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. 2025 Jan 15;124(1):5. doi: 10.1007/s00436-024-08450-4

Regulatory B cells in parasitic infections: roles and therapeutic potential

Haojun Cai 1, Qianqian Mu 1, Haiting Xiong 1, Meichen Liu 1, Fengjiao Yang 1, Ling Zhou 2, Biying Zhou 1,✉
PMCID: PMC11732949  PMID: 39809978

Abstract

Parasitic infection is a complex process involving interactions among various immune cells. Regulatory B cells (Breg cells), a subset of B lymphocytes with immunosuppressive functions, play a role in modulating immune responses during infection to prevent excessive immune activation. This article reviews the origin, phenotype, and immunoregulatory mechanisms of Breg cells. We summarize the immunomodulatory roles of Breg cells in various parasitic infections. We also discuss the potential applications of activating Breg cells through parasitic infections and their derived molecules in the treatment of certain allergic, autoimmune, and inflammatory diseases. The aim is to provide new perspectives for the future treatment of parasitic diseases and other related conditions.

Keywords: Parasitic infections, Regulatory B cells, Immunoregulation, Allergy, Inflammation

Introduction

Parasitic diseases represent one of the most prevalent and challenging issues in the global public health sector, causing millions of illnesses and deaths annually (Wang 2017). B cells play a critical role in defending against parasitic infections, not only by producing antibodies against parasites but also by participating in antigen processing and presentation (Constant et al. 1995). Parasitic infections induce a series of immune responses in the host, which, while combating the infection, can also cause varying degrees of damage to the host. For instance, in chronic infections, hosts may experience allergic reactions, tissue damage, and cytokine storms (Allen and Sutherland 2014; Minciullo et al. 2012). Therefore, the immune response during parasitic infections needs to be appropriately regulated to effectively eliminate pathogens while avoiding excessive inflammatory responses. Research has shown that Breg cell populations with immunoregulatory functions can maintain immune balance by suppressing excessive inflammatory responses (Bosma et al. 2012).

The concept of inhibitory B cell subsets was first proposed in 1974 during studies on guinea pig delayed-type hypersensitivity (DTH) (Katz et al. 1974). With further research, it was discovered that in mouse models deficient in B cells, the conditions of experimental autoimmune encephalomyelitis (EAE) and chronic colitis were more severe (Mizoguchi et al. 1997; Wolf et al. 1996). In 2002, Mizoguchi et al. first used the term "regulatory B cells" to describe B cells that play a role in suppressing inflammatory bowel disease (Mizoguchi et al. 2002). These B cells execute their immunoregulatory functions by producing cytokines such as IL-10, IL-35, and TGF-β (Rosser and Mauri 2015). Abnormalities in the number and function of Breg cells have been widely documented in various immune-related pathological conditions, including autoimmune diseases, chronic infections, cancer, and transplant rejection (Mauri 2021). Although Breg cells constitute a small proportion of the total B cell population, their immunoregulatory role in parasitic infections is significant (Mengmeng et al. 2020). Bregs not only suppress excessive inflammatory responses, thereby protecting the host from tissue damage, but also exert regulatory effects on other diseases.

Regulatory B cell differentiation and function

Currently, it is generally believed that Breg cells differentiate from other types of B cells (such as transitional, memory, or plasma cells) under specific stimuli or signals (Matsumoto et al. 2014). These stimuli include immune complexes, CD40 ligand, Toll-like receptor ligands, and various cytokines (Rosser and Mauri 2015), as illustrated in Fig. 1. Considering that Breg cells can originate from different types of B cells, they can be further subdivided into B1-type, B2-type, and plasma cell-type Bregs (including plasmablasts and mature plasma cells) (Mauri and Bosma 2012; Mizoguchi et al. 2002).

Fig. 1.

Fig. 1

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Proposed development and differentiation pathways of Breg cells. In response to the influence of Toll-like receptor (TLR) ligands, CD40, and various cytokines, immature B cells are capable of differentiating into several forms, including B10 cells, T2-MZP cells, and mature B cells. These cell forms serve as precursors to regulatory B cells. Furthermore, both B10 and T2-MZP cells have the capacity to differentiate into mature B cells. Furthermore, from these mature B cells, plasmablasts that are capable of secreting cytokines such as IL-10, IL-35, and TGF-β can develop. Finally, regulatory B cells have the potential to differentiate into conventional plasma cells, which are responsible for antibody production

At present, there is a lack of standardized and unified methods to clearly define and identify regulatory B cells. For a long time, B lymphocytes that secrete IL-10 were considered to be regulatory B cells. However, subsequent research revealed that regulatory B cells can also secrete a variety of other immunoregulatory cytokines, such as IL-35, TGF-β, and granzyme B. These cells play a critical role in maintaining immune system balance and tolerance through various mechanisms (Rosser and Mauri 2015), as illustrated in Fig. 2.

Fig. 2.

