Btn2a2 Regulates ILC2-T Cell Cross Talk in Type 2 Immune Responses.

Innate lymphoid cells (ILC) not only are responsible for shaping the innate immune response but also actively modulate T cell responses. However, the molecular processes regulating ILC-T cell interaction are not yet completely understood. The protein butyrophilin 2a2 (Btn2a2), a co-stimulatory molecule first identified on antigen-presenting cells, has a pivotal role in the maintenance of T cell homeostasis, but the main effector cell and the respective ligands remain elusive. We analyzed the role of Btn2a2 in the ILC-T cell cross talk. We found that the expression of Btn2a2 is upregulated in ILC2 following stimulation with IL-33/IL-25/TSLP. In vitro and in vivo experiments indicated that lack of Btn2a2 expression on ILC2 resulted in elevated T cell responses. We observed an enhanced proliferation of T cells as well as increased secretion of the type 2 cytokines IL-4/IL-5/IL-13 following cocultures with Btn2a2-deficient ILC2. In vivo transfer experiments confirmed the regulatory role of Btn2a2 on ILC2 as Btn2a2-deficient ILC2 induced stronger T cell responses and prevented chronic helminth infections. Taken together, we identified Btn2a2 as a significant player in the regulation of ILC2-T cell interactions.

Gene-Specific Sex Effects on Susceptibility to Infectious Diseases.

Inflammation is an integral part of defense against most infectious diseases. These pathogen-induced immune responses are in very many instances strongly influenced by host's sex. As a consequence, sexual dimorphisms were observed in susceptibility to many infectious diseases. They are pathogen dose-dependent, and their outcomes depend on pathogen and even on its species or subspecies. Sex may differentially affect pathology of various organs and its influence is modified by interaction of host's hormonal status and genotype: sex chromosomes X and Y, as well as autosomal genes. In this Mini Review we summarize the major influences of sex in human infections and subsequently focus on 22 autosomal genes/loci that modify in a sex-dependent way the response to infectious diseases in mouse models. These genes have been observed to influence susceptibility to viruses, bacteria, parasites, fungi and worms. Some sex-dependent genes/loci affect susceptibility only in females or only in males, affect both sexes, but have stronger effect in one sex; still other genes were shown to affect the disease in both sexes, but with opposite direction of effect in females and males. The understanding of mechanisms of sex-dependent differences in the course of infectious diseases may be relevant for their personalized management.

Neglected Tropical Diseases: The Potential Application of microRNAs for Monitoring NTDs in the Real World.

Neglected Tropical Diseases (NTDs) are a common health problem and require an efficient campaign to be eradicated from tropical countries. Almost a million people die of NTDs every year in the world, and almost forty percent of the patients are under 20 years. Mass Drug Administration (MDA) is an effective tool for eradication of this health condition. However, a monitoring system is required to evaluate treatment-response and early detection of the re-emerging NTD. The relevance of current tests depends on good quality of the specimen. Thus, new molecular methods with high sensitivity and specificity are required. In this review, we focus on microRNAs (miRNAs) as biomarkers of NTDs through a narrative review on human research. We searched for reliable search engines using a systematical literature review algorithm and included studies that fit the criterion. Five NTDs (lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiases, and trachoma) were set as our target diseases. Later on, the data were extracted and classified as monitoring response and early detection. Four miRNAs were studied in filariasis as a monitoring response. There were 12 miRNAs related to onchocerciasis infection, and 6 miRNAs with schistosomiasis infection. Six miRNAs showed a link to soil-transmitted helminths. Only 3 miRNAs correlated with trachoma infection. In conclusion, circulating miR is a less invasive and promising approach to evaluate NTDs. Further field study may translate those candidate miRs to clinical application of the prevention and control of NTDs.

Genomic analyses of aminoacyl tRNA synthetases from human-infecting helminths.

