CD20-mediated B cell depletion in acetylcholine receptor autoantibody-positive myasthenia gravis

Myasthenia gravis (MG) is an autoimmune disorder characterized by muscle weakness and fatigue, mediated in the majority of cases by IgG1 autoantibodies targeting the acetylcholine receptor (AChR). As AChR autoantibodies have been shown to be pathogenic, therapies targeting B cells have been applied in patients with AChR MG for more than a decade. Recently, a phase 2 trial of the CD20-targeting agent, rituximab, in AChR MG unfortunately failed to meet its primary endpoint. Converging data however from non-randomized clinical series, some of which with more participants than the phase 2 trial, support efficacy of rituximab in AChR MG, especially early onset disease. In this opinion article, we summarize both clinical data and mechanistic principles on the use of CD20 depletion therapy in AChR MG, which we believe lend support to the argument that CD20 depletion can still be a useful therapeutic strategy for patients with AChR MG

Relation of gallbladder function and Helicobacter pylori infection to gastric mucosa inflammation in patients with symptomatic cholecystolithiasis

Background. Inflammatory alterations of the gastric mucosa are commonly caused by Helicobacter pylori (Hp) infection in patients with symptomatic gallstone disease. However, the additional pathogenetic role of an impaired gallbladder function leading to an increased alkaline duodenogastric reflux is controversially discussed. Aim:To investigate the relation of gallbladder function and Hp infection to gastric mucosa inflammation in patients with symptomatic gallstones prior to cholecystectomy. Patients: Seventy-three patients with symptomatic gallstones were studied by endoscopy and Hp testing. Methods: Gastritis classification was performed according to the updated Sydney System and gallbladder function was determined by total lipid concentration of gallbladder bile collected during mainly laparoscopic cholecystectomy. Results: Fifteen patients revealed no, 39 patients mild, and 19 moderate to marked gastritis. No significant differences for bile salts, phospholipids, cholesterol, or total lipids in gallbladder bile were found between these three groups of patients. However, while only 1 out of 54 (< 2%) patients with mild or no gastritis was found histologically positive for Hp, this infection could be detected in 14 (74%) out of 19 patients with moderate to marked gastritis. Conclusion: Moderate to marked gastric mucosa inflammation in gallstone patients is mainly caused by Hp infection, whereas gallbladder function is not related to the degree of gastritis. Thus, an increased alkaline duodenogastric reflux in gallstone patients seems to be of limited pathophysiological relevance. Copyright (c) 2006 S. Karger AG, Basel

Compromised fidelity of B-cell tolerance checkpoints in AChR and MuSK myasthenia gravis

Myasthenia gravis () is an autoimmune condition in which neurotransmission is impaired by binding of autoantibodies to acetylcholine receptors (hR) or, in a minority of patients, to muscle specific kinase (Mu). There are differences in the dominant IgG subclass, pathogenic mechanisms, and treatment responses between the two subtypes (hR or Mu). The antibodies are thought to be T-cell dependent, but the mechanisms underlying their production are not well understood. One aspect not previously described is whether defects in central and peripheral tolerance checkpoints, which allow autoreactive B cells to accumulate in the naive repertoire, are found in both or either form of . An established set of assays that measure the frequency of both polyreactive and autoreactive B cell receptors () in naive populations was applied to specimens collected from patients with either hR or Mu and healthy controls. Radioimmuno- and cell-based assays were used to measure binding to hR and Mu. The frequency of polyreactive and autoreactive s (n = 262) was higher in both hR and Mu patients than in healthy controls. None of the -derived s bound hR or Mu. The results indicate that both these subtypes harbor defects in central and peripheral B cell tolerance checkpoints. Defective B cell tolerance may represent a fundamental contributor to autoimmunity in and is of particular importance when considering the durability of myasthenia gravis treatment strategies, particularly biologics that eliminate B cells

Toward Precision Phenotyping of Multiple Sclerosis

The classification of multiple sclerosis (MS) has been established by Lublin in 1996 and revised in 2013. The revision includes clinically isolated syndrome, relapsing-remitting, primary progressive and secondary progressive MS, and has added activity (i.e., formation of white matter lesions or clinical relapses) as a qualifier. This allows for the distinction between active and nonactive progression, which has been shown to be of clinical importance. We propose that a logical extension of this classification is the incorporation of additional key pathological processes, such as chronic perilesional inflammation, neuroaxonal degeneration, and remyelination. This will distinguish MS phenotypes that may present as clinically identical but are driven by different combinations of pathological processes. A more precise description of MS phenotypes will improve prognostication and personalized care as well as clinical trial design. Thus, our proposal provides an expanded framework for conceptualizing MS and for guiding development of biomarkers for monitoring activity along the main pathological axes in MS.</p

Autoantibody-producing plasmablasts after B cell depletion identified in muscle-specific kinase myasthenia gravis

Myasthenia gravis (MG) is a B cell-mediated autoimmune disorder of neuromuscular transmission. Pathogenic autoantibodies to muscle-specific tyrosine kinase (MuSK) can be found in patients with MG who do not have detectable antibodies to the acetylcholine receptor (AChR). MuSK MG includes immunological and clinical features that are generally distinct from AChR MG, particularly regarding responsiveness to therapy. B cell depletion has been shown to affect a decline in serum autoantibodies and to induce sustained clinical improvement in the majority of MuSK MG patients. However, the duration of this benefit may be limited, as we observed disease relapse in MuSK MG patients who had achieved rituximab-induced remission. We investigated the mechanisms of such relapses by exploring autoantibody production in the reemerging B cell compartment. Autoantibody-expressing CD27+ B cells were observed within the reconstituted repertoire during relapse but not during remission or in controls. Using two complementary approaches, which included production of 108 unique human monoclonal recombinant immunoglobulins, we demonstrated that antibody-secreting CD27hiCD38hi B cells (plasmablasts) contribute to the production of MuSK autoantibodies during relapse. The autoantibodies displayed hallmarks of antigen-driven affinity maturation. These collective findings introduce potential mechanisms for understanding both MuSK autoantibody production and disease relapse following B cell depletion

Flame (v2.0): advanced integration and interpretation of functional enrichment results from multiple sources.

UNLABELLED: Functional enrichment is the process of identifying implicated functional terms from a given input list of genes or proteins. In this article, we present Flame (v2.0), a web tool which offers a combinatorial approach through merging and visualizing results from widely used functional enrichment applications while also allowing various flexible input options. In this version, Flame utilizes the aGOtool, g: Profiler, WebGestalt, and Enrichr pipelines and presents their outputs separately or in combination following a visual analytics approach. For intuitive representations and easier interpretation, it uses interactive plots such as parameterizable networks, heatmaps, barcharts, and scatter plots. Users can also: (i) handle multiple protein/gene lists and analyse union and intersection sets simultaneously through interactive UpSet plots, (ii) automatically extract genes and proteins from free text through text-mining and Named Entity Recognition (NER) techniques, (iii) upload single nucleotide polymorphisms (SNPs) and extract their relative genes, or (iv) analyse multiple lists of differentially expressed proteins/genes after selecting them interactively from a parameterizable volcano plot. Compared to the previous version of 197 supported organisms, Flame (v2.0) currently allows enrichment for 14&nbsp;436 organisms. AVAILABILITY AND IMPLEMENTATION: Web Application: http://flame.pavlopouloslab.info. Code: https://github.com/PavlopoulosLab/Flame. Docker: https://hub.docker.com/r/pavlopouloslab/flame