The nature of circulating CD27+CD43+ B cells

Letter to the Editor.-- et al.M.C. van Zelm is supported by fellowships from the Erasmus University Rotterdam (EUR-Fellowship) and the Erasmus MC, and by Veni grant 916.110.90 from ZonMW/NWO.Peer Reviewe

Defective formation of IgA memory B cells, Th1 and Th17 cells in symptomatic patients with selective IgA deficiency

Objective: Selective IgA deficiency (sIgAD) is the most common primary immunodeficiency in Western countries. Patients can suffer from recurrent infections and autoimmune diseases because of a largely unknown aetiology. To increase insights into the pathophysiology of the disease, we studied memory B and T cells and cytokine concentrations in peripheral blood. Methods: We analysed 30 sIgAD patients (12 children, 18 adults) through detailed phenotyping of peripheral B-cell, CD8+ T-cell and CD4+ T-cell subsets, sequence analysis of IGA and IGG transcripts, in vitro B-cell activation and blood cytokine measurements. Results: All patients had significantly decreased numbers of T-cell-dependent (TD; CD27+) and T-cell-independent (TI; CD27−) IgA memory B cells and increased CD21low B-cell numbers. IgM+IgD− memory B cells were decreased in children and normal in adult patients. IGA and IGG transcripts contained normal SHM levels. In sIgAD children, IGA transcripts more frequently used IGA2 than controls (58.5% vs. 25.1%), but not in adult patients. B-cell activation after in vitro stimulation was normal. However, adult sIgAD patients exhibited increased blood levels of TGF-β1, BAFF and APRIL, whereas they had decreased Th1 and Th17 cell numbers. Conclusion: Impaired IgA memory formation in sIgAD patients is not due to a B-cell activation defect. Instead, decreased Th1 and Th17 cell numbers and high blood levels of BAFF, APRIL and TGF-β1 might reflect disturbed regulation of IgA responses in vivo. These insights into B-cell extrinsic immune defects suggest the need for a broader immunological focus on genomics and functional analyses to unravel the pathogenesis of sIgAD

Circulating Human CD27(-)IgA(+) Memory B Cells Recognize Bacteria with Polyreactive Igs

The vast majority of IgA production occurs in mucosal tissue following T cell-dependent and T cell-independent Ag responses. To study the nature of each of these responses, we analyzed the gene-expression and Ig-reactivity profiles of T cell-dependent CD27(+)IgA(+) and T cell-independent CD27(-)IgA(+) circulating memory B cells. Gene-expression profiles of IgA(+) subsets were highly similar to each other and to IgG(+) memory B cell subsets, with typical upregulation of activation markers and downregulation of inhibitory receptors. However, we identified the mucosa-associated CCR9 and RUNX2 genes to be specifically upregulated in CD27(-)IgA(+) B cells. We also found that CD27(-)IgA(+) B cells expressed Abs with distinct Ig repertoire and reactivity compared with those from CD27(+)IgA(+) B cells. Indeed, Abs from CD27(-)IgA(+) B cells were weakly mutated, often used Igl chain, and were enriched in polyreactive clones recognizing various bacterial species. Hence, T cell-independent IgA responses are likely involved in the maintenance of gut homeostasis through the production of polyreactive mutated IgA Abs with cross-reactive anticommensal reactivity

Circulating Human CD27(-)IgA(+) Memory B Cells Recognize Bacteria with Polyreactive Igs

The vast majority of IgA production occurs in mucosal tissue following T cell-dependent and T cell-independent Ag responses. To study the nature of each of these responses, we analyzed the gene-expression and Ig-reactivity profiles of T cell-dependent CD27(+)IgA(+) and T cell-independent CD27(-)IgA(+) circulating memory B cells. Gene-expression profiles of IgA(+) subsets were highly similar to each other and to IgG(+) memory B cell subsets, with typical upregulation of activation markers and downregulation of inhibitory receptors. However, we identified the mucosa-associated CCR9 and RUNX2 genes to be specifically upregulated in CD27(-)IgA(+) B cells. We also found that CD27(-)IgA(+) B cells expressed Abs with distinct Ig repertoire and reactivity compared with those from CD27(+)IgA(+) B cells. Indeed, Abs from CD27(-)IgA(+) B cells were weakly mutated, often used Igl chain, and were enriched in polyreactive clones recognizing various bacterial species. Hence, T cell-independent IgA responses are likely involved in the maintenance of gut homeostasis through the production of polyreactive mutated IgA Abs with cross-reactive anticommensal reactivity