BACKGROUND: Helminth infections affect ~ 60% of the human population that lives in tropical and subtropical regions worldwide. These infections result in diseases like schistosomiasis, lymphatic filariasis, river blindness and echinococcosis. Here we provide a comprehensive computational analysis of the aminoacyl tRNA synthetase (aaRS) enzyme family from 27 human-infecting helminths. Our analyses support the idea that several helminth aaRSs can be targeted for drug repurposing or for development of new drugs. For experimental validation, we focused on Onchocerciasis (also known as "river blindness"), a filarial vector-borne disease that is prevalent in Africa and Latin America. We show that halofuginone (HF) can act as a potent inhibitor of Onchocerca volvulus prolyl tRNA synthetase (OvPRS). RESULTS: The conserved enzyme family of aaRSs has been validated as druggable targets in numerous eukaryotic parasites. We thus embarked on assessing aaRSs from the genomes of 27 helminths that cause infections in humans. In order to delineate the distribution of aaRSs per genome we utilized Hidden Markov Models of aaRS catalytic domains to identify all orthologues. We note that Fasciola hepatica genome encodes the highest number of aaRS-like proteins (69) whereas Taenia asiatica has the lowest count (32). The number of genes for any particular aaRS-like protein varies from 1 to 8 in these 27 studied helminths. Sequence alignments of helminth-encoded lysyl, prolyl, leucyl and threonyl tRNA synthetases suggest that various known aaRS inhibitors like Cladosporin, Halofuginone, Benzoborale and Borrelidin may be of utility against helminths. The recombinantly expressed Onchocerca volvulus PRS was used as proof of concept for targeting aaRS with drug-like molecules like HF. CONCLUSIONS: Systematic analysis of unique subdomains within helminth aaRSs reveals the presence of a number of non-canonical domains like PAC3, Utp-14, Pex2_Pex12 fused to catalytic domains in the predicted helminth aaRSs. We have established a platform for biochemical validation of a large number of helminth aaRSs that can be targeted using available inhibitors to jump-start drug repurposing against human helminths.

Variants in the CYSLTR2 are associated with asthma, atopy markers and helminths infections in the Brazilian population.

BACKGROUND: Asthma is a chronic disease of the airways and its most common phenotype is characterized by a T2 type response with IgE production and inflammatory mediators in response to common allergens. Cysteinyl leukotrienes (CysLTs), LTC4, LTD4 and LTE4, are mediators known to possess important proinflammatory action. CysLTs can bind to the Cysteinyl leukotriene receptor type 2 (CysLTR2) and activate an inflammatory. Polymorphisms in CysLTR2 have been associated with asthma and atopy, although the mechanism is not clear. OBJECTIVE: To evaluate the association between genetic polymorphisms in CYSLTR2 with asthma phenotypes, atopy markers and helminth infection. METHODS: Genotyping was performed using a panel Illumina and carried out in 1245 participants of SCAALA program (Social Change, Asthma, Allergy in Latin American). Logistic regressions for asthma, helminth infections (Trichuris trichiura and Ascaris lumbricoides) and allergy markers (skin tests and IgE production) were performed using PLINK 1.9 software adjusted for sex, age, helminth infection and ancestry markers. RESULTS: The G allele of rs1323556 was negatively associated with asthma in the additive model (OR 0.74, 95% CI 0.59-0.93) and in the dominant model (OR 0.71, 95% CI 0.53-0.74). The G allele of rs1575464 was also negatively associated with asthma in two genetic models, additive (OR 0.77, 95% CI 0.62-0.96) and dominant (OR 0.73, 95% CI 0.55-0.97). The G allele of rs61735175 was positively associated with asthma severity in the additive model (OR 1.72, 95% CI 1.07-2.77) and in the dominant model (OR 1.77, 95% CI 1.09-2.85). Five SNVs were associated with atopy markers and four SNVs were associated with helminth infections. CONCLUSION: Polymorphisms in the CYSLTR2 gene are associated with asthma, atopy markers and helminth infection in Brazilian individuals, which may lead to protection or risk for such conditions, however, more studies are needed to evaluate the functional of this variants here in described.

Library Preparation for ATAC-Sequencing of Mouse CD4+ T Cells Isolated from the Lung and Lymph Nodes After Helminth Infection.

Although conventional methods such as MNase-seq, DNase-seq, and ChIP-seq have been used effectively to assess chromatin and locus accessibility at the genome level, these techniques generally require large numbers of input cells. As such, much of what we understand in terms of epigenetic regulation and locus accessibility in CD4+ T cell subsets comes from in vitro culture systems, which allow for the production of large numbers of polarized T cells. However, obtaining such numbers directly ex vivo from tissues of individual mice is difficult. Here we describe a method combining cytokine reporter mice and Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) to identify genome wide locus accessibility in a small number of cytokine-expressing CD4+ T cells. This method takes you from cell isolation to library generation and quality control to query. Because the Il4 and Ifng loci are reciprocally regulated in polarized CD4+ T cell subsets (Th1 vs. Th2), we investigated the ability of this approach to identify transposase integration in both IL-4- and IFN-γ-expressing CD4+ T cells isolated directly from the lung and lymph nodes after helminth infection.