Fig. 2

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The impact of Breg cells on other immune cells. Regulatory B cells are pivotal in sustaining immune system balance and tolerance through multiple mechanisms. They efficiently curb the growth, differentiation, and functionality of CD4+ and CD8+ T cells through the release of anti-inflammatory cytokines like interleukin-10 (IL-10), IL-35, and transforming growth factor-beta (TGF-β). Additionally, Bregs influence T cell activities by reducing pro-inflammatory factor production in dendritic cells, decreasing the activities of Th1, Th17, and CD8+ T cells, and fostering the transformation of CD4+ T cells into regulatory T cells (Tregs) and IL-10-producing Type 1 regulatory T cells (Tr1). Moreover, they suppress tumor necrosis factor-alpha (TNF-α) production in monocytes, curtail interferon-alpha (IFN-α) secretion by plasmacytoid dendritic cells (PDCs) and IL-12-dependent dendritic cells, promoting Th2-type responses

Unlike Treg cells, Breg cells do not have distinctive surface markers or release factors. Therefore, the identification of Bregs typically relies not only on surface markers but also on functional assays, such as the ability to produce IL-10 or suppress immune responses. We have summarized the phenotypes and the immunosuppressive molecules secreted by the various Breg subsets reported to date, as shown in Table 1.

Table 1.

Phenotypes of various Breg subgroups and the immunosuppressive molecules

Breg cells Mouse Human Location Suppressive cytokines References
B10 cells CD19+CD5+CD1dhi, CD19+CD1dhiCD5+CD9+ CD19+CD24hiCD27+ Spleen,Peripheral blood, Gastric mucosa IL-10 (Daïen et al. 2021; Ding et al. 2011; Iwata et al. 2011; Sun et al. 2015; Yanaba et al. 2008)
Br1 cells -

CD19+CD25+CD71hi

CD73lo

 Peripheral blood

IL-10

IgG4

 (van de Veen et al. 2013)
Immature B cells -

CD19+CD24hi

CD38hiCD1dhi

 Peripheral blood, Liver

IL-10

CD80/86

 (Blair et al. 2010)
Plasma blasts CD138+CD44hi

CD19+CD24hi

CD27intCD38+

 Lymph nodes, Peripheral blood, Spleen

IL-10

TGF-β

 (Matsumoto et al. 2014; Shalapour et al. 2015)
Plasma cells CD138+IgA+, CD138hiCD1dintTIM-1int CD138+IgA+ Lymph nodes, Peripheral blood, Spleen

IL-10

TGF-β

 (Pröbstel et al. 2020; Rojas et al. 2019; Shalapour et al. 2015; Shen et al. 2014)
Tim-1+ B cells CD19+TIM-1+ CD19+TIM-1+ Spleen, Peripheral blood IL-10 (Aravena et al. 2017; Ding et al. 2011)
GrB+ B cells -

CD19+CD38+CD1d+

IgM+CD147+

 Peripheral blood, Solid tumors GrB (Lindner et al. 2013)
Memory B cells -

CD19+CD24hi

CD27hi

 Peripheral blood IL-10 (Iwata et al. 2011)
CD9+ B cells CD19+CD9+ CD19+CD9+ Peripheral blood, Spleen IL-10 (Brosseau et al. 2018; Li et al. 2022)
CD5+ B cells CD19+CD5+CD1dhi

CD19+CD5+GrB+

CD1dhi

 Peripheral blood, Spleen

GrB

IL-10

 (Hagn et al. 2010; Tian et al. 2023; Zhang et al. 2012)
MZ B cells CD19+CD21hiCD23−CD24hi - Spleen IL-10 (Bankoti et al. 2012; Gray et al. 2007; Miles et al. 2012)
T2-MZP B cells

CD19+CD21hiCD23hi

CD24hi

 - Spleen IL-10 (Blair et al. 2009; Carter et al. 2011; Evans et al. 2007)
B1a cells CD19+CD5+ - Spleen IL-10 (Zhang et al. 2007)
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The role of Bregs in certain parasitic infections

As our understanding of the functions of Breg cells deepens, their role in immunoregulation during parasitic infections has become increasingly evident. A review of recent literature indicates that while Breg cells are generally immunosuppressive within the immune system, their impact across various parasitic infections can be complex and diverse. At present, investigations are primarily focused on the regulatory functions of Breg cells on host immunity, employing B cell-deficient mouse models and B cell adoptive transfer experiments. In parasitic infections, Breg cells exhibit a dual nature: on one hand, they regulate immune responses to prevent the parasite from causing excessive damage to the host; on the other hand, this regulatory capacity could offer parasites chances to avoid being cleared by the host’s immune system, thus hindering the host’s recovery.

Host immune responses to parasitic infections exhibit significant pathogen-specific differences. Protozoan infections predominantly induce Th1-type immune responses characterized by the secretion of pro-inflammatory cytokines such as IFN-γ and TNF-α, accompanied by CD8+ T cell activation. While this response pattern is effective in eliminating intracellular parasites, it may also result in host tissue damage. In striking contrast, helminth infections tend to elicit Th2-type immune responses, manifested by elevated levels of cytokines including IL-4, IL-5, and IL-13, coupled with enhanced IgE production and eosinophil recruitment. Although this polarized Th2 response facilitates helminth expulsion, its hyperactivation may lead to complications such as allergic reactions and tissue fibrosis. In these two distinctly different immune responses, Bregs play a crucial role in maintaining immune homeostasis and preventing inflammatory dysregulation through the secretion of inhibitory cytokines, including IL-10, IL-35, and TGF-β. Notably, due to the fundamental differences in initial immune responses induced by protozoa and helminths, the regulatory mechanisms and functional effects of Bregs demonstrate unique characteristics in these two types of infections. A comprehensive understanding of these differences not only helps elucidate the immune regulatory networks during parasitic infections but also provides critical theoretical foundations for developing targeted therapeutic strategies.

