No abstract

Objectives: To identify dietary and lifestyle variables that may affect cognitive function in the elderly. Design: Population-based prospective cohort study. Setting: General community residing in Athens and the surrounding Attica region of Greece.

Myasthenia gravis (MG) is a chronic autoimmune disorder characterized by muscle weakness and caused by pathogenic autoantibodies that bind to membrane proteins at the neuromuscular junction. Most patients have autoantibodies against the acetylcholine receptor (AChR), but a subset of patients have autoantibodies against muscle-specific tyrosine kinase (MuSK) instead. MuSK is an essential component of the pathway responsible for synaptic differentiation, which is activated by nerve-released agrin. Through binding MuSK, serum-derived autoantibodies inhibit agrin-induced MuSK autophosphorylation, impair clustering of AChRs, and block neuromuscular transmission. We sought to establish individual MuSK autoantibody clones so that the autoimmune mechanisms could be better understood. We isolated MuSK autoantibody-expressing B cells from 6 MuSK MG patients using a fluorescently tagged MuSK antigen multimer, then generated a panel of human monoclonal autoantibodies (mAbs) from these cells. Here we focused on 3 highly specific mAbs that bound quantitatively to MuSK in solution, to MuSK-expressing HEK cells, and at mouse neuromuscular junctions, where they colocalized with AChRs. These 3 IgG isotype mAbs (2 IgG4 and 1 IgG3 subclass) recognized the Ig-like domain 2 of MuSK. The mAbs inhibited AChR clustering, but intriguingly, they enhanced rather than inhibited MuSK phosphorylation, which suggests an alternative mechanism for inhibiting AChR clustering.

Identification of dietary and lifestyle variables associated with the development of Parkinson's disease (PD) may offer pathogenetic clues and prevention opportunities. In a population-based prospective cohort study, 26,173 participants in the EPIC-Greece cohort had sociodemographic, anthropometric, medical, dietary and lifestyle variables ascertained at enrolment and periodically reassessed with follow-up contacts. Based on these data, subjects were screened as possible PD cases if they (1) reported either a medical diagnosis of PD or use of anti-PD drugs and (2) did not report preceding causes of secondary parkinsonism. For diagnostic validation, possible incident PD cases were assessed by a focused 3-item telephone questionnaire. Cox proportional hazards regression was used to evaluate associations between potential predictors and incident PD. The main multivariate model included gender, age, marital status, schooling years, farming occupation, smoking status, caffeinated coffee, body mass index, physical activity and energy intake. Additional models included all above variables plus one dietary item at a time. Incidence rate adjusted to the European population was 16.9 per 100,000 person-years. In multivariate models, incident PD exhibited strong positive association with consumption of milk, but not cheese or yoghurt. This finding may help narrow down the search for potential dairy product components with a facilitatory role in PD. Concerning other dietary components, inverse association was found between polyunsaturated fat intake and incident PD. Also, inverse association was found with tobacco smoking, in line with previous studies, but not with caffeine.

Myasthenia gravis (MG) is a prototypical B cell-mediated autoimmune disease affecting 20–50 per 100,000 people. The majority of patients fall into two clinically distinguishable types based on whether they produce autoantibodies targeting the acetylcholine receptor (AChR-MG) or muscle specific kinase (MuSK-MG). The autoantibodies are pathogenic, but whether their generation is associated with broader defects in the B cell repertoire is unknown. To address this question, we performed deep sequencing of the B cell receptor repertoire of AChR-MG, MuSK-MG and healthy subjects to generate approximately 518,000 unique VH and VL sequences from sorted naïve and memory B cell populations. AChR-MG and MuSK-MG subjects displayed distinct gene segment usage biases in both VH and VL sequences within the naïve and memory compartments. The memory compartment of AChR-MG was further characterized by reduced positive selection of somatic mutations in the H-CDR regions and altered H-CDR3 physicochemical properties. The VL repertoire of MuSK-MG was specifically characterized by reduced V/J segment distance in recombined sequences, suggesting diminished VL receptor editing during B cell development. Our results identify large-scale abnormalities in both the naïve and memory B cell repertoires. Particular abnormalities were unique to either AChR-MG or MuSK-MG indicating that the repertoires reflect the distinct properties of the subtypes. These repertoire abnormalities are consistent with previously observed defects in B cell tolerance checkpoints in MG, thereby offering additional insight regarding the impact of tolerance defects on peripheral autoimmune repertoires. These collective findings point toward a deformed B cell repertoire as a fundamental component of MG.