Bcl11b is essential for licensing Th2 differentiation during helminth infection and allergic asthma.

During helminth infection and allergic asthma, naive CD4+ T-cells differentiate into cytokine-producing Type-2 helper (Th2) cells that resolve the infection or induce asthma-associated pathology. Mechanisms regulating the Th2 differentiation in vivo remain poorly understood. Here we report that mice lacking Bcl11b in mature T-cells have a diminished capacity to mount Th2 responses during helminth infection and allergic asthma, showing reduced Th2 cytokines and Gata3, and elevated Runx3. We provide evidence that Bcl11b is required to maintain chromatin accessibility at Th2-cytokine promoters and locus-control regions, and binds the Il4 HS IV silencer, reducing its accessibility. Bcl11b also binds Gata3-intronic and downstream-noncoding sites, sustaining the Gata3 expression. In addition, Bcl11b binds and deactivates upstream enhancers at Runx3 locus, restricting the Runx3 expression and its availability to act at the Il4 HS IV silencer. Thus, our results establish novel roles for Bcl11b in the regulatory loop that licenses Th2 program in vivo.

The Immune and Non-Immune Pathways That Drive Chronic Gastrointestinal Helminth Burdens in the Wild.

Parasitic helminths are extremely resilient in their ability to maintain chronic infection burdens despite (or maybe because of) their hosts' immune response. Explaining how parasites maintain these lifelong infections, identifying the protective immune mechanisms that regulate helminth infection burdens, and designing prophylactics and therapeutics that combat helminth infection, while preserving host health requires a far better understanding of how the immune system functions in natural habitats than we have at present. It is, therefore, necessary to complement mechanistic laboratory-based studies with studies on wild populations and their natural parasite communities. Unfortunately, the relative paucity of immunological tools for non-model species has held these types of studies back. Thankfully, recent progress in high-throughput 'omics platforms provide powerful and increasingly practical means for immunologists to move beyond traditional lab-based model organisms. Yet, assigning both metabolic and immune function to genes, transcripts, and proteins in novel species and assessing how they interact with other physiological and environmental factors requires identifying quantitative relationships between their expression and infection. Here, we used supervised machine learning to identify gene networks robustly associated with burdens of the gastrointestinal nematode Heligmosomoides polygyrus in its natural host, the wild wood mice Apodemus sylvaticus. Across 34 mice spanning two wild populations and across two different seasons, we found 17,639 transcripts that clustered in 131 weighted gene networks. These clusters robustly predicted H. polygyrus burden and included well-known effector and regulatory immune genes, but also revealed a number of genes associated with the maintenance of tissue homeostasis and hematopoiesis that have so far received little attention. We then tested the effect of experimentally reducing helminth burdens through drug treatment on those putatively protective immune factors. Despite the near elimination of H. polygyrus worms, the treatment had surprisingly little effect on gene expression. Taken together, these results suggest that hosts balance tissue homeostasis and protective immunity, resulting in relatively stable immune and, consequently, parasitological profiles. In the future, applying our approach to larger numbers of samples from additional populations will help further increase our ability to detect the immune pathways that determine chronic gastrointestinal helminth burdens in the wild.

Paper-Based DNA Reader for Visualized Quantification of Soil-Transmitted Helminth Infections.

Soil-transmitted helminth (STH) infections are a global health issue affecting nearly one-third of the world's population. As most endemic areas of STH are impoverished countries or regions with limited healthcare resources, the accurate diagnosis of STH requires analytical tools that are not only quantitative, but also portable, inexpensive, and with no or minimal demand for external instrument. Herein, we introduce a novel paper-based diagnostic device, termed quantitative paper-based DNA reader (qPDR), capable of quantifying STH at the molecular level by measuring distance as readout, thus eliminating the need for external readers. On the basis of the unique interfacial interaction of a DNA intercalating dye, SYBR Green I, with native cellulose on a chromatographic paper, qPDR allows the distance-based quantification of minute amounts of double-stranded DNA as short as 6 min. By integrating qPDR with polymerase chain reactions that were performed using a smartphone-controlled portable thermal cycler, we were able to quantify minute amount of genetic markers from adult worms of an STH (Trichuris trichiura) that were expelled post-treatment by infected children living in the rural areas of Honduras.

Recent Advances in Type-2-Cell-Mediated Immunity: Insights from Helminth Infection.