Protozoan infections

Leishmania

Leishmaniasis, a vector-borne parasitic illness, is caused by protozoans from the genus Leishmania, spread among mammalian hosts by female phlebotomine sandflies. This zoonotic condition is one of the foremost neglected tropical diseases, endangering 350 million people in 98 countries (Alvar et al. 2012). It is categorized based on tissue affinity into cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), and visceral leishmaniasis (VL). Various Leishmania species induce different symptoms, from self-healing skin sores to severe visceral afflictions that are potentially fatal, with visceral leishmaniasis (VL) being the deadliest, causing about 40,000 deaths each year (Andreani et al. 2015).

The contribution of B cells to the development of leishmaniasis remains unclear. Ongoing studies indicate that B cells could facilitate the progression of leishmaniasis either directly or indirectly by generating polyclonal antibodies and immunosuppressive agents like IL-10, which have been shown to have detrimental effects in experimental models (Arcanjo et al. 2017; Rodrigues et al. 2016). Particularly, muMT mice, which possess a genetic mutation resulting in the absence of mature B lymphocytes, show increased resistance to Leishmania parasites compared to their wild-type counterparts. These muMT mice are better at clearing parasites from the liver and exhibit no infections in the spleen (Smelt et al. 2000). Subsequent research has demonstrated that BALB/c mice infected with Leishmania experience a significant increase in IL-10-producing Bregs (Ronet et al. 2010). These cells prevent dendritic cells (DCs) from secreting IL-12 via IL-10, thus fostering a Th2 immune response. Conversely, the removal of Breg cells or inhibition of IL-10 signalling results in an elevation of IFN-γ and TNF-α levels and a reduction in IL-4 and IL-13 production in infected mice, suggesting a stronger Th1 immune response. Additionally, transferring B cells lacking IL-10 to muMT mice in an adoptive transfer experiment does not significantly alter the resistance of mice to Leishmania parasites. The results of this study indicate that in Leishmania infections, Bregs enhance a Th2 immune response and inhibit a Th1 immune response via IL-10 activity, thereby increasing the vulnerability of mice to leishmaniasis. In research on Leishmania infections in both children and dogs, critical modifications to the immune response have been observed. In children, Leishmania infection is associated with increased IL-10 mRNA expression and IL-10 production in B cells, which are characterised by CD27+ and CD24+CD38+ markers (Andreani et al. 2015). These cells notably suppress the Th1 immune response by hindering TNF-α and IFN-γ production in CD4+ T cells. Similarly, in canine studies, dogs with chronic Leishmania infections displayed a rise in IgDhi B cells, which also suppress T cell activity (Schaut et al. 2016). This suppression is facilitated through IL-10 and the interaction of PD-L1 on B cells with PD-1 on T cells, which inhibits T cell proliferation and further promotes IL-10 production, dampening the Th1 immune response.

The results of various studies demonstrate that Leishmania infection activates regulatory B cells that suppress the Th1 immune response and enhance the Th2 immune response, aiding the parasite in evading immune detection. This regulatory mechanism underscores the potential of IL-10 as a therapeutic target. Strategies such as inhibiting the IL-10 signalling pathway or eliminating IL-10-producing B cells may offer promising approaches for the treatment of visceral leishmaniasis (VL) (Nylén and Sacks 2007).

Babesia

Babesiosis is a zoonotic parasitic disease caused by intraerythrocytic protozoa belonging to the genus Babesia. These parasites invade the red blood cells of various domestic and wild mammals, causing the cells to lyse and be destroyed. In humans, this infection can lead to babesiosis (Vannier and Krause 2020). The disease is primarily transmitted through tick bites, but can also spread via blood transfusions and from mother to fetus through the placenta. Babesiosis is particularly severe and often fatal in individuals with weakened immune systems (Krause 2019).

Research on the immune responses of mice infected with Babesia has yielded valuable insights (Jeong et al. 2012). Post-infection, there is a notable increase in the populations of IL-10-producing CD1dhiCD5+ Bregs and CD4+CD25+FoxP3+ Tregs in the host, accompanied by elevated IL-10 levels in the serum. In vitro studies have demonstrated that stimulation of B cells with Babesia extracts prompts them to produce IL-10. Furthermore, adoptive transfer experiments demonstrated that transferring IL-10-producing Bregs into another group of mice increased their vulnerability to Babesia infection. Additionally, muMT mice, which lack B cells, exhibited lower IL-10 levels post-infection and exhibited milder disease symptoms compared to wild-type mice. The absence of Bregs also impeded the development of Tregs. These findings emphasise the pivotal regulatory function of Bregs in the management of Babesia infections. The expansion of IL-10+ Breg cells not only increases the susceptibility of the host but also facilitates the induction of Tregs, thereby enhancing the parasite's survival.

Trypanosoma cruzi

The genus Trypanosoma encompasses a number of parasites, including Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, which are responsible for the disease known as African sleeping sickness. Additionally, Trypanosoma cruzi is a parasite that causes Chagas disease, also known as American trypanosomiasis. Trypanosoma cruzi, a fecal–oral parasite, is predominantly prevalent in rural areas of South and Central America and can infect a variety of mammalian hosts. It is a zoonotic and natural focal disease (Brener 1973; Nóbrega et al. 2009). The amastigote stage is the main pathogenic phase of the parasite, with the disease progressing through acute and chronic stages, where cardiac lesions are the most common sequelae and cause of death during the chronic phase (Cardoso et al. 2016).

