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During chronic schistosome infections, a complex regulatory network is induced to regulate the host immune system, in which IL-10-producing regulatory B (Breg) cells play a significant role. Schistosoma mansoni soluble egg antigens (SEA) are bound and internalized by B cells and induce both human and mouse IL-10 producing Breg cells. To identify Breg-inducing proteins in SEA, we fractionated SEA by size exclusion chromatography and found 6 fractions able to induce IL-10 production by B cells (out of 18) in the high, medium and low molecular weight (MW) range. The high MW fractions were rich in heavily glycosylated molecules, including multi-fucosylated proteins. Using SEA glycoproteins purified by affinity chromatography and synthetic glycans coupled to gold nanoparticles, we investigated the role of these glycan structures in inducing IL-10 production by B cells. Then, we performed proteomics analysis on active low MW fractions and identified a number of proteins with putative immunomodulatory properties, notably thioredoxin (SmTrx1) and the fatty acid binding protein Sm14. Subsequent splenic murine B cell stimulations and hock immunizations with recombinant SmTrx1 and Sm14 showed their ability to dose-dependently induce IL-10 production by B cells both in vitro and in vivo. Identification of unique Breg cells-inducing molecules may pave the way to innovative therapeutic strategies for inflammatory and auto-immune diseases. Author summary: Worm parasites, such as schistosomes, are master regulators of the human immune system, manipulating the host response in order to prolong their survival in their host. As a bystander effect, they also reduce immune responses to allergens and/or auto antigens, thus protecting their host against inflammatory and auto-immune diseases. One of the immune cells involved in immune regulation is the IL-10-producing regulatory B (Breg) cells. Schistosome eggs release various molecules that induce the development of Breg cells, but the identity of these molecules is not yet fully known. In this study, the authors aimed to identify some of these molecules. They investigated both the involvement of glycans on high molecular weight schistosomal egg molecules, as well as dissected the role of proteins with a lower molecular weight coming from schistosomal eggs. Using proteomics, they targeted various interesting molecules, which they recombinantly expressed and confirmed the IL-10 inducing capacity in B cells in vitro and in vivo for 2 molecules. This new knowledge may explain the hyporesponsiveness found in chronic schistosome-infected people and may pave the way to new innovative therapies for inflammatory and auto-immune diseases. [ABSTRACT FROM AUTHOR]

Summary: Type 2 immune responses are most commonly associated with allergy and helminth parasite infections. Since the discovery of Th1 and Th2 immune responses more than 30 years ago, models of both allergic disease and helminth infections have been useful in characterizing the development, effector mechanisms and pathological consequences of type 2 immune responses. The observation that some helminth infections negatively correlate with allergic and inflammatory disease led to a large field of research into parasite immunomodulation. However, it is worth noting that helminth parasites are not always benign infections, and that helminth immunomodulation can have stimulatory as well as suppressive effects on allergic responses. In this review, we will discuss how parasitic infections change host responses, the consequences for bystander immunity and how this interaction influences clinical symptoms of allergy. [ABSTRACT FROM AUTHOR]

B-cells play a critical role in the formation of immune responses against pathogens by acting as antigen-presenting cells, by modulating immune responses and by generating immune memory and antibody responses. Here, we studied B-cell subset distributions between regions with higher and lower microbial exposure, i.e. by comparing peripheral blood B-cells from people living in Indonesia or Ghana to those from healthy Dutch residents using a 36-marker mass cytometry panel. By applying an unbiased multidimensional approach, we observed differences in the balance between the naïve and memory compartments, with higher CD11c+ and double negative (DN-IgDnegCD27neg) memory (M)B-cells in individuals from rural tropical areas, and conversely lower naïve B-cells compared to residents from an area with less pathogen exposure. Furthermore, characterization of total B-cell populations, CD11c+, DN and Breg cells showed the emergence of specific memory clusters in individuals living in rural tropical areas. Some of these differences were more pronounced in children compared to adults and suggest that a higher microbial exposure accelerates memory B cell formation, which 'normalizes' with age., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology.)

