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Multiple sclerosis (MS) is an inflammatory neurodegenerative disorder of the central nervous system (CNS). The migration of immune cells into the CNS is essential for its development, and plasma membrane molecules play an important role in triggering and maintaining the inflammation. We previously identified ninjurin2, a plasma membrane protein encoded by NINJ2 gene, as involved in the occurrence of relapse under Interferon-β treatment in MS patients. The aim of the present study was to investigate the involvement of NINJ2 in inflammatory conditions and in the migration of monocytes through the blood-brain barrier (BBB). We observed that NINJ2 is downregulated in monocytes and in THP-1 cells after stimulation with the pro-inflammatory cytokine LPS, while in hCMEC/D3 cells, which represent a surrogate of the BBB, LPS stimulation increases its expression. We set up a transmigration assay using an hCMEC/D3 transwell-based model, finding a higher transmigration rate of monocytes from MS subjects compared to healthy controls (HCs) in the case of an activated hCMEC/D3 monolayer. Moreover, a positive correlation between NINJ2 expression in monocytes and monocyte migration rate was observed. Overall, our results suggest that ninjurin2 could be involved in the transmigration of immune cells into the CNS in pro-inflammatory conditions. Further experiments are needed to elucidate the exact molecular mechanisms., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Background: The genetic component of multiple sclerosis (MS) is now set to 200 autosomal common variants. However, it is unclear how genetic knowledge be clinically used in the differential diagnosis between MS and other inflammatory conditions like adult-onset postinfectious neurological syndromes (PINS). The aim of this study was to investigate whether PINS and MS have a shared genetic background using an updated polygenic risk scores., Methods: Eighty-eight PINS patients have been consecutively recruited between 1996 and 2016 at Mondino Foundation of Pavia, diagnosed according to clinical, MRI and CSF findings and followed-up for several years. Patients were typed using Illumina array, and genotypes imputed using the 1000 Genomes Project reference panel. A weighted genetic risk score (wGRS) has been calculated based on autosomal MS risk loci derived from large-scale studies, and an HLA genetic burden (HLAGB) was also calculated on loci associated to MS., Results: PINS occurred as an episode of myelitis in 44% of patients, encephalomyelitis in 44%, and encephalitis in remaining cases, with an involvement of peripheral nervous system in 41% of patients. Mean age of onset was 50.1 years, and female:male ratio was 1.4. Patients were followed-up for a mean of 7.2 years, and at last visit 55% had a low disability grade (mRS 0-1). Disease was monophasic in 67% of patients, relapsing in 18% and chronic-progressive in 15%. The wGRS of PINS cases was comparable to 370 healthy controls, while significantly lower compared to 907 bout-onset MS (BOMS) cases (wGRS= 20.9 vs 21.2; p<0.0001). The difference was even larger for PINS with peripheral nervous system involvement (wGRS=20.6) vs BOMS., Conclusion: The distinction between MS and PINS is not easy to make in clinical practice. However, our study shows that the new set of MS risk alleles does not confer increased susceptibility to PINS. These data support the importance to discriminate these cases from MS with pathophysiological and therapeutic implications., (Copyright © 2020. Published by Elsevier B.V.)

Background: Multiple sclerosis (MS) is a disease in which biomarker identification is fundamental to predict response to treatments and to deliver the optimal drug to patients. We previously found an association between rs7298096, a polymorphism upstream to the NINJ2 gene, and the 4-year response to interferon-β (IFNβ) treatment in MS patients., Objectives: To analyse the association between rs7298096 and time to first relapse (TTFR) during IFNβ therapy in MS patients and to better investigate its functional role., Methods: Survival analysis was applied in three MS cohorts from different countries ( n  = 1004). We also studied the role of the polymorphism on gene expression using GTEx portal and a luciferase assay. We interrogated GEO datasets to explore the relationship between NINJ2 expression, IFNβ and TTFR., Results: Rs7298096 AA patients show a shorter TTFR than rs7298096 G -carriers (P meta-analysis  = 3 × 10 -4 , hazard ratio = 1.41). Moreover, rs7298096 AA is associated with a higher NINJ2 expression in blood ( p  = 7.0 × 10 -6 ), which was confirmed in vitro ( p  = 0.009). Finally, NINJ2 expression is downregulated by IFNβ treatment and related to TTFR., Conclusions: Rs7298096 could influence MS disease activity during IFNβ treatment by modulating NINJ2 expression in blood. The gene encodes for an adhesion molecule involved in inflammation and endothelial cells activation, supporting its role in MS.

We aimed to investigate whether NLR family, pyrin domain containing 3 (NLRP3) polymorphisms are associated with the response to interferon-beta (IFNβ) in multiple sclerosis (MS) patients. A total of 14 NLRP3 polymorphisms were genotyped in a cohort of 665 relapsing-remitting MS patients recruited across 5 centers and classified into responders and non-responders according to clinical-radiological criteria after 1 year of IFNβ treatment. A meta-analysis failed to demonstrate significant associations between the response to IFNβ and NLRP3 polymorphisms. These findings do not support a role of polymorphisms located in the NLRP3 gene and the response to IFNβ in MS patients.

Background: Multiple sclerosis (MS) is a disease in which biomarker identification is fundamental to predict response to treatments and to deliver the optimal drug to patients. We previously found an association between rs7298096, a polymorphism upstream to the NINJ2 gene, and the 4-year response to interferon-β (IFNβ) treatment in MS patients. Objectives: To analyse the association between rs7298096 and time to first relapse (TTFR) during IFNβ therapy in MS patients and to better investigate its functional role. Methods: Survival analysis was applied in three MS cohorts from different countries (n = 1004). We also studied the role of the polymorphism on gene expression using GTEx portal and a luciferase assay. We interrogated GEO datasets to explore the relationship between NINJ2 expression, IFNβ and TTFR. Results: Rs7298096AA patients show a shorter TTFR than rs7298096G-carriers (Pmeta-analysis = 3 × 10−4, hazard ratio = 1.41). Moreover, rs7298096AA is associated with a higher NINJ2 expression in blood (p = 7.0 × 10−6), which was confirmed in vitro (p = 0.009). Finally, NINJ2 expression is downregulated by IFNβ treatment and related to TTFR. Conclusions: Rs7298096 could influence MS disease activity during IFNβ treatment by modulating NINJ2 expression in blood. The gene encodes for an adhesion molecule involved in inflammation and endothelial cells activation, supporting its role in MS. [ABSTRACT FROM AUTHOR]

We aimed to investigate whether NLR family, pyrin domain containing 3 (NLRP3) polymorphisms are associated with the response to interferon-beta (IFNβ) in multiple sclerosis (MS) patients. A total of 14 NLRP3 polymorphisms were genotyped in a cohort of 665 relapsing-remitting MS patients recruited across 5 centers and classified into responders and non-responders according to clinical-radiological criteria after 1 year of IFNβ treatment. A meta-analysis failed to demonstrate significant associations between the response to IFNβ and NLRP3 polymorphisms. These findings do not support a role of polymorphisms located in the NLRP3 gene and the response to IFNβ in MS patients. [ABSTRACT FROM AUTHOR]