Recent research has delved into the mechanisms by which Trypanosoma cruzi induces changes in Bregs in patients with chronic Chagas disease (Girard et al. 2021). The findings revealed that T. cruzi stimulation increased both the frequency of B10 cells and their IL-10 secretion levels in peripheral blood samples from chronic Chagas disease patients as well as healthy individuals. Additionally, elevated levels of IL-17 secretion by B cells were observed in the subgroup of patients with chagasic cardiomyopathy. The research also revealed a rise in CD24−CD27− B cells and a decrease in CD24hiCD27+ Bregs in patients' blood, which was inversely associated with the presence of Trypanosoma cruzi DNA. This suggests that the parasite may play a role in modulating immune responses through changes in Breg cell characteristics. The C57BL/6 J mouse model was employed by researchers to conduct both in vivo and in vitro studies with the objective of exploring the effects of Trypanosoma cruzi on B cells (Somoza et al. 2022). The results of these experiments demonstrated that the parasite stimulates B cell proliferation and increases the production of IL-10 and IL-6. Notably, IL-10+B220lo cells were observed in vivo. Further analysis revealed elevated expression of FasL and PD-L1, proteins that induce apoptosis and inhibit TCR signalling, respectively, as well as BAFF and APRIL, which are B cell growth factors. These results suggest that Trypanosoma cruzi infection modifies the phenotype and function of Breg cells, promoting an immune environment that hinders the host's ability to eliminate the parasite.

Plasmodium

The genus Plasmodium comprises single-celled protozoan parasites that are responsible for malaria, a major infectious disease in human history. These parasites infect various vertebrates, including reptiles, birds, and mammals. Notably, five species specifically target humans: Plasmodium vivax, Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, and Plasmodium knowlesi. Their lifecycle requires two hosts (Sutherland 2016), humans and Anopheles mosquitoes, with the parasites undergoing schizogonic multiplication in both liver and red blood cells in humans. Despite effective antimalarial drugs, malaria still poses a significant infection risk, particularly in poorer regions, and continues to cause several hundred thousand deaths annually (Cibulskis et al. 2016).

Recent studies have demonstrated that infection of C57BL/6 mice with Plasmodium berghei results in an expansion of IL-10+ Bregs (Liu et al. 2013), which exhibit elevated levels of IgM, CD21, CD1d, and CD5. Transferring these cells into mice that have already been infected has been shown to significantly enhance survival rates, as it notably reduces NK cell and CD8+ T cell accumulation in the brain, as well as haemorrhaging. Notably, while the transferred Bregs improved survival, they did not affect parasitemia levels. The protective role of these Bregs was confirmed to be IL-10 dependent, as neutralising IL-10 with antibodies reversed their beneficial effects. A recent study on a cerebral malaria (ECM) model has demonstrated that IL-10 in plasma is predominantly produced by CD19+ B cells (Bao et al. 2013), particularly the CD5−CD19+ subset. Transferring these cells to uninfected mice effectively prevented ECM onset. In a separate study utilising a Plasmodium yoelii infection model in BALB/c mice (Kalkal et al. 2022), IL-10-producing B220+CD5+CD1d+ Bregs were observed to expand dynamically during infection. Transferring these Bregs to uninfected mice not only increased survival rates and inhibited parasite growth, but also modulated immune responses by reducing IFN-γ and increasing IL-10 expression in the spleen, thereby minimising damage from excessive inflammation. A recent study analysed peripheral blood samples from patients infected with Plasmodium falciparum using single-cell RNA sequencing and standard bioinformatics (Dooley et al. 2023). The findings indicated that the infection prompts an expansion of IL-10-producing regulatory CD4+ T cells (Tr1) and Bregs. This suggests that regulatory immune cells are crucial in dampening inflammation during infection. These findings underscore the role of regulatory immune cells in modulating immune responses and preventing severe outcomes in malaria infections.

Toxoplasma gondii

Toxoplasma gondii is a globally distributed apicomplexan protozoan. Felines serve as its definitive hosts, although it can infect humans and many other animals, causing the zoonotic disease toxoplasmosis (Kaushik et al. 2014). Toxoplasma infections are typically asymptomatic, but congenital infections and acquired infections in immunocompromised individuals often lead to severe toxoplasmosis. Toxoplasma gondii is a significant opportunistic pathogen (Kochanowsky and Koshy 2018).

Recent experiments utilising the C57BL/6 mouse model have demonstrated that following infection with Toxoplasma gondii, there is a significant increase in the number and proportion of IL-10-producing B cells, which predominantly exhibit a CD1dhiCD5+ phenotype, in comparison to uninfected mice (Jeong et al. 2016). Furthermore, studies involving muMT mice, which lack mature B cells, revealed a notably lower number of cysts in their brains compared to wild-type controls, underscoring the crucial role of B cells in the formation of cysts induced by Toxoplasma. Early in the infection, these regulatory B cells (Bregs) were found to suppress the production of IFN-γ, which helps in maintaining a chronic infection. Further investigations indicated that excretory-secretory products (ESPs) from the parasite, particularly during its cell lysis and release stages, effectively encourage the differentiation of naive B cells into IL-10 producing Bregs. These results emphasize the central role of Bregs in modulating host immune responses, promoting cyst formation, and maintaining chronic infection. These cells not only help to alleviate inflammatory responses but also have a crucial impact on the control of pathogens and the balance of host immunity.

