20) and rs2298428-UBE2L3 (P=5.44 × 10(-5), OR: 2.59) associated with pediatric UC and CD, respectively. In the meta-analysis, rs4819388-ICOSLG (P=0.00042, OR: 0.79) associated with UC. In the subphenotype meta-analysis, rs1738074-TAGAP (P=7.40 × 10(-5), OR: 0.61), rs6974491-ELMO1 (P=0.00052, OR: 1.73) and rs4819388-ICOSLG (P=0.00019, OR: 0.75) associated with familial UC, pediatric UC and sporadic UC, respectively. Multiple CelD risk loci also confer susceptibility for CD and/or UC in the Finnish and Swedish populations. Certain genetic risk variants may furthermore predispose an individual for developing a particular disease phenotype.
Asunto(s)
Enfermedad Celíaca/genética , Enfermedad Celíaca/inmunología , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Adulto , Estudios de Casos y Controles , Niño , Colitis Ulcerosa/genética , Colitis Ulcerosa/inmunología , Enfermedad de Crohn/genética , Enfermedad de Crohn/inmunología , Finlandia , Estudios de Asociación Genética , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Polimorfismo de Nucleótido Simple , Factores de Riesgo , SueciaRESUMEN
Coeliac disease is a chronic inflammatory condition of the small intestine, triggered by dietary exposure to gluten in genetically susceptible individuals. Risk alleles at HLA-DQA1 and HLA-DQB1 are necessary for disease development, but are alone not sufficient for disease onset. We aimed to identify novel loci underlying susceptibility to coeliac disease through the use of extended Finnish and Hungarian families with multiple affected individuals. An initial whole-genome linkage approach yielded several loci that were followed up further using the Immunochip custom array. Loci with a parametric logarithm of odds (LOD) score of >1.3 were identified at 4q, 6p [human leukocyte antigen (HLA) region], 6q, 7p, 17p, 17q and at 22p. The 4q and 6q loci have been identified previously in coeliac disease risk, whereas follow-up analyses indicate that the 17p and 22p loci may be novel risk loci for coeliac disease. These loci harbour previously described risk variants for other autoimmune diseases, but their segregation patterns do not explain the linkage to coeliac disease. We followed up the linkage to the 4q region, containing the previously described interleukin (IL)2 and IL21 genes. The risk variants at 4q in the studied pedigrees are most likely distinct from previously described risk variants, indicating that the observed linkage may be due to rare high-risk variants of still unknown nature. The importance of this locus to coeliac disease risk was further shown by the finding that serum levels of IL21 were elevated in both untreated and treated coeliac patients compared to controls.
Asunto(s)
Enfermedad Celíaca/genética , Cromosomas Humanos/genética , Ligamiento Genético , Sitios Genéticos , Interleucina-2/genética , Interleucinas/genética , Linaje , Enfermedad Celíaca/sangre , Femenino , Finlandia , Estudio de Asociación del Genoma Completo , Humanos , Hungría , Interleucina-2/sangre , Interleucinas/sangre , Masculino , Factores de RiesgoRESUMEN
Neuropeptide S receptor 1 (NPSR1) was recently found to be genetically associated with inflammatory bowel disease in addition to asthma and related traits. Epithelia of several organs express NPSR1 isoforms A and B, including the intestine and the skin, and NPSR1 appears to be upregulated in inflammation. In this study, we used cell lines and tissue samples to characterize the expression of NPSR1 and its ligand neuropeptide S (NPS) in inflammation. We used polyclonal and monoclonal antibodies to investigate the expression of NPS and NPSR1 in intestinal diseases, such as celiac disease and food allergy, and in cutaneous inflammatory disorders. We found that NPSR1-A was expressed by the enteroendocrine cells of the gut. Overall, the expression pattern of NPS was similar to its receptor suggesting an autocrine mechanism. In an NPSR1-A overexpressing cell model, stimulation with NPS resulted in a dose-dependent upregulation of glycoprotein hormone, alpha polypeptide (CGA), tachykinin 1 (TAC1), neurotensin (NTS) and galanin (GAL) encoding peptide hormones secreted by enteroendocrine cells. Because NPSR1 was also expressed in macrophages, neutrophils, and intraepithelial lymphocytes, we demonstrated that stimulation with the pro-inflammatory cytokines tumour necrosis factor alpha and interferon gamma increased NPSR1 expression in the THP-1 monocytic cells. In conclusion, similar to other neuropeptides and their receptors, NPSR1 signalling might play a dual role along the gut-brain axis. The NPS/NPSR1 pathway may participate in the regulation of the peptide hormone production in enteroendocrine cells of the small intestine.