Type-2-cell-mediated immune responses play a critical role in mediating both host-resistance and disease-tolerance mechanisms during helminth infections. Recently, type 2 cell responses have emerged as major regulators of tissue repair and metabolic homeostasis even under steady-state conditions. In this review, we consider how studies of helminth infection have contributed toward our expanding cellular and molecular understanding of type-2-cell-mediated immunity, as well as new areas such as the microbiome. By studying how these successful parasites form chronic infections without overt pathology, we are gaining additional insights into allergic and inflammatory diseases, as well as normal physiology.

Mast Cells Are Crucial for Induction of Group 2 Innate Lymphoid Cells and Clearance of Helminth Infections.

Mast cells are important for eradication of intestinal nematodes; however, their precise mechanisms of action have remained elusive, especially in the early phase of infection. We found that Spi-B-deficient mice had increased numbers of mast cells and rapidly expelled the Heligmosomoides polygyrus (Hp) nematode. This was accompanied by induction of interleukin-13 (IL-13)-producing group 2 innate lymphoid cells (ILC2) and goblet cell hyperplasia. Immediately after Hp infection, mast cells were rapidly activated to produce IL-33 in response to ATP released from apoptotic intestinal epithelial cells. In vivo inhibition of the P2X7 ATP receptor rendered the Spi-B-deficient mice susceptible to Hp, concomitant with elimination of mast cell activation and IL-13-producing ILC2 induction. These results uncover a previously unknown role for mast cells in innate immunity in that activation of mast cells by ATP orchestrates the development of a protective type 2 immune response, in part by producing IL-33, which contributes to ILC2 activation.

Impact of Helminth Infections and Nutritional Constraints on the Small Intestine Microbiota.

Helminth infections and nutrition can independently alter the composition and abundance of the gastrointestinal microbiota, however, their combined effect is poorly understood. Here, we used the T. retortaeformis-rabbit system to examine how the helminth infection and host restriction from coprophagy/ready-to-absorb nutrients affected the duodenal microbiota, and how these changes related to the acquired immune response at the site of infection. A factorial experiment was performed where the bacterial community, its functionality and the immune response were examined in four treatments (Infect, Infect+Collar, Control+Collar and Control). Helminths reduced the diversity and abundance of the microbiota while the combination of parasites and coprophagic restriction led to a more diversified and abundant microbiota than infected cases, without significantly affecting the intensity of infection. Animals restricted from coprophagy and free from parasites exhibited the richest and most abundant bacterial community. By forcing the individuals to absorb nutrients from less digested food, the coprophagic restriction appears to have facilitated the diversity and proliferation of bacteria in the duodenum. Changes in the microbiota were more clearly associated with changes in the immune response for the infected than the nutrient restricted animals. The functional and metabolic characteristics of the duodenal microbiota were not significantly different between treatments. Overall, infection and diet affect the gut microbiota but their interactions and outcome can be complex. These findings can have important implications for the development of control measures to helminth infections where poor nutrition/malnutrition can also be a concern.

Critical role of fatty acid metabolism in ILC2-mediated barrier protection during malnutrition and helminth infection.

Innate lymphoid cells (ILC) play an important role in many immune processes, including control of infections, inflammation, and tissue repair. To date, little is known about the metabolism of ILC and whether these cells can metabolically adapt in response to environmental signals. Here we show that type 2 innate lymphoid cells (ILC2), important mediators of barrier immunity, predominantly depend on fatty acid (FA) metabolism during helminth infection. Further, in situations where an essential nutrient, such as vitamin A, is limited, ILC2 sustain their function and selectively maintain interleukin 13 (IL-13) production via increased acquisition and utilization of FA. Together, these results reveal that ILC2 preferentially use FAs to maintain their function in the context of helminth infection or malnutrition and propose that enhanced FA usage and FA-dependent IL-13 production by ILC2 could represent a host adaptation to maintain barrier immunity under dietary restriction.

Early-life enteric infections: relation between chronic systemic inflammation and poor cognition in children.

The intestinal microbiota undergoes active remodeling in the first 6 to 18 months of life, during which time the characteristics of the adult microbiota are developed. This process is strongly influenced by the early diet and enteric pathogens. Enteric infections and malnutrition early in life may favor microbiota dysbiosis and small intestinal bacterial overgrowth, resulting in intestinal barrier dysfunction and translocation of intestinal bacterial products, ultimately leading to low-grade, chronic, subclinical systemic inflammation. The leaky gut-derived low-grade systemic inflammation may have profound consequences on the gut-liver-brain axis, compromising normal growth, metabolism, and cognitive development. This review examines recent data suggesting that early-life enteric infections that lead to intestinal barrier disruption may shift the intestinal microbiota toward chronic systemic inflammation and subsequent impaired cognitive development.

