Associating biological context with protein-protein interactions through text mining at PubMed scale.

Inferring knowledge from known relationships between drugs, proteins, genes, and diseases has great potential for clinical impact, such as predicting which existing drugs could be repurposed to treat rare diseases. Incorporating key biological context such as cell type or tissue of action into representations of extracted biomedical knowledge is essential for principled pharmacological discovery. Existing global, literature-derived knowledge graphs of interactions between drugs, proteins, genes, and diseases lack this essential information.

EBNA-1 titer gradient in families with multiple sclerosis indicates a genetic contribution.

Objective: In multiplex MS families, we determined the humoral immune response to Epstein-Barr virus nuclear antigen 1 (EBNA-1)-specific immunoglobulin γ (IgG) titers in patients with MS, their healthy siblings, and biologically unrelated healthy spouses and investigated the role of specific genetic loci on the antiviral IgG titers.

Methods: IgG levels against EBNA-1 and varicella zoster virus (VZV) as control were measured. and tagging single-nucleotide polymorphisms (SNPs) were genotyped.

The Role of Autoimmunity-Related Gene in the B Cell Receptor-Mediated HLA Class II Pathway.

C-type lectin is located next to , the master transcription factor of HLA class II (HLA-II), at a susceptibility locus for several autoimmune diseases, including multiple sclerosis (MS). We previously found that promotes the biogenesis of HLA-II peptide-loading compartments (MIICs) in myeloid cells. Given the emerging role of B cells as APCs in these diseases, in this study, we addressed whether and how is involved in the BCR-dependent HLA-II pathway.

HLA association in MOG-IgG- and AQP4-IgG-related disorders of the CNS in the Dutch population.

Objective: To investigate the possible human leukocyte antigen (HLA) association of both myelin oligodendrocyte glycoprotein (MOG-IgG)-associated diseases (MOGAD) and aquaporin-4 antibody (AQP4-IgG)-positive neuromyelitis optica spectrum disorders (NMOSDs) in the Dutch population with European ancestry to clarify similarities or differences in the immunogenetic background of both diseases.

Methods: Blood samples from patients in the Dutch national MS/NMOSD expert clinic were tested for MOG-IgG and AQP4-IgG using a cell-based assay. HLA Class I and II genotyping was performed in 43 MOG-IgG-seropositive and 42 AQP4-IgG-seropositive Dutch patients with European ancestry and compared with those of 5,604 Dutch healthy blood donors.

Polygenic Multiple Sclerosis Risk and Population-Based Childhood Brain Imaging.

Objective: Multiple sclerosis (MS) is a neurological disease with a substantial genetic component and immune-mediated neurodegeneration. Patients with MS show structural brain differences relative to individuals without MS, including smaller regional volumes and alterations in white matter (WM) microstructure. Whether genetic risk for MS is associated with brain structure during early neurodevelopment remains unclear.

Relationship between conservation biology and ecology shown through machine reading of 32,000 articles.

Conservation biology was founded on the idea that efforts to save nature depend on a scientific understanding of how it works. It sought to apply ecological principles to conservation problems. We investigated whether the relationship between these fields has changed over time through machine reading the full texts of 32,000 research articles published in 16 ecology and conservation biology journals.

Serum neurofilament light chain in pediatric MS and other acquired demyelinating syndromes.

Objective: To explore the correlation between serum and CSF neurofilament light chain (NfL) and the association of NfL levels and future disease activity in pediatric patients with a first attack of acquired demyelinating syndromes (ADS).

Methods: In total, 102 children <18 years with a first attack of CNS demyelination and 23 age-matched controls were included. Clinically definite multiple sclerosis (CDMS) was set as an endpoint for analysis.

Induction of brain-infiltrating T-bet-expressing B cells in multiple sclerosis.

Objective: Results from anti-CD20 therapies demonstrate that B- and T-cell interaction is a major driver of multiple sclerosis (MS). The local presence of B-cell follicle-like structures and oligoclonal bands in MS patients indicates that certain B cells infiltrate the central nervous system (CNS) to mediate pathology. Which peripheral triggers underlie the development of CNS-infiltrating B cells is not fully understood.

Clinical trials of disease-modifying agents in pediatric MS: Opportunities, challenges, and recommendations from the IPMSSG.

Objective: The impetus for this consensus discussion was to recommend clinical trial designs that can deliver high-quality data for effective therapies for pediatric patients, in a reasonable timeframe, with a key focus on short- and long-term safety.

Methods: The International Pediatric Multiple Sclerosis Study Group convened a meeting of experts to review the advances in the understanding of pediatric-onset multiple sclerosis (MS) and the advent of clinical trials for this population.

Results: In the last few years, convincing evidence has emerged that the biological processes involved in MS are largely shared across the age span.

Real-world validation of the 2017 McDonald criteria for pediatric MS.