Helminth infections

Echinococcus granulosus

Echinococcus granulosus is a member of the Taeniidae family and genus Echinococcus, commonly referred to as the hydatid worm. It primarily infests the small intestines of canid carnivores in its adult stages. Its larval stage, known as hydatid cysts, parasitizes the liver, lungs, brain, and other tissues of humans and various herbivorous domestic and other animals, causing a severe zoonotic disease known as cystic echinococcosis. This disease has a wide geographic distribution, posing significant threats to human health and livestock production, and has become a global public health issue (Wen et al. 2019).

A study utilising intraperitoneal injections of Echinococcus multilocularis protoscoleces in BALB/c mice revealed notable findings (Qi et al. 2021). In advanced infection stages, there was a significant elevation in serum IL-10 and TGF-β1 levels, accompanied by an increased presence of CD1dhiCD5+CD19hiIL-10+ Bregs in the spleen. These findings suggest that regulatory B cells may exert an immunosuppressive function in Echinococcus multilocularis infections by enhancing the levels of inhibitory cytokines IL-10 and TGF-β1. Further studies involving BALB/c mice stimulated with excretory-secretory products (ESPs) from Echinococcus multilocularis protoscoleces (EgPSC-ESPs) demonstrated significant increases in the proportions of regulatory B cells (B10), pro-inflammatory B cells (B17), and Th17 cells (Pan et al. 2017). Additionally, serum levels of IL-10 and IL-17A were elevated. Further in vitro tests demonstrated that EgPSC-ESPs directly enhance the differentiation of B10 cells, while suppressing B17 and Th17 cell differentiation. These findings suggest that ESPs promote Breg cells to curb Th17 responses and augment Th2 responses, aiding in the parasite's immune evasion. Further research has demonstrated that EgPSC-ESPs activate the PTEN/AKT/PI3K signalling pathway in B cells via the TLR-2 pathway (Pan et al. 2018), resulting in enhanced IL-10 production. This mechanism is likely a strategic adaptation by Echinococcus multilocularis to evade the host’s immune response.

Filarial helminths

Filariasis, a disease caused by parasitic nematodes transmitted via arthropods, primarily affects humans in tropical and subtropical areas (Ramaiah and Ottesen 2014). Notably, Wuchereria bancrofti and Brugia malayi are responsible for lymphatic filariasis, while Onchocerca volvulus leads to onchocerciasis or river blindness. These diseases are significant enough to be targeted for global prevention and control by the World Health Organization. The clinical manifestations of filariasis differ depending on the species involved. Lymphatic filariasis may result in conditions such as lymphadenitis and elephantiasis, whereas onchocerciasis typically leads to subcutaneous nodules and potentially blindness (Taylor et al. 2010).

Recent studies on filariasis have highlighted the pivotal role of regulatory immune cells in managing the body's response to the infection. Specifically, research using mice infeced with Brugia pahangi has shown that B cells are the predominant proliferating cell type in vitro (Gillan 2005). When these B cells are depleted or experiments are carried out in muMT mice—which lack mature B cells—there is a noticeable reduction in antigen-specific cell proliferation. Furthermore, in mice infected with the parasite, elevated levels of IL-10 enhance the function of B cells as antigen-presenting cells (APCs) for activating CD4+ T cells. This is achieved by modulating the expression of co-stimulatory molecules B7-1 and B7-2 on B cells, which in turn limits both their proliferation and overall function. Recent research has investigated the role of specific B cell subgroups in Brugia malayi infection (Mitre et al. 2019). This has revealed significant increases in the frequency of IL-10-producing B cell subgroups, including CD19+CD24hi and CD19+CD24hiCD5+CD1dhi Bregs, as well as immature B cells (CD19+CD24hiCD38hiIL-10+), in the peripheral blood of infected individuals. The study additionally observed that anti-filarial treatments can reduce the frequency of these B cell subgroups. These cells are implicated in suppressing effector T cell responses, inhibiting Th1 and Th17 differentiation, and promoting the transformation of CD4+ T cells into regulatory T cells (Tregs) and Type I regulatory T cells (Tr1). This indicates that IL-10-producing regulatory B cells play a pivotal role in the parasite's immune evasion strategies, impeding the host's capacity to effectively clear the infection. Further research involving patients infected with Brugia malayi has revealed an increase in both the quantity of B-1 cells and the expression of their Fas ligands (Mishra et al. 2017), which can induce Th cell apoptosis during filariasis infection. This Th cell apoptosis mediated by B-1 cells may be one of the key factors in the host's immune regulation imbalance and abnormal cellular immune function. During acute infection, B cells facilitate early infection control by presenting antigens and initiating specific immune responses; in chronic infection, Bregs exert immunomodulatory effects through secretion of suppressive mediators such as IL-10, which mitigates excessive inflammation and prevents tissue damage while potentially promoting infection persistence.

Schistosoma

Schistosomiasis, also known as bilharzia, is an infection caused by parasitic flatworms belonging to the genus Schistosoma. Six species within this genus are known to infect humans. These adult parasites reside within the veins of humans and other mammals, leading to significant health issues globally. The disease manifestations include Egyptian, Mansoni, and Japanese schistosomiasis, primarily found in Asia, Latin America, and Africa. Schistosomiasis, a parasitic disease affecting at least 230 million people globally, represents a significant global health concern (Vos et al. 2012). The primary pathogenic stage involves the parasite's eggs, which trigger an immune-mediated granulomatous reaction. This reaction leads to a range of pathological effects, including anaemia, growth retardation, cognitive impairment, decreased physical fitness, and organ-specific damage (Colley et al. 2014).

