Glycosylation Alterations in Multiple Sclerosis Show Increased Proinflammatory Potential.

Multiple sclerosis (MS) is an inflammatory autoimmune disorder affecting the central nervous system (CNS), with unresolved aetiology. Previous studies have implicated N-glycosylation, a highly regulated enzymatic attachment of complex sugars to targeted proteins, in MS pathogenesis. We investigated individual variation in N-glycosylation of the total plasma proteome and of IgG in MS. Both plasma protein and IgG N-glycans were chromatographically profiled and quantified in 83 MS cases and 88 age- and sex-matched controls. Comparing levels of glycosylation features between MS cases and controls revealed that core fucosylation (p = 6.96 × 10-3) and abundance of high-mannose structures (p = 1.48 × 10-2) were the most prominently altered IgG glycosylation traits. Significant changes in plasma protein N-glycome composition were observed for antennary fucosylated, tri- and tetrasialylated, tri- and tetragalactosylated, high-branched N-glycans (p-value range 1.66 × 10-2-4.28 × 10-2). Classification performance of N-glycans was examined by ROC curve analysis, resulting in an AUC of 0.852 for the total plasma N-glycome and 0.798 for IgG N-glycome prediction models. Our results indicate that multiple aspects of protein glycosylation are altered in MS, showing increased proinflammatory potential. N-glycan alterations showed substantial value in classification of the disease status, nonetheless, additional studies are warranted to explore their exact role in MS development and utility as biomarkers.

Season of infectious mononucleosis as a risk factor for multiple sclerosis: A UK primary care case-control study.

BACKGROUND: Infectious mononucleosis (IM) and vitamin D deficiency are both risk factors for multiple sclerosis (MS). OBJECTIVE: We wished to establish if IM in the winter months when vitamin D levels are low may be a greater risk factor for MS than IM in the summer months. METHODS: We identified all patients with MS diagnosed aged 16-60 in a large primary care database in the United Kingdom and matched each by age, sex, general practice and observation period with up to six controls. We identified a coded diagnosis of IM prior to the index date (date of diagnosis). Logistic regression was used to calculate the odds ratio for prior IM exposure in cases versus controls and for winter versus summer exposure in cases and controls with prior IM exposure. RESULTS: Based on 9247 cases and 55,033 matched controls (246 and 846 with prior IM respectively), IM was associated with the development of MS (OR 1.77, 95%CI 1.53-2.05) but there was no evidence that IM in the winter as opposed to summer was associated with developing MS (OR 1.09, 95%CI 0.72-1.66). CONCLUSION: We found no evidence that the season of IM influences the risk of subsequent MS.

The epidemiology of infectious mononucleosis in Northern Scotland: a decreasing incidence and winter peak.

BACKGROUND: Infection with Epstein-Barr virus (EBV) is almost ubiquitous in humans and generally occurs at two ages: infantile, which is usually asymptomatic and associated with poorer socioeconomic conditions, and adolescent, which causes infectious mononucleosis (IM) in ~25% cases. The determinants of whether the infection causes IM remain uncertain. We aimed to evaluate seasonality and temporal trends in IM. METHODS: Data from all Monospot tests, used as a marker for IM, were collected from the Grampian population over 16 years. RESULTS: Positive Monospot test results peaked at 17 years in females and 19 in males. Females had 16% more diagnoses, although 55% more tests. IM was ~38% more common in winter than summer. The annual rate of positive tests decreased progressively over the study period, from 174/100 000 (95% CI 171-178) in 1997 to 67/100 000 (95% CI 65-69) in 2012. CONCLUSIONS: IM appears to be decreasing in incidence, which may be caused by changing environmental influences on immune systems. One such factor may be exposure to sunlight.Words 168. FUNDING: The Medical Research Council and NHS Grampian-MS endowments.

A new prevalence study of multiple sclerosis in Orkney, Shetland and Aberdeen city.

BACKGROUND: 30 years ago very high multiple sclerosis (MS) prevalence rates were recorded in northern Scotland. A prevalence study was repeated in Aberdeen, Orkney and Shetland to see if prevalence rates had changed, assess which factors affect prevalence and record disability status. METHODS: Hospital, general practice and laboratory records were searched to identify prevalent MS patients (alive and registered with a participating general practice on 24 September 2009). Records were reviewed to confirm diagnoses applying Poser definite and probable and McDonald diagnostic criteria. Disability status (Expanded Disability Status Scale) was recorded from records and questionnaires. Rates were standardised to the Scottish population. RESULTS: 590 patients were found (Aberdeen 442, Orkney 82, Shetland 66). Mean age and disease duration were 53 and 19.4 years, respectively. The standardised prevalence rates for Poser probable/definite MS per 100, 000 were: combined area 248 (95% CI 229 to 269), Orkney 402 (95% CI 319 to 500), Shetland 295 (95% CI 229 to 375) and Aberdeen 229 (95% CI 208 to 250). McDonald diagnostic criteria gave a lower prevalence (202, 95% CI 198 to 206). Prevalence was highest in women (2.55:1, 95% CI 2.26 to 2.89) with about 1 in 170 women in Orkney affected. Prevalence was lowest in the most deprived socioeconomic group. 45% had significant disability (Expanded Disability Status Scale ≥6). CONCLUSION: The prevalence of MS has increased in the overall area, most markedly in Orkney, then Shetland, over the past 30 years. This increase could be due to a number of factors, but rising incidence as reflected by a rising sex ratio, influenced by gene-environment interaction, is the most likely. Orkney has the highest prevalence rate recorded worldwide.

Genome-wide homozygosity and multiple sclerosis in Orkney and Shetland Islanders.

There is strong evidence for both genetic and environmental risk factors comprising the aetiology of multiple sclerosis (MS). While much progress has been made in recent years in identifying common genetic variants using genome-wide association studies, alternative approaches have remained relatively neglected. The prevalence of MS in Orkney and Shetland is among the highest in the world. Previous studies have suggested that a higher degree of parental relatedness in these isolated communities may contribute to the high rates of MS, indicating that recessive effects have an important role in MS aetiology. The Northern Isles Multiple Sclerosis (NIMS) study investigated the potential role of genome-wide homozygosity in MS risk by genotyping 88 MS patients, 89 controls matched by age, sex and ancestry, and a further 89 controls matched for sex and ancestry, but passed the majority of lifetime risk of developing MS (>70 years of age). Three participants were removed on the basis of pedigree-genomic anomalies (n=263). Three measures of genome-wide homozygosity were generated for each individual, and association with MS was assessed using logistic regression models. No effect of genome-wide homozygosity was detected, indicating that inbreeding and consanguinity are not risk factors for MS in this population.