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OBJECTIVES: Serum neurofilament light chain (sNfL), an indicator of neuronal damage, is increasingly recognized as a potential biomarker for disease activity in neurodegenerative disorders. In this study, we wanted to investigate sNfL as a prognostic marker in a large, well-defined population of 90 patients with Lyme neuroborreliosis (LNB). In addition, we sought to explore associations between symptoms and sNfL levels during the acute phase of LNB. MATERIALS AND METHODS: Patients diagnosed with definite or possible LNB were recruited from a double-blinded, placebo-controlled, multi-center trial, in which the participants were randomly assigned to 2 or 6 weeks of oral doxycycline treatment. The sNfL levels were measured using a single molecule array assay at both diagnosis and 6-month follow-up, and analysed against clinical parameters, variations in symptom burden and long-term complaints as assessed by a composite clinical score. RESULTS: At the time of diagnosis, approximately 60% of the patients had elevated sNfL levels adjusted for age. Notably, mean sNfL levels were significantly higher at diagnosis (52 pg/ml) compared to 6 months after treatment (12 pg/ml, p < 0.001), when sNfL levels had normalized in the majority of patients. Patients with objective signs of spinal radiculitis had significantly higher baseline sNfL levels compared to patients without spinal radiculitis (p = 0.033). CONCLUSION: Our findings suggest that sNfL can serve as a biomarker for peripheral nerve tissue involvement in the acute phase of LNB. As found in an earlier study, we confirm normalization of sNfL levels in blood after treatment. We found no prognostic value of acute-phase sNfL levels on patient outcome.
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Biomarcadores , Neuroborreliose de Lyme , Proteínas de Neurofilamentos , Humanos , Neuroborreliose de Lyme/sangue , Neuroborreliose de Lyme/tratamento farmacológico , Neuroborreliose de Lyme/diagnóstico , Masculino , Feminino , Proteínas de Neurofilamentos/sangue , Pessoa de Meia-Idade , Noruega , Adulto , Biomarcadores/sangue , Idoso , Estudos Longitudinais , Método Duplo-Cego , Antibacterianos/administração & dosagem , Doxiciclina/administração & dosagem , Estudos de Coortes , Carga de SintomasRESUMO
BACKGROUND: Multiple sclerosis (MS) is an autoimmune, neuroinflammatory disease, with an unclear etiology. However, T cells play a central role in the pathogenesis by crossing the blood-brain-barrier, leading to inflammation of the central nervous system and demyelination of the protective sheath surrounding the nerve fibers. MS has a complex inheritance pattern, and several studies indicate that gene interactions with environmental factors contribute to disease onset. METHODS: In the current study, we evaluated T cell dysregulation at the protein level using electrospray liquid chromatography-tandem mass spectrometry to get novel insights into immune-cell processes in MS. We have analyzed the proteomic profiles of CD4+ and CD8+ T cells purified from whole blood from 13 newly diagnosed, treatment-naive female patients with relapsing-remitting MS and 14 age- and sex-matched healthy controls. RESULTS: An overall higher protein abundance was observed in both CD4+ and CD8+ T cells from MS patients when compared to healthy controls. The differentially expressed proteins were enriched for T-cell specific activation pathways, especially CTLA4 and CD28 signaling in CD4+ T cells. When selectively analyzing proteins expressed from the genes most proximal to > 200 non-HLA MS susceptibility polymorphisms, we observed differential expression of eight proteins in T cells between MS patients and healthy controls, and there was a correlation between the genotype at three MS genetic risk loci and protein expressed from proximal genes. CONCLUSION: Our study provides evidence for proteomic differences in T cells from relapsing-remitting MS patients compared to healthy controls and also identifies dysregulation of proteins encoded from MS susceptibility genes.
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A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 × 10-7, 4.3 × 10-9) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.
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Genotyping chips for rare and low-frequent variants have recently gained popularity with the introduction of exome chips, but the utility of these chips remains unclear. These chips were designed using exome sequencing data from mainly American-European individuals, enriched for a narrow set of common diseases. In addition, it is well-known that the statistical power of detecting associations with rare and low-frequent variants is much lower compared to studies exclusively involving common variants. We developed a simulation program adaptable to any exome chip design to empirically evaluate the power of the exome chips. We implemented the main properties of the Illumina HumanExome BeadChip array. The simulated data sets were used to assess the power of exome chip based studies for varying effect sizes and causal variant scenarios. We applied two widely-used statistical approaches for rare and low-frequency variants, which collapse the variants into genetic regions or genes. Under optimal conditions, we found that a sample size between 20,000 to 30,000 individuals were needed in order to detect modest effect sizes (0.5% < PAR > 1%) with 80% power. For small effect sizes (PAR <0.5%), 60,000-100,000 individuals were needed in the presence of non-causal variants. In conclusion, we found that at least tens of thousands of individuals are necessary to detect modest effects under optimal conditions. In addition, when using rare variant chips on cohorts or diseases they were not originally designed for, the identification of associated variants or genes will be even more challenging.