Initial studies on CBA/J mice infected with Schistosoma mansoni demonstrated an increase in B1 cells and IL-10 production within the peritoneal cavity (Velupillai et al. 1997). However, when treatments involving IL-12, IFN-γ, or anti-IL-10 were introduced, a reduction in B1 cell proliferation was observed. This suggests that the growth of B-1 cells may be regulated by the interactions among these cytokines. Further investigations revealed that Xid mice, which are deficient in B1 cells, show increased vulnerability to Schistosoma mansoni infections compared to normal controls (Gaubert et al. 1999). This increased susceptibility is characterised by higher mortality, more eggs present in the body, and denser liver granulomas. Additionally, these mice exhibited elevated levels of IFN-γ and IL-4 along with decreased IL-10 production, pointing to a stronger Th1 immune response. These findings underscore the pivotal role of B1 cells in regulating the immune response to Schistosoma mansoni, suggesting that they help to mitigate excessive immune reactions, which is crucial for the host's survival. Research into Schistosoma haematobium infection has demonstrated that regulatory B cells (Bregs) with a CD1dhi phenotype are capable of producing IL-10 in significant quantities (van der Vlugt et al. 2014). When these Bregs were co-cultured with T cells, they were observed to effectively suppress inflammatory cytokine production from effector T cells and also to increase both FoxP3 expression and the proportion of IL-10+ T cells. This indicates that Bregs induced by infection can inhibit effector T cell functions and facilitate the development of regulatory T cells, thereby contributing to a balanced immune response. A reduction in both B-1a cells and marginal zone B cells (MZB) was observed in the peritoneum and spleen of infected mice compared to their uninfected counterparts in studies on Schistosoma japonicum infection in BALB/c mice (Xiao et al. 2020). In vitro experiments revealed that stimulating B cells with Schistosoma japonicum egg antigen (SEA) markedly increased the expression of IL-10, PD-L1, and TGF-β within these cells. Moreover, when these activated B cells were co-cultured with CD4+ T cells, they suppressed the production of cytokines such as IL-4 by the T cells while enhancing the expression of the T follicular helper (Tfh) transcription factor Bcl6. This suggests that the B cells inhibit effector T cell function, thus preventing an excessive immune response, which is beneficial for the host.

The regulatory role of parasite-induced Breg cells in certain diseases

B cells are traditionally recognized for their role in producing antibodies and contributing to humoral immunity, which is essential for pathogen clearance. However, they can also play pathogenic roles in autoimmune diseases by producing autoantibodies that target and damage the body's own tissues. Alongside these pathogenic B cells, protective B cells, known as Bregs, are induced during autoimmune responses. Bregs are crucial for suppressing inflammatory responses, and their dysfunction is commonly observed in autoimmune disease conditions, which highlights a therapeutic area of interest.

Current research underscores that parasitic infections can activate and increase the production of Bregs. This activation has shown promising results in managing allergic and autoimmune diseases, suggesting that inducing Bregs could be a beneficial strategy in these conditions. Moreover, Bregs have also demonstrated potential in preventing and treating certain metabolic diseases, further expanding their therapeutic relevance and the need for ongoing research into conditions that enhance Breg production.

Parasite-induced Bregs and allergic diseases

Allergic diseases represent a significant global health burden, affecting hundreds of millions of individuals worldwide. These disorders, including allergic asthma, atopic dermatitis, food allergies, and allergic rhinitis, are characterized by dysregulated immune responses to typically harmless environmental antigens. Over recent decades, the prevalence of allergic diseases has increased dramatically in developed nations, particularly in urban areas (Hossny et al. 2019; Loh and Tang 2018). This trend is partially attributed to the "hygiene hypothesis," which suggests that reduced exposure to diverse microorganisms and parasites during early life may lead to insufficient immune regulation and increased susceptibility to allergic disorders.

In allergic diseases, the immune system exhibits an exaggerated Th2-type response, characterized by elevated IgE antibody levels and increased numbers of eosinophils, mast cells, and innate lymphoid cells (ILC2s). These responses typically involve the production of type 2 cytokines, such as IL-4, IL-5, and IL-13, which promote inflammation and tissue damage (Larché et al. 2006). However, emerging evidence indicates that regulatory immune cells, particularly Bregs, play a crucial role in maintaining immune tolerance and preventing excessive allergic responses. Recent studies have demonstrated that various parasitic infections can induce Bregs that help modulate allergic responses through multiple mechanisms (Palomares et al. 2017). These Breg cells primarily execute their immunosuppressive functions through the production of IL-10 and other regulatory cytokines, directly inhibiting inflammatory responses and promoting the development of Tregs. The therapeutic potential of parasite-induced Bregs in allergic diseases has been substantiated through several key studies:

Research utilising Penicillin V (Pen V) to model Schistosoma mansoni infections in mice has demonstrated that these mice are fully resistant to anaphylactic shock and show a marked rise in IL-10-producing B cells (Mangan et al. 2004). Further investigations that involved either depleting B cells or inhibiting IL-10 signals revealed that such interventions rendered the infected mice susceptible to anaphylactic reactions. Further research indicates that infection with S. mansoni enhances the production of IL-10+CD1dhi Bregs in both humans and mice, while also boosting the numbers of FoxP3+ T cells in vitro (van der Vlugt et al. 2012). Studies involving chimeric models with IL-10-deficient B cells and control mice demonstrate that the absence of IL-10 in B cells leads to exacerbated allergic airway inflammation (AAI) in these models. This highlights the pivotal role of Breg cells in dampening experimental allergic inflammation in mice. Similar observations in allergic pneumonitis indicate that in mice infected with S. mansoni (Khan et al. 2015), there is a significant increase in TLR7 expression and IL-10 production within CD19+CD1dhi Bregs. When these cells are transferred to mice allergic to ovalbumin (OVA), there is a notable reduction in airway resistance and a suppression of allergic pneumonitis symptoms.

