RESUMEN
Vitamin D deficiency is a risk factor for developing multiple sclerosis (MS). However, the immune effects of vitamin D in people with MS are not well understood. We analyzed transcriptomic datasets generated by RNA sequencing of immune cell subsets (CD4+, CD8+ T cells, B cells, monocytes) from 33 healthy controls and 33 untreated MS cases. We utilized a traditional bioinformatic pipeline and weighted gene co-expression network analysis (WGCNA) to determine genes and pathways correlated with endogenous vitamin D. In controls, CD4+ and CD8+ T cells had 1079 and 1188 genes, respectively, whose expressions were correlated with plasma 25-hydroxyvitamin D level (P < 0.05). Functional enrichment analysis identified association with TNF-alpha and MAPK signaling. In CD4+ T cells of controls, vitamin D level was associated with expression levels of several genes proximal to multiple sclerosis risk loci (P = 0.01). Genes differentially associated with endogenous vitamin D by case-control status were enriched in TNF-alpha signaling via NF-κB. WGCNA suggested a blunted response to vitamin D in cases relative to controls. Collectively, our findings provide further evidence for the immune effects of vitamin D, and demonstrate a differential immune response to vitamin D in cases relative to controls, highlighting a possible mechanism contributing to MS pathophysiology.
Asunto(s)
Esclerosis Múltiple , Humanos , Esclerosis Múltiple/metabolismo , Factor de Necrosis Tumoral alfa , Linfocitos T CD8-positivos/metabolismo , Vitamina D , Inmunidad , Vitaminas , Perfilación de la Expresión GénicaRESUMEN
BACKGROUND: Pregnancy in women with multiple sclerosis (wwMS) is associated with a reduction of long-term disability progression. The mechanism that drives this effect is unknown, but converging evidence suggests a role for epigenetic mechanisms altering immune and/or central nervous system function. In this study, we aimed to identify whole blood and immune cell-specific DNA methylation patterns associated with parity in relapse-onset MS. RESULTS: We investigated the association between whole blood and immune cell-type-specific genome-wide methylation patterns and parity in 192 women with relapse-onset MS, matched for age and disease severity. The median time from last pregnancy to blood collection was 16.7 years (range = 1.5-44.4 years). We identified 2965 differentially methylated positions in whole blood, 68.5% of which were hypermethylated in parous women; together with two differentially methylated regions on Chromosomes 17 and 19 which mapped to TMC8 and ZNF577, respectively. Our findings validated 22 DMPs and 366 differentially methylated genes from existing literature on epigenetic changes associated with parity in wwMS. Differentially methylated genes in whole blood were enriched in neuronal structure and growth-related pathways. Immune cell-type-specific analysis using cell-type proportion estimates from statistical deconvolution of whole blood revealed further differential methylation in T cells specifically (four in CD4+ and eight in CD8+ T cells). We further identified reduced methylation age acceleration in parous women, demonstrating slower biological aging compared to nulligravida women. CONCLUSION: Differential methylation at genes related to neural plasticity offers a potential molecular mechanism driving the long-term effect of pregnancy on MS outcomes. Our results point to a potential 'CNS signature' of methylation in peripheral immune cells, as previously described in relation to MS progression, induced by parity. As the first epigenome-wide association study of parity in wwMS reported, validation studies are needed to confirm our findings.
Asunto(s)
Metilación de ADN , Esclerosis Múltiple , Embarazo , Humanos , Femenino , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Paridad , Linfocitos T CD8-positivos/metabolismo , Plasticidad Neuronal , Proteínas de la Membrana/genéticaRESUMEN
OBJECTIVES: Population prevalence studies of migraine report prevalence rates of between 2.6 and 21.7%, with an average of ~12%. However, migraine prevalence among neurologists is reported to be significantly higher, between 27.6% and 48.6%. Increasing knowledge of the protean manifestations of migraine may explain this difference. Similarly, under-recognition of migraine in control groups may explain the lack of genetic and biomarker findings in this disorder. We therefore sought to determine the prevalence of migraine in an admixed group of individuals with varied knowledge of migraine symptomatology. METHODS: Attendees at the Australian and New Zealand Association of Neurologists Annual Scientific Meeting (ANZAN ASM) 2017 were surveyed anonymously. Those surveyed included three groups: neurologists, neurology trainees, and others including nonclinical researchers, members of lay organizations, and representatives of the pharmaceutical industry. RESULTS: In total, 313 of 606 attendees responded (51.7%). 65.9% of neurologist, 57.4% of trainee, and 52.5% of others respondents had a personal history of migraine, with the difference between neurologists and others being statistically significant (p = .03). Migraine in migraineurs and nonmigraine headache in nonmigraineurs were nearly all self-diagnosed. Among neurologist migraineurs, 51.2% experienced migraine with aura and 43% migraine without aura. CONCLUSIONS: Migraine prevalence is significantly higher in neurologists compared to non-neurologists and at least 2-3 times higher than reported in population prevalence studies. This may be due to significant under-recognition of migraine in non-neurologists. This under-recognition of migraine may significantly influence the search for genetic predictors and biomarkers of migraine.
Asunto(s)
Errores Diagnósticos , Trastornos Migrañosos , Neurólogos , Actitud del Personal de Salud , Australia/epidemiología , Estudios Transversales , Errores Diagnósticos/prevención & control , Errores Diagnósticos/estadística & datos numéricos , Humanos , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/epidemiología , Evaluación de Necesidades , Prevalencia , Proyectos de Investigación/estadística & datos numéricos , Investigadores/clasificación , Encuestas y CuestionariosRESUMEN
The production and delivery of functional perforin (PRF; PRF1 gene) by cytotoxic lymphocytes maintains immune homeostasis and tumour immune surveillance. In humans, inheritance of the common PRF1 polymorphism, p.A91V, (c.272C>T) found in 8-9% of the Caucasian population, with another mutated allele resulting in reduced PRF function or trafficking, has been shown to result in hyperinflammatory diseases and/or haematological cancers. In this study, we sought to investigate the function of p.A91V on a wild-type (WT) perforin background. We first developed an assay that distinguishes the relative levels of transcription of individual PRF1 alleles, including p.A91V. The p.A91V allele was seen to be expressed at similar levels as the WT allele in primary human natural killer (NK) cells, ruling out that allelic expression imbalance influenced their function. We then demonstrated that the p.A91V mutation results in protein misfolding and an appreciable reduction in NK-cell cytotoxicity in healthy carriers of p.A91V. We propose that this level of cytotoxic dysfunction may readily account for the predisposition to immune-mediated disease in individuals homozygous for p.A91V. Also, the fact that monoallelic mutations of PRF1 decrease NK-cell cytotoxicity should be considered in individuals presenting with the manifestations of immune deficiency states that impinge on NK-cell cytotoxicity.