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Simulação por Computador , Exoma/genética , Técnicas de Genotipagem/instrumentação , Modelos Genéticos , Análise de Sequência com Séries de Oligonucleotídeos , Alelos , Desenho de Equipamento , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
We have explored the beneficial effects of retinoic acid (RA) on B cells from multiple sclerosis (MS) patients. When co-stimulated via the toll-like receptors (TLRs) TLR9 and RP105, MS B cells secreted less of the anti-inflammatory cytokine interleukin 10 (IL-10) compared to B cells from healthy controls. Importantly, RA enhanced the secretion of IL-10 by MS-derived B cells without affecting the levels of the pro-inflammatory cytokine TNF-α. RA revealed the same ability to induce IL-10 as did interferon-ß-1b (IFN-ß-1b), and B-cells from patients treated with glatiramer acetate or IFN-ß-1b still displayed the beneficial effects of RA on the IL-10/TNF-α ratio.
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Antígenos CD/farmacologia , Linfócitos B/efeitos dos fármacos , Interleucina-10/metabolismo , Ceratolíticos/farmacologia , Esclerose Múltipla Recidivante-Remitente/patologia , Tretinoína/farmacologia , Adulto , Idoso , Antígenos CD19/metabolismo , Linfócitos B/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Acetato de Glatiramer , Humanos , Imunossupressores/farmacologia , Pessoa de Meia-Idade , Peptídeos/farmacologia , Receptor Toll-Like 9/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVES: Individual metabolic characteristics and age-related changes may affect osteoarthritis (OA) risk as well as levels of potential OA biomarkers such as serum cartilage oligomeric protein (sCOMP) and urinary cross-linked C-telopeptide of type 2 collagen (uCTX2). We investigated hand OA and these putative OA biomarker characteristics at different ages in individuals with a propensity for healthy ageing, in controls, and in patients with OA. METHODS: We investigated hand radiological OA (ROA) and levels of sCOMP and uCTX2 in the Leiden Longevity Study, which consisted of the middle-aged offspring of long-lived sibling pairs as metabolically healthy agers and their partners as controls, and for ROA we compared patients with OA at multiple joint sites from the Genetics, osteoARthritis and Progression Study with the healthy agers and controls. RESULTS: Hand ROA mean scores were lower in the healthy agers than in controls. Lower hand ROA scores at higher ages were observed in healthy agers with low glucose levels. Furthermore, in healthy agers, a higher mean sCOMP level was observed than in controls. All study groups had higher sCOMP levels at higher chronological age. Likewise, uCTX2 levels were higher at higher chronological age in the controls and patients with OA, which was not observed in the healthy agers. CONCLUSIONS: Metabolic health in middle age is associated with less ROA and influences putative OA marker profiles, independently of chronological age. When used as OA biomarkers, it is relevant that independently of hand ROA status, uCTX2 is influenced by healthy metabolism and sCOMP is higher at higher chronological age.
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Articulação da Mão , Longevidade/fisiologia , Osteoartrite/metabolismo , Idoso , Envelhecimento/genética , Envelhecimento/metabolismo , Biomarcadores/sangue , Biomarcadores/urina , Glicemia/metabolismo , Estudos de Casos e Controles , Colágeno Tipo II/urina , Feminino , Articulação da Mão/diagnóstico por imagem , Humanos , Longevidade/genética , Masculino , Proteínas Matrilinas/sangue , Pessoa de Meia-Idade , Osteoartrite/diagnóstico por imagem , Osteoartrite/genética , Fragmentos de Peptídeos/urina , RadiografiaRESUMO
PURPOSE OF REVIEW: This review addresses possible common mechanisms of how recently identified consistent osteoarthritis susceptibility genes influence both the onset of osteoarthritis and its progression towards clinical outcomes. RECENT FINDINGS: Genetic association studies have identified a few consistent osteoarthritis susceptibility genes (FRZB, GDF5, and DIO2) that replicate across different populations. Remarkably, each of these genes appears to be primarily involved in the endochondral ossification processes. SUMMARY: We hypothesize that these osteoarthritis susceptibility genes may play a dual negative role. In early developmental processes, they may involve aberrant skeletal morphogenesis leading to either malformation of joints or aberrant bone composition or both, thereby increasing the biomechanical burden on the articular cartilage surface. Later in life in articular cartilage, these genes may affect the propensity of articular chondrocytes to become hypertrophic. As hypertrophic chondrocytes are not able to maintain cartilage homeostasis, these genes may, in part, be responsible for both the onset of osteoarthritis and the progression towards clinical outcomes. Major therapeutic advances may come from a focus on factors that enhance phenotypic stability of the articular chondrocyte during life, promoting the healthy articular cartilage.