Background: The parasitic trematode Fasciola hepatica evades host immune defenses through secretion of various immunomodulatory molecules. Fatty Acid Binding Proteins ( fh FABPs) are among the main excreted/secreted proteins and have been shown to display anti-inflammatory properties. However, little is currently known regarding their impact on dendritic cells (DCs) and their subsequent capacity to prime specific CD4 + T cell subsets., Methodology/principal Findings: The immunomodulatory effects of both native F. hepatica extracts and recombinant fh FABPs were assessed on monocyte-derived human DCs (moDCs) and the underlying mechanism was next investigated using various approaches, including DC-allogenic T cell co-culture and DC phenotyping through transcriptomic, proteomic and FACS analyses. We mainly showed that fh FABP1 induced a tolerogenic-like phenotype in LPS-stimulated moDCs characterized by a dose-dependent increase in the cell-surface tolerogenic marker CD103 and IL-10 secretion, while DC co-stimulatory markers were not affected. A significant decrease in secretion of the pro-inflammatory cytokines IL-12p70 and IL-6 was also observed. In addition, these effects were associated with an increase in both Th2-on-Th1 ratio and IL-10 secretion by CD4 + T cells following DC-T cell co-culture. RNA sequencing and targeted proteomic analyses identified thrombospondin-1 (TSP-1) as a non-canonical factor highly expressed and secreted by fh FABP1-primed moDCs. The effect of fh FABP1 on T cell skewing was abolished when using a TSP-1 blocking antibody during DC-T cell co-culture. Immunomodulation by helminth molecules has been linked to improved metabolic homeostasis during obesity. Although fh FABP1 injection in high-fat diet-fed obese mice induced a potent Th2 immune response in adipose tissue, it did not improved insulin sensitivity or glucose homeostasis., Conclusions/significance: We show that fh FABP1 modulates T cell polarization, notably by promoting DC TSP-1 secretion in vitro , without affecting metabolic homeostasis in a mouse model of type 2 diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zawistowska-Deniziak, Lambooij, Kalinowska, Patente, Łapiński, van der Zande, Basałaj, de Korne, Chayé, Gasan, Norbury, Giera, Zaldumbide, Smits and Guigas.)

Toll-like receptors (TLRs) are pattern recognition receptors (PRRs), which constitute key components in the recognition of pathogens, thereby initiating innate immune responses and promoting adaptive immune responses. In B cells, TLR ligation is important for their activation and, together with CD40, for their differentiation. TLR ligands are also strong promoters of regulatory B (Breg)-cell development, by enhancing the production of IL-10 and their capacity to induce tolerance. In inflammatory diseases, such as autoimmunity or allergies, Breg-cell function is often impaired, while in chronic infections, such as with helminths, or cancer, Breg-cell function is boosted. Following pathogen exposure, B cells can respond directly by producing cytokines and/or IgM (innate response) and develop into various memory B (Bmem)-cell subsets with class-switched immunoglobulin receptors. Depending on the disease state or chronic infection conditions, various Breg subsets can be recognized as well. Currently, a large array of surface markers is known to distinguish between these large range of B-cell subsets. In recent years, the development of mass cytometers and spectral flow cytometry has allowed for high-dimensional detection of up to 48 markers, including both surface and intracellular/intranuclear markers. Therefore, this novel technology is highly suitable to provide a comprehensive overview of Bmem/Breg-cell subsets in different disease states and/or in clinical intervention trials. Here, we provide detailed instructions of the steps necessary to obtain high-quality data for high-dimensional analysis of multiple human Breg-cell subsets using various TLR ligands.

Infection with the helminth Schistosoma (S.) mansoni drives the development of interleukin (IL)-10-producing regulatory B (Breg) cells in mice and man, which have the capacity to reduce experimental allergic airway inflammation and are thus of high therapeutic interest. However, both the involved antigen and cellular mechanisms that drive Breg cell development remain to be elucidated. Therefore, we investigated whether S. mansoni soluble egg antigens (SEA) directly interact with B cells to enhance their regulatory potential, or act indirectly on B cells via SEA-modulated macrophage subsets. Intraperitoneal injections of S. mansoni eggs or SEA significantly upregulated IL-10 and CD86 expression by marginal zone B cells. Both B cells as well as macrophages of the splenic marginal zone efficiently bound SEA in vivo, but macrophages were dispensable for Breg cell induction as shown by macrophage depletion with clodronate liposomes. SEA was internalized into acidic cell compartments of B cells and induced a 3-fold increase of IL-10, which was dependent on endosomal acidification and was further enhanced by CD40 ligation. IPSE/alpha-1, one of the major antigens in SEA, was also capable of inducing IL-10 in naïve B cells, which was reproduced by tobacco plant-derived recombinant IPSE. Other major schistosomal antigens, omega-1 and kappa-5, had no effect. SEA depleted of IPSE/alpha-1 was still able to induce Breg cells indicating that SEA contains more Breg cell-inducing components. Importantly, SEA- and IPSE-induced Breg cells triggered regulatory T cell development in vitro. SEA and recombinant IPSE/alpha-1 also induced IL-10 production in human CD1d+ B cells. In conclusion, the mechanism of S. mansoni-induced Breg cell development involves a direct targeting of B cells by SEA components such as the secretory glycoprotein IPSE/alpha-1.