Binding of von Willebrand factor and plasma proteins to the eggshell of Schistosoma mansoni

Schistosoma mansoni eggs have to cross the endothelium and intestinal wall to leave the host and continue the life cycle. Mechanisms involved in this essential step are largely unknown. Here we describe direct binding to the S. mansoni eggshell of von Willebrand factor and other plasma proteins involved in haemostasis. Using deletion-mutants, we demonstrated that it is the A1 domain of von Willebrand factor that binds to the eggshell. Our results suggest that binding of plasma proteins to the eggshell promotes binding to the endothelium, initiating the passage of the egg through the blood-vessel wall to be excreted in the end. (C) 2014 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved

Differences in Systemic IgA Reactivity and Circulating Th Subsets in Healthy Volunteers With Specific Microbiota Enterotypes

Changes in the intestinal microbiota have been associated with the development of immune-mediated diseases in humans. Additionally, the introduction of defined bacterial species into the mouse intestinal microbiota has been shown to impact on the adaptive immune response. However, how much impact the intestinal microbiota composition actually has on regulating adaptive immunity remains poorly understood. Therefore, we studied aspects of the adaptive immunity in healthy adults possessing distinct intestinal microbiota profiles. The intestinal microbiota composition was determined via Illumina sequencing of bacterial 16S rRNA genes extracted from the feces of 35 individuals. Blood B-cell and T-cell subsets from the same individuals were studied using flow cytometry. Finally, the binding of fecal and plasma Immunoglobulin A (IgA) to intestinal bacteria (associated with health and disease) Bacteroides fragilis, Prevotella copri, Bifidobacterium longum, Clostridium difficile, and Escherichia coli was analyzed using ELISA. Unsupervised clustering of microbiota composition revealed the presence of three clusters within the cohort. Cluster 1 and 2 were similar to previously-described enterotypes with a predominance of Bacteroides in Cluster 1 and Prevotella in Cluster 2. The bacterial diversity (Shannon index) and bacterial richness of Cluster 3 was significantly higher than observed in Clusters 1 and 2, with the Ruminococacceae tending to predominate. Within circulating B- and T-cell subsets, only Th subsets were significantly different between groups of distinct intestinal microbiota. Individuals of Cluster 3 have significantly fewer Th17 and Th22 circulating cells, while Th17.1 cell numbers were increased in individuals of Cluster 1. IgA reactivity to intestinal bacteria was higher in plasma than feces, and individuals of Cluster 1 had significant higher plasma IgA reactivity against B. longum than individuals of Cluster 2. In conclusion, we identified three distinct fecal microbiota clusters, of which two clusters resembled previously-described "enterotypes". Global T-cell and B-cell immunity seemed unaffected, however, circulating Th subsets and plasma IgA reactivity were significantly different between Clusters. Hence, the impact of intestinal bacteria composition on human B cells, T cells and IgA reactivity appears limited in genetically-diverse and environmentally-exposed humans, but can skew antibody reactivity and Th cell subsets.</p

Binding of von Willebrand factor and plasma proteins to the eggshell of Schistosoma mansoni

Schistosoma mansoni eggs have to cross the endothelium and intestinal wall to leave the host and continue the life cycle. Mechanisms involved in this essential step are largely unknown. Here we describe direct binding to the S. mansoni eggshell of von Willebrand factor and other plasma proteins involved in haemostasis. Using deletion-mutants, we demonstrated that it is the A1 domain of von Willebrand factor that binds to the eggshell. Our results suggest that binding of plasma proteins to the eggshell promotes binding to the endothelium, initiating the passage of the egg through the blood-vessel wall to be excreted in the end