Asunto(s)
Mucosa Intestinal/metabolismo , Hormonas Peptídicas/metabolismo , Isoformas de Proteínas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Piel/metabolismo , Adulto , Animales , Línea Celular , Niño , Humanos , Inflamación/inmunología , Inflamación/patología , Interferón gamma/metabolismo , Enfermedades Intestinales/metabolismo , Enfermedades Intestinales/patología , Intestinos/citología , Monocitos/inmunología , Isoformas de Proteínas/genética , Conejos , Receptores Acoplados a Proteínas G/genética , Piel/citología , Enfermedades de la Piel/metabolismo , Enfermedades de la Piel/patología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Celiac disease is a chronic inflammation of the small intestine, arising in genetically predisposed individuals as a result of ingestion of dietary gluten. The only confirmed and functionally characterised genetic risk factors for celiac disease are the DQ2 or DQ8 heterodimers at the major histocompatibility complex (MHC) class II locus (CELIAC1). These genes are necessary but alone not sufficient for disease onset. Genome-wide linkage scans have suggested chromosome 5q31-q33 (CELIAC2) as an important risk locus for celiac disease. This region has also been associated to other inflammatory disorders, although as yet, no clear gene associations have been found. In the current study, 11 celiac disease candidate loci were screened for genetic linkage in the Hungarian population. As the CELIAC2 locus showed the strongest evidence for linkage, this locus was selected for follow-up. Seventeen candidate genes were selected from the CELIAC2 locus, and genotyped using 48 haplotype tagging single nucleotide polymorphisms (SNPs) in large Finnish and Hungarian family materials. A subset of these, 40 tagging SNPs in 15 genes, were genotyped in an independent set of Finnish and Hungarian cases and controls. We confirmed linkage of this region with celiac disease and report strong linkage in both the Finnish and Hungarian populations. The association analysis showed modest associations throughout the whole region. These association findings were not replicated in the case-control datasets. Our study strongly supports the role of the CELIAC2 locus in celiac disease, but it also highlights the need for a more powerful study design in the region, to locate the true disease risk variants.
Asunto(s)
Enfermedad Celíaca/genética , Mapeo Cromosómico , Cromosomas Humanos Par 5 , Sitios Genéticos/genética , Estudios de Casos y Controles , Mapeo Cromosómico/métodos , Familia , Finlandia , Frecuencia de los Genes , Ligamiento Genético , Genética de Población/métodos , Humanos , Hungría , Polimorfismo de Nucleótido SimpleRESUMEN
The Fcgamma receptor cluster on chromosome 1q23 contains a number of genes that may affect susceptibility to celiac disease, but previous studies have yielded contradictory results. We studied the FcgammaRIIa*A519G (rs1801274) and FcgammaRIIIa*A559C (rs396991) single nucleotide polymorphisms in celiac disease families from Hungary and Finland and in celiac disease case-control materials from Hungary and Italy. Neither the Hungarian nor the Italian case-control material or a meta-analysis of the combined case-control material showed significant single-marker or haplotype association. In addition, neither linkage nor family-based association tests showed evidence for association in the Finnish or Hungarian family material. This study thus does not support a previous publication showing FcgammaR association with celiac disease.
