The gut microbiome plays an important role in immune function and has been implicated in several autoimmune disorders. Here we use 16S rRNA sequencing to investigate the gut microbiome in subjects with multiple sclerosis (MS, n=60) and healthy controls (n=43). Microbiome alterations in MS include increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, and correlate with variations in the expression of genes involved in dendritic cell maturation, interferon signalling and NF-kB signalling pathways in circulating T cells and monocytes. Patients on disease-modifying treatment show increased abundances of Prevotella and Sutterella, and decreased Sarcina, compared with untreated patients. MS patients of a second cohort show elevated breath methane compared with controls, consistent with our observation of increased gut Methanobrevibacter in MS in the first cohort. Further study is required to assess whether the observed alterations in the gut microbiome play a role in, or are a consequence of, MS pathogenesis.

FcgammaRIIIa plays a prominent role in the elimination of tumor cells by antibody-based cancer therapies. Non-fucosylated bisected IgGs bind this receptor with increased affinity and trigger FcgammaRIII-mediated effector functions more efficiently than native, fucosylated antibodies. In this study the contribution of the carbohydrates of both binding partners to the strength of the complex was analyzed. Glycoengineering of the antibody increased affinity for two polymorphic forms of soluble human FcgammaRIIIa (by up to 50-fold) but did not affect binding to the inhibitory FcgammaRIIb receptor. While the absence of carbohydrate at FcgammaRIIIa's Asn-162 increased affinity for native IgG, presumably due to the removal of steric hindrance caused by the bulky sugars, it unexpectedly reduced affinity for glycoengineered (GE) antibodies by over one order of magnitude, bringing the affinity down to the same level as for native IgG. We conclude that the high affinity between GE antibodies and FcgammaRIII is mediated by productive interactions formed between the receptor carbohydrate attached at Asn-162 and regions of the Fc that are only accessible when it is nonfucosylated. As FcgammaRIIIa and FcgammaRIIIb are the only human Fcgamma receptors glycosylated at this position, the proposed interactions explain the observed selective affinity increase of GE antibodies for only these receptors. Furthermore, we predict from our structural model that only one of the two Fc-fucose residues needs to be absent for increased binding affinity toward FcgammaRIII. This information can be exploited for the design of new antibodies with altered Fc receptor binding affinity and enhanced therapeutic potential.

Background Type 1 diabetes results from autoimmune-mediated destruction of β cells. The tyrosine kinase inhibitor imatinib might affect relevant immunological and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our aim was to evaluate the safety and efficacy of imatinib in preserving β-cell function in patients with recent-onset type 1 diabetes. MethodsWe did a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients with recentonset type 1 diabetes (<100 days from diagnosis), aged 18-45 years, positive for at least one type of diabetesassociated autoantibody, and with a peak stimulated C-peptide of greater than 0•2 nmol L -¹ on a mixed meal tolerance test (MMTT) were enrolled from nine medical centres in the USA (n=8) and Australia (n=1). Participants were randomly assigned (2:1) to receive either 400 mg imatinib mesylate (4 × 100 mg film-coated tablets per day) or matching placebo for 26 weeks via a computer-generated blocked randomisation scheme stratified by centre. Treatment assignments were masked for all participants and study personnel except pharmacists at each clinical site. The primary endpoint was the difference in the area under the curve (AUC) mean for C-peptide response in the first 2 h of an MMTT at 12 months in the imatinib group versus the placebo group, with use of an ANCOVA model adjusting for sex, baseline age, and baseline C-peptide, with further observation up to 24 months. The primary analysis was by intention to treat (ITT). Safety was assessed in all randomly assigned participants. This study is registered with ClinicalTrials.gov, NCT01781975 (completed).Findings Patients were screened and enrolled between Feb 12, 2014, and May 19, 2016. 45 patients were assigned to receive imatinib and 22 to receive placebo. After withdrawals, 43 participants in the imatinib group and 21 in the placebo group were included in the primary ITT analysis at 12 months. The study met its primary endpoint: the adjusted mean difference in 2-h C-peptide AUC at 12 months for imatinib versus placebo treatment was 0•095 (90% CI -0•003 to 0•191; p=0•048, one-tailed test). This effect was not sustained out to 24 months. During the 24-month follow-up, 32 (71%) of 45 participants who received imatinib had a grade 2 severity or worse adverse event, compared with 13 (59%) of 22 participants who received placebo. The most common adverse events (grade 2 severity or worse) that differed between the groups were gastro intestinal issues (six [13%] partici pants in the imatinib group, primarily nausea, and none in the placebo group) and additional laboratory investigations (ten [22%] participants in the imatinib group and two [9%] in the placebo group). Per the trial protocol, 17 (38%) participants in the imatinib group required a temporary modification in drug dosing and six (13%) permanently discontinued imatinib due to adverse events; five (23%) participants in the placebo group had temporary modifications in dosing and none had a permanent discontinuation du...

A straightforward and effective method of stabilizing a β‐hairpin conformation in a cyclic protein loop mimetic is described, which exploits the templating effect of a heterochiral D‐Pro‐L‐Pro dipeptide unit. A twelve‐residue β‐hairpin loop was grafted from the extracellular interferon γ receptor onto the heterochiral D‐Pro‐L‐Pro dipeptide template to afford a fourteen‐residue cyclic peptide. The residues directly attached to the D‐Pro‐L‐Pro template are shown by NMR spectroscopy to structurally mimic corresponding residues in adjacent antiparallel β‐strands in the receptor. MD Simulations with and without time‐averaged distance restraints support this view and indicate that the tip of the loop is more flexible, as inferred also for the receptor protein from crystallographic data. The templating effect of the heterochiral diproline unit also promotes efficient backbone cyclization of the fourteen‐residue linear peptide precursor, suggesting that a wide variety of related protein loop mimetics incorporating the D‐Pro‐L‐Pro template might be readily accessible.