Cellular gene expression induced by parasite antigens and allergens in neonates from parasite-infected mothers.

Prenatal exposure to parasite antigens or allergens will influence the profile and strength of postnatal immune responses, such contact may tolerize and increase susceptibility to future infections or sensitize to environmental allergens. Exposure in utero to parasite antigens will distinctly alter cellular gene expression in newborns. Gene microarrays were applied to study gene expression in umbilical cord blood cell (UCBC) from parasite-exposed (Para-POS) and non-exposed (Para-NEG) neonates. UCBC were activated with antigens of helminth (Onchocerca volvulus), amoeba (Entamoeba histolytica) or allergens of mite (Dermatophagoides farinae). When UCBC from Para-POS and Para-NEG newborns were exposed to helminth antigens or allergens consistent differences occurred in the expression of genes encoding for MHC class I and II alleles, signal transducers of activation and transcription (STATs), cytokines, chemokines, immunoglobulin heavy and light chains, and molecules associated with immune regulation (SOCS, TLR, TGF), inflammation (TNF, CCR) and apoptosis (CASP). Expression of genes associated with innate immune responses were enhanced in Para-NEG, while in Para-POS, the expression of MHC class II and STAT genes was reduced. Within functional gene networks for cellular growth, proliferation and immune responses, Para-NEG neonates presented with significantly higher expression values than Para-POS. In Para-NEG newborns, the gene cluster and pathway analyses suggested that gene expression profiles may predispose for the development of immunological, hematological and dermatological disorders upon postnatal helminth parasite infection or allergen exposure. Thus, prenatal parasite contact will sensitize without generating aberrant inflammatory immune responses, and increased pro-inflammatory but decreased regulatory gene expression profiles will be present in those neonates lacking prenatal parasite antigen encounter.

Intrinsic functional defects of type 2 innate lymphoid cells impair innate allergic inflammation in promyelocytic leukemia zinc finger (PLZF)-deficient mice.

BACKGROUND: The transcription factor promyelocytic leukemia zinc finger (PLZF) is transiently expressed during development of type 2 innate lymphoid cells (ILC2s) but is not present at the mature stage. We hypothesized that PLZF-deficient ILC2s have functional defects in the innate allergic response and represent a tool for studying innate immunity in a mouse with a functional adaptive immune response. OBJECTIVE: We determined the consequences of PLZF deficiency on ILC2 function in response to innate and adaptive immune stimuli by using PLZF(-/-) mice and mixed wild-type:PLZF(-/-) bone marrow chimeras. METHODS: PLZF(-/-) mice, wild-type littermates, or mixed bone marrow chimeras were treated with the protease allergen papain or the cytokines IL-25 and IL-33 or infected with the helminth Nippostrongylus brasiliensis to induce innate type 2 allergic responses. Mice were sensitized with intraperitoneal ovalbumin-alum, followed by intranasal challenge with ovalbumin alone, to induce adaptive TH2 responses. Lungs were analyzed for immune cell subsets, and alveolar lavage fluid was analyzed for ILC2-derived cytokines. In addition, ILC2s were stimulated ex vivo for their capacity to release type 2 cytokines. RESULTS: PLZF-deficient lung ILC2s exhibit a cell-intrinsic defect in the secretion of IL-5 and IL-13 in response to innate stimuli, resulting in defective recruitment of eosinophils and goblet cell hyperplasia. In contrast, the adaptive allergic inflammatory response to ovalbumin and alum was unimpaired. CONCLUSIONS: PLZF expression at the innate lymphoid cell precursor stage has a long-range effect on the functional properties of mature ILC2s and highlights the importance of these cells for innate allergic responses in otherwise immunocompetent mice.

Evidence of Helminth Infection in Guanche Mummies: Integrating Paleoparasitological and Paleogenetic Investigations.