A study utilising the NC/Nga mouse model to investigate the impact of Toxoplasma gondii infection on atopic dermatitis (AD)-like skin lesions has demonstrated that T. gondii significantly reduces both the severity of skin lesions and the infiltration of inflammatory cells (Jeong et al. 2015), including eosinophils and mast cells. This reduction is accompanied by an expansion of IL-10+ Bregs and CD4+CD25+FoxP3+ Tregs, which highlights their crucial role in modulating immune responses to suppress AD. Additionally, the studies show a decrease in serum IgE and IgG1 levels, an increase in IgG2a levels, and elevated IFN-γ and IL-10 expression in the skin, which suggests a shift from a Th2 to a Th1 immune response profile. These findings indicate that T. gondii infection may mitigate AD inflammation by promoting regulatory B and T cell expansion and altering the Th2/Th1 balance.

Studies involving Heligmosomoides polygyrus have demonstrated its significant therapeutic potential in allergic airway inflammation. Research has established infection models by orally administering H. polygyrus to mice (Wilson et al. 2010b). The adoptive transfer of CD19+CD23hi B cells isolated from infected mice significantly alleviated Derp1-induced airway allergic inflammation, as evidenced by reduced eosinophil infiltration in airways, decreased IL-5 secretion, and attenuated airway pathological damage. In another study, researchers developed an ovalbumin (OVA)-induced allergic airway inflammation model in H. polygyrus-infected mice (Gao et al. 2019). The infection significantly suppressed OVA-induced AAI, resulting in reduced lung pathological changes and decreased inflammatory cell infiltration. Notably, in infected mice, the numbers of both IL-10+ Bregs and IL-10+ Treg cells were significantly increased. Transfer of these cells to AAI mice prevented AAI development and reduced lung pathological changes and inflammatory cell infiltration. H. polygyrus infection induces the expansion of IL-10-producing B cells, which exhibit regulatory functions through IL-10 production and contribute to the immunomodulatory effects observed in allergic diseases. These Bregs play a crucial role in maintaining immune homeostasis during infection and mediating protection against allergic inflammation.

Parasite-induced Bregs and multiple sclerosis

Multiple sclerosis (MS) is a prevalent chronic condition among young adults, characterised by inflammation, demyelination, and neurodegeneration. It is a diverse and multifactorial immune-mediated disorder influenced by both genetic and environmental factors. Over time, many patients experience irreversible clinical and cognitive deficits, with a few presenting a progressive disease course from the outset. A key pathological feature of MS is the formation of demyelinating lesions in the brain and spinal cord, which can lead to axonal damage. These lesions are believed to arise from the infiltration of immune cells, including T cells, B cells, and myeloid cells, into the central nervous system, which subsequently causes tissue damage (Dobson and Giovannoni 2019; Ebers 2008).

A study of MS patients over a period of 4.6 years revealed that those with parasitic infections (comprising Hymenolepis nana, Trichuris trichiura, Ascaris lumbricoides, Strongyloides stercoralis, and Enterobius vermicularis) exhibited fewer relapses and less disability progression (Correale and Farez 2007), alongside minimal changes in MRI results, when compared to uninfected MS patients (Correale and Equiza 2014). Additionally, significant increases in anti-inflammatory cytokines IL-10 and TGF-β were noted in the blood of infected patients, accompanied by decreased levels of pro-inflammatory cytokines IL-12 and interferon-γ. This was correlated with an increase in regulatory T cells (CD4+CD25+FoxP3+), which are known for their high inhibitory capacity and role in modulating the disease course of MS through the secretion of IL-10 and TGF-β. Subsequent studies (Correale and Equiza 2014; Correale et al. 2008) demonstrated that a population of B cells producing high levels of IL-10 was identified in the peripheral blood of MS patients infected with Hymenolepis nana and Trichuris trichiura. These B cells expressed elevated levels of CD1d and suppressed harmful immune responses through the ICOS-B7RP-1 pathway. Furthermore, peripheral blood B cells from helminth-infected MS patients produced significantly higher amounts of BDNF and NGF compared to control groups, suggesting these factors may exert neuroprotective effects on the central nervous system. Further studies revealed elevated IL-35 levels in the blood of worm-infected MS patients and a greater prevalence of IL-35-producing Breg cells compared to non-infected patients (Correale et al. 2021). This correlated with decreased disease activity observed in MRI scans. In vitro experiments demonstrated that antigens derived from Hymenolepis nana and Trichuris trichiura (soluble egg antigens, SEA) induced IL-35 production in naïve B cells through the activation of specific transcription factors, including BATF, IRF4, and IRF8 (Correale et al. 2021). The presence of IL-35 notably reduced T cell proliferation and the secretion of Th1/Th17 cytokines, thus mitigating autoimmune reactions. These findings not only deepen our understanding of how worm infections can modulate autoimmune diseases but also point to new therapeutic avenues for treating multiple sclerosis.