Objective: To compare the diagnostic accuracy of the McDonald 2017 vs the McDonald 2010 criteria to predict a second attack of MS (clinically definite MS [CDMS]) at the first attack of acquired demyelinating syndromes (ADS).

Methods: One hundred sixty-four children (aged <18 years) with an incident attack of ADS were included in a prospective multicenter study between June 2006 and December 2016. Brain (and spinal if available) MRI was performed ≤3 months after symptom onset.

The macrophage migration inhibitory factor pathway in human B cells is tightly controlled and dysregulated in multiple sclerosis.

In MS, B cells survive peripheral tolerance checkpoints to mediate local inflammation, but the underlying molecular mechanisms are relatively underexplored. In mice, the MIF pathway controls B-cell development and the induction of EAE. Here, we found that MIF and MIF receptor CD74 are downregulated, while MIF receptor CXCR4 is upregulated in B cells from early onset MS patients.

Application of the 2017 Revised McDonald Criteria for Multiple Sclerosis to Patients With a Typical Clinically Isolated Syndrome.

Importance: In 2017, the International Panel on Diagnosis of Multiple Sclerosis revised the McDonald 2010 criteria for the diagnosis of multiple sclerosis (MS). The new criteria are easier to apply and could lead to more and earlier diagnoses. It is important to validate these criteria globally for their accuracy in clinical practice.

Chemical and genetic control of IFNγ-induced MHCII expression.

The cytokine interferon-γ (IFNγ) can induce expression of MHC class II (MHCII) on many different cell types, leading to antigen presentation to CD4 T cells and immune activation. This has also been linked to anti-tumour immunity and graft-versus-host disease. The extent of MHCII upregulation by IFNγ is cell type-dependent and under extensive control of epigenetic regulators and signalling pathways.

T-cell activation marker sCD27 is associated with clinically definite multiple sclerosis in childhood-acquired demyelinating syndromes.

Background: Cerebrospinal fluid (CSF) levels of T-cell activation marker soluble CD27 (sCD27) are associated with subsequent disease activity after a first attack of suspected MS in adults. The predictive value for disease course in children with acquired demyelinating syndromes (ADS) is unknown.

Objectives: To assess the predictive value of sCD27 levels for clinically definite multiple sclerosis (CDMS) diagnosis in childhood ADS.

Linkage analysis and whole exome sequencing identify a novel candidate gene in a Dutch multiple sclerosis family.

Background: Multiple sclerosis (MS) is a complex disease resulting from the joint effect of many genes. It has been speculated that rare variants might explain part of the missing heritability of MS.

Objective: To identify rare coding genetic variants by analyzing a large MS pedigree with 11 affected individuals in several generations.

High neurofilament levels are associated with clinically definite multiple sclerosis in children and adults with clinically isolated syndrome.

Background: A promising biomarker for axonal damage early in the disease course of multiple sclerosis (MS) is neurofilament light chain (NfL). It is unknown whether NfL has the same predictive value for MS diagnosis in children as in adults.

Objective: To explore the predictive value of NfL levels in cerebrospinal fluid (CSF) for MS diagnosis in paediatric and adult clinically isolated syndrome (CIS) patients.

Smoking at time of CIS increases the risk of clinically definite multiple sclerosis.

Background: Cigarette smoking is a modifiable risk factor that influences the disease course of patients with multiple sclerosis (MS). However, in patients with a clinically isolated syndrome (CIS), there are conflicting results about the association between smoking and the risk of a subsequent MS diagnosis. The aim of this study was to determine the risk of clinically definite MS (CDMS) in smoking and non-smoking patients at time of a first demyelinating event.

Elevated EBNA-1 IgG in MS is associated with genetic MS risk variants.

Objective: To assess whether MS genetic risk polymorphisms (single nucleotide polymorphism [SNP]) contribute to the enhanced humoral immune response against Epstein-Barr virus (EBV) infection in patients with MS.

Methods: Serum anti-EBV nuclear antigen 1 (EBNA-1) and early antigen D (EA-D) immunoglobulin γ (IgG) levels were quantitatively determined in 668 genotyped patients with MS and 147 healthy controls. Anti-varicella-zoster virus (VZV) IgG levels were used as a highly prevalent, non-MS-associated control herpesvirus.

Disease Course and Treatment Responses in Children With Relapsing Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

Importance: Myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) are consistently identified in a range of demyelinating disorders in adults and children. Current therapeutic strategies are largely center specific, and no treatments have been formally evaluated.

Objective: To examine the clinical phenotypes, treatment responses, and outcomes of children with relapsing MOG-Ab-associated disease.

Regulator of oligodendrocyte maturation, miR-219, a potential biomarker for MS.

Background: Multiple sclerosis (MS) is a demyelinating and degenerative disease of the central nervous system. Normally, demyelination is followed by remyelination, which requires repopulation of a demyelinated area by oligodendrocyte precursor cells. Although large numbers of precursor cells are present in MS lesions, remyelination often fails, in part by the inability of precursor cells to differentiate into mature myelin-forming cells.