The Guanches, ancient inhabitants of the Canary Islands, Spain, practiced mummification of their dead. A paleoparasitological and paleogenetic analysis was conducted on mummified bodies (n = 6) (AD 1200, Cal BP 750) belonging to the Guanche culture from Gran Canaria Island. Coprolite and sediment samples (n = 19) were removed from below the abdominal region or sacral foramina. The samples were rehydrated in 0.5% trisodium phosphate solution for 72 hr at 4 C, and the paleoparasitological investigation was conducted by spontaneous sedimentation method and microscopic examination. The results revealed the presence of well-preserved eggs of Ascaris sp., Trichuris trichiura , Enterobius vermicularis , and hookworms. Ancient DNA was extracted from sediment samples to elucidate the ancestry of the mummies and for molecular detection of Ascaris sp. infection. Results of paleogenetic analysis demonstrated Ascaris sp. infection using 2 molecular targets, cytb and nad1. The mtDNA haplotypes U6b, U6b1, and HV were identified, which confirmed records of Guanche ancestry. The excellent preservation of Guanche mummies facilitated the paleoparasitological and paleogenetic study, the results of which contribute to our knowledge of Guanche culture and their health status.

Migratory CD103+ dendritic cells suppress helminth-driven type 2 immunity through constitutive expression of IL-12.

CD8α(+) and CD103(+) dendritic cells (DCs) play a central role in the development of type 1 immune responses. However, their role in type 2 immunity remains unclear. We examined this issue using Batf3(-/-) mice, in which both of these DC subsets are missing. We found that Th2 cell responses, and related events such as eosinophilia, alternative macrophage activation, and immunoglobulin class switching to IgG1, were enhanced in Batf3(-/-) mice responding to helminth parasites. This had beneficial or detrimental consequences depending on the context. For example, Batf3 deficiency converted a normally chronic intestinal infection with Heligmosomoides polygyrus into an infection that was rapidly controlled. However, liver fibrosis, an IL-13-mediated pathological consequence of wound healing in chronic schistosomiasis, was exacerbated in Batf3(-/-) mice infected with Schistosoma mansoni. Mechanistically, steady-state production of IL-12 by migratory CD103(+) DCs, independent of signals from commensals or TLR-initiated events, was necessary and sufficient to exert the suppressive effects on Th2 response development. These findings identify a previously unrecognized role for migratory CD103(+) DCs in antagonizing type 2 immune responses.

Pleiotropic Effects of Immune Responses Explain Variation in the Prevalence of Fibroproliferative Diseases.

Many diseases are differentially distributed among human populations. Differential selection on genetic variants in ancestral environments that coincidentally predispose to disease can be an underlying cause of these unequal prevalence patterns. Selected genes may be pleiotropic, affecting multiple phenotypes and resulting in more than one disease or trait. Patterns of pleiotropy may be helpful in understanding the underlying causes of an array of conditions in a population. For example, several fibroproliferative diseases are more prevalent and severe in populations of sub-Saharan ancestry. We propose that this disparity is due to selection for an enhanced Th2 response that confers resistance to helminthic infections, and concurrently increases susceptibility to fibrosis due to the profibrotic action of Th2 cytokines. Many studies on selection of Th2-related genes for host resistance to helminths have been reported, but the pleiotropic impact of this selection on the distribution of fibrotic disorders has not been explicitly investigated. We discuss the disproportionate occurrence of fibroproliferative diseases in individuals of African ancestry and provide evidence that adaptation of the immune system has shaped the genetic structure of these human populations in ways that alter the distribution of multiple fibroproliferative diseases.

Suppressive functions of B cells in infectious diseases.

B lymphocytes are often essential to successfully control invading pathogens and play a primary role in the protection afforded by successful vaccines through the production of specific antibodies. However, recent studies have highlighted the complex roles of B cells in infectious diseases, showing unexpectedly that some activated B cells limited host defense towards pathogens. This B-cell function involves production of regulatory cytokines including IL-10 and IL-35 and is reminiscent of the regulatory functions of B cells initially defined in autoimmune diseases. It is now known that various types of microbes including bacteria, helminths and viruses can induce IL-10-expressing B cells with inhibitory functions, indicating that this response is a general component of anti-microbial immunity. Interestingly, IL-10-producing B cells induced in the course of some microbial infections can inhibit concurrent immune responses directed towards unrelated antigens in a bystander manner and as a consequence ameliorate the course of autoimmune or allergic diseases. This could explain how some micro-organisms might provide protection from these pathologies, as formulated in the 'hygiene hypothesis'. In this review, we discuss the regulatory functions of B cells in bacterial, parasitic and viral infections, taking into account the phenotype of the B cells implicated, the signals controlling their induction and the cell types targeted by their suppressive activities.