RESUMEN
BACKGROUND: Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS. METHODS: MOG(35-55) induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses. RESULTS: EAE disease course was slightly attenuated in male apoE-deficient (apoE (-/-) ) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 2 [IQR 0.0-4.5]; wildtype = 4 [IQR 1.0-5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE (-/-) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 3 [IQR 2.0-4.5]; wildtype = 3 [IQR 0.0-4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naïve animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex. CONCLUSIONS: apoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease.
Asunto(s)
Apolipoproteínas E/genética , Encefalomielitis Autoinmune Experimental/genética , Esclerosis Múltiple/genética , Animales , Apolipoproteínas E/inmunología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Técnica del Anticuerpo Fluorescente , Genotipo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores SexualesRESUMEN
Variations in two genes of the tumour necrosis factor (TNF) alpha pathway have been implicated in the pathogenesis of autoimmune diseases: polymorphisms in the TNFRSF1A gene, encoding TNF receptor 1, showed significant association with MS in genomewide association scans, and variation in or near the TNFAIP3 gene, coding for a negative regulator of NFkB, was associated with MS, systemic lupus erythematosus, diabetes and rheumatoid arthritis. This study aimed at investigating association of MS with variation in the TNFRSF1A gene as well as in the TNFAIP3 gene region in an independent German case-control cohort. Four hundred and ninety-seven unrelated patients with MS and 878 healthy controls were genotyped with restriction enzyme digestion or TaqMan assays for three polymorphisms in the TNFRSF1A gene and seven in the region of the TNFAIP3 gene. Allele, genotype and haplotype frequencies were compared between cases and controls by chi-square testing. We found significant association of rs10499194, located in the intergenic region upstream of TNFAIP3, with MS (pc = 3.4 × 10(-4) ). Further, the intronic SNP rs1800693 in TNFRSF1A showed moderate association (pc = 0.033) with MS. In conclusion, evidence is accumulating that polymorphisms in both TNFAIP3 and TNFRSF1A genes play a role in MS pathogenesis. Additional studies are warranted to further elucidate the role of TNF pathway variation for MS development.
Asunto(s)
Proteínas de Unión al ADN/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Péptidos y Proteínas de Señalización Intracelular/genética , Esclerosis Múltiple/genética , Proteínas Nucleares/genética , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Adulto , Alelos , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Genotipo , Alemania , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfaRESUMEN
Variation in the genes encoding the interleukin (IL) 7 and IL2 receptor alpha chains (IL7RA, IL2RA) was recently found associated with multiple sclerosis (MS). We evaluated the role of these two genes in a large German MS case-control cohort. Five single nucleotide polymorphisms (SNPs) in IL7RA and four in IL2RA were genotyped in 1319 MS patients and 908 controls by means of restriction enzyme digestion or TaqMan assays and subsequently evaluated for association with MS. IL7RA expression was measured via quantitative real time PCR in 24 subjects. We replicated the association of exon 6 variation (rs6897932) in IL7RA with MS. Yet, this association was only found in patients with primary progressive (pp) or secondary progressive (sp) disease course (p=0.0004). Expression analysis did not show differences in IL7RA expression depending on genotypes at this locus, while reduced expression of the soluble receptor was observed in patients with pp and sp MS irrespective of genotype. In the IL2RA gene, significant associations of SNPs in introns 3 and 7 with MS subtypes were obvious. Together these results confirm involvement of polymorphisms in the IL7RA and IL2RA genes in MS pathogenesis and suggest that IL7RA variation may primarily affect chronic disease courses.
Asunto(s)
Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/inmunología , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/inmunología , Adulto , Alelos , ADN Complementario/genética , Femenino , Regulación de la Expresión Génica/inmunología , Genotipo , Alemania , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/epidemiologíaRESUMEN
Recent studies have revealed an association between interleukin 28B (IL28B) and response to IFN-alpha treatment in hepatitis C patients. Here we investigated the influence of IL28B polymorphisms in the response to interferon-beta (IFNß) in multiple sclerosis (MS) patients. We genotyped two SNPs of the IL28B gene (rs8099917 and rs12979860) in 588 MS patients classified into responders (n=281) and non-responders (n=307) to IFNß. Combined analysis of the study cohorts showed no significant associations between SNPs rs8099917 and rs12979860 and the response to treatment. These findings do not support a role of IL28B polymorphisms in the response to IFNß in MS patients.
Asunto(s)
Interferón beta/fisiología , Interleucinas/genética , Esclerosis Múltiple/inmunología , Polimorfismo de Nucleótido Simple , Adulto , Estudios de Cohortes , Femenino , Genotipo , Humanos , Interferón beta/uso terapéutico , Interferones , Masculino , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/genéticaRESUMEN
The interleukin 4 promoter polymorphism -589 C/T (rs2243250) was genotyped in 869 multiple sclerosis (MS) patients and 595 healthy blood donors. Sex-specific MS association was evident whereas two flanking polymorphisms showed insignificant P values. In dual luciferase assays of cultured Jurkat cells the cloned promoter comprising the -589 T allele leads to higher expression as compared to the respective construct with the C allele. Together these findings may be discussed functionally as contributing to the genetic predisposition and to the pathogenesis in MS.
Asunto(s)
Expresión Génica , Pruebas Genéticas , Interleucina-4/genética , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple , Femenino , Frecuencia de los Genes , Genes Reporteros , Humanos , Luciferasas/análisis , Luciferasas/genética , Masculino , Regiones Promotoras Genéticas/genética , Factores SexualesRESUMEN
We analysed whether the single nucleotide polymorphism (SNP) rs3087456 in the promoter of the MHC class II transactivator (MHC2TA) gene is associated with manifestation of rheumatoid arthritis, multiple sclerosis, narcolepsy and Wegener granulomatosis. The recently reported association in a northern population of the MHC2TA variation with these autoimmune diseases is not evident in the German population.