Asunto(s)
Enfermedad Celíaca/genética , Cromosomas Humanos Par 1/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Receptores de IgG/genética , Estudios de Casos y Controles , Enfermedad Celíaca/epidemiología , Finlandia/epidemiología , Frecuencia de los Genes , Ligamiento Genético , Haplotipos/genética , Humanos , Hungría/epidemiología , Italia/epidemiología , Epidemiología MolecularRESUMEN
IgA deficiency (IgAD) and common variable immunodeficiency (CVID) often co-occur in families, associating with chronic inflammatory diseases such as celiac disease (CD). ICOS (inducible co-stimulator) and CTLA4 (cytotoxic T-lymphocyte-associated protein-4) may be important in both disorders, as ICOS is necessary for Ig class-switching and CTLA4 negatively regulates T-cell activation. Linkage and association of CD with CTLA4-ICOS is well documented, we thus aimed to further pinpoint CD susceptibility by haplotype-tagging analysis. We genotyped 663 CD families from Finland and Hungary, 575 additional CD patients from Finland, Hungary and Italy; 275 Swedish and Finnish IgAD individuals and 87 CVID individuals for 14-18 genetic markers in CTLA4-ICOS. Association was found between CTLA4-ICOS and both IgAD (P=0.0015) and CVID (P=0.0064). We confirmed linkage of CTLA4-ICOS with CD (LOD 2.38, P=0.0005) and found association of CTLA4-ICOS with CD (P=0.0009). Meta-analysis of the IgAD, CVID and CD materials revealed intergenic association (P=0.0005). Disease-associated markers were associated with lower ICOS and higher CTLA4 expression, indicating that the risk haplotypes contain functional variants. In summary, we identified a novel shared risk locus for IgAD, CVID and CD, the first report of association between CTLA4-ICOS and IgAD. Association between CD and CTLA4-ICOS was also confirmed in a large European data set.
Asunto(s)
Antígenos CD/genética , Antígenos de Diferenciación de Linfocitos T/genética , Enfermedad Celíaca/genética , Deficiencia de IgA/genética , Sitios de Carácter Cuantitativo/genética , Antígeno CTLA-4 , Inmunodeficiencia Variable Común , Femenino , Finlandia , Ligamiento Genético , Genotipo , Humanos , Hungría , Proteína Coestimuladora de Linfocitos T Inducibles , MasculinoRESUMEN
BACKGROUND: Coeliac disease is caused by dietary gluten, which triggers chronic inflammation of the small intestine in genetically predisposed individuals. In one quarter of the patients the disease manifests in the skin as dermatitis herpetiformis. Recently, a novel candidate gene, myosin IXB on chromosome 19p13, was shown to be associated with coeliac disease in the Dutch and Spanish populations. The same gene has previously been associated with inflammatory bowel disease, systemic lupus erythematosus and rheumatoid arthritis risk, making myosin IXB a potential shared risk factor in these inflammatory disorders. METHODS: In this study, previously reported myosin IXB variants were tested for genetic linkage and association with coeliac disease in 495 Hungarian and Finnish families and in an additional 270 patients and controls. RESULTS AND CONCLUSION: The results show significant linkage (logarithm of odds (LOD) 3.76, p = 0.00002) to 19p13 which supports the presence of a genuine risk factor for coeliac disease in this locus. Myosin IXB variants were not associated with coeliac disease in this study; however, weak evidence of association with dermatitis herpetiformis was found. The association could not explain the strong linkage seen in both phenotypes, indicating that the role of other neighbouring genes in the region cannot be excluded. Therefore, more detailed genetic and functional studies are required to characterise the role of the myosin IXB gene in both coeliac disease and dermatitis herpetiformis.
Asunto(s)
Enfermedad Celíaca/genética , Dermatitis Herpetiforme/genética , Miosinas/genética , Alelos , Estudios de Casos y Controles , Enfermedad Celíaca/complicaciones , Cromosomas Humanos Par 19/genética , Dermatitis Herpetiforme/complicaciones , Femenino , Finlandia , Predisposición Genética a la Enfermedad , Variación Genética , Glútenes/efectos adversos , Haplotipos , Homocigoto , Humanos , Hungría , Enfermedades Inflamatorias del Intestino/genética , Desequilibrio de Ligamiento , Masculino , Factores de RiesgoRESUMEN
As persons on the autistic spectrum are known not to use semantic features of word lists to aid recall, they might show diminished susceptibility to illusory memories that typically occur with lists of associated items. Alternatively, since such individuals also have poor source monitoring, they might show greater susceptibility. The authors found that adults with Asperger's syndrome (n = 10) recalled similar proportions of a nonpresented strong associate of the study list items, compared with controls (n = 15). In Experiment 2, rates of true and false recognition of study list associates did not differ significantly between Asperger (n = 10) and control (n = 10) participants. Moreover, the Asperger participants made fewer remember and more know judgments than controls for veridical but not for false recognitions. Thus, deficits found in some aspects of memory in people with Asperger's syndrome do not affect their susceptibility to memory illusions.