Parasite-induced Bregs and inflammatory bowel disease

Inflammatory Bowel Disease (IBD) represents a group of chronic inflammatory disorders affecting the gastrointestinal tract, primarily comprising Crohn's Disease and Ulcerative Colitis, characterized by alternating periods of disease activity and remission. The pathogenesis of IBD involves complex interactions among genetic susceptibility, environmental factors, and dysregulated immune responses (Zhang and Li 2014). Recent studies have demonstrated that regulatory immune cells, including regulatory B cells (Bregs), play crucial roles in maintaining intestinal homeostasis and controlling IBD-associated inflammation (Bing et al. 2018).

Hymenolepis diminuta is a cestode that predominantly parasitizes rodents (as definitive hosts) and arthropods (as intermediate hosts) (Arai 2012). Although this parasite rarely causes significant pathological alterations in immunocompetent hosts, research has shown that the parasite and its products can modulate host immune responses, particularly through the induction of regulatory immune cells. Initial studies employed Hymenolepis diminuta infection in BALB/c mice by oral administration of cysticercoids to establish an infection model (Hunter et al. 2005). Colitis was induced using dinitrobenzene sulfonic acid (DNBS), and it was found that this parasitic infection could alleviate chemically induced colitis by elevating IL-10 levels, with neutralization of IL-10 significantly weakening this protective effect. Further investigation utilising the identical model demonstrated that CD19+ B cells, when isolated from infected mice, were capable of significantly alleviating the symptoms of chemically induced colitis in healthy mice. Additionally, these cells exhibited elevated levels of TGF-β (Reyes et al. 2015), without showing increased expression of IL-4 or IL-10. Through macrophage function inhibition experiments and B cell interaction tests, the presence of macrophages was confirmed as critical for the Breg cells' effectiveness in alleviating colitis. Mice treated with B cells showed notable improvements in colon length, histopathological scores, and intestinal inflammation markers, such as myeloperoxidase activity. Further studies examined the effects of both single and repeated parasite infections (to assess immune memory) on colitis severity (Wang et al. 2017). The findings indicated that reactivating immune memory with parasite antigens in mice previously exposed to infections significantly reduced colitis symptoms and increased IL-4 and IL-10 expression, enhancing Th2 immune responses. This supports the critical role of immune memory in managing colitis. Furthermore, experimental evidence indicates that infection with Hymenolepis diminuta can induce splenic Breg cells in mice, which possess immunoregulatory functions. These Breg cells produce anti-inflammatory cytokines and interact with macrophages to effectively alleviate chemically induced colitis, thereby underscoring the importance of immune memory in controlling inflammatory responses. These insights offer valuable cellular and molecular targets for developing new treatments for inflammatory bowel disease.

Parasite-induced Bregs and diabetes and obesity

Epidemiological data indicates a potential link between helminth infections and lower obesity rates in certain populations. Observations show a negative correlation between the prevalence of worm infections and the incidence of specific metabolic diseases, including type 1 diabetes and obesity (Hotez and Herricks 2015; Okada et al. 2010). Additionally, numerous animal studies support this finding, indicating that worm infections may help prevent obesity and enhance insulin sensitivity (Hussaarts et al. 2015), and provide protection against type 2 diabetes (T2D) (Sikder et al. 2024).

Research (Luo et al. 2017; Ni et al. 2021) has shown that hyperlipidemic mice infected with Schistosoma japonicum exhibit a range of lipid-lowering effects compared to control mice. In mice infected with the parasitic worm Schistosoma japonicum, research has demonstrated that CD19+CD9+ B cells exhibit heightened IL-10 production capabilities (Li et al. 2022). These cells not only promote the proliferation of regulatory T cells and Th2 cells but also suppress Th1 and Th17 cell responses, effectively mitigating the inflammatory response in mice on high-fat diets. Further in vitro experiments demonstrated that when isolated B cells were stimulated with CD40 monoclonal antibodies, CD19+CD9+ B cells produced more IL-10 than conventional B10 cells. This highlighted their enhanced anti-inflammatory effects. Additionally, transferring CD9+ B cells from chronically infected mice to those on high-fat diets resulted in significant health improvements, including reduced body weight, better insulin sensitivity, decreased liver fat, and improved lipid profiles. These findings highlight the potential of leveraging immune cell regulation, particularly through CD9+ B cells, to develop new treatments for obesity and its associated metabolic disorders.

Conclusion

After parasitic infection, hosts' immune systems are modulated to facilitate parasite survival, yet these immunomodulatory molecules may also exert beneficial effects on human health. Over the past four decades, there has been a significant increase in the incidence of allergic and autoimmune diseases in developed countries, while simultaneously experiencing a marked decline in infectious disease rates (Hotez and Herricks 2015; Okada et al. 2010). The "Hygiene Hypothesis" provides an explanation for this phenomenon: improved sanitary conditions have reduced human exposure to pathogens, leading to dysregulation of the immune system and consequently increasing the risk of allergic and autoimmune diseases. Experimental models have further demonstrated that certain bacterial, viral, and parasitic infections can effectively prevent the development of autoimmune diseases (Bach 2018).

During different pathogenic infections, Breg cells exhibit distinct regulatory mechanisms and functional characteristics in their expansion. In viral and bacterial infections, Bregs primarily suppress the function of effector cells, such as CD8+ T cells, potentially contributing to the chronicity of infection (Dai et al. 2019; Das et al. 2012; Gong et al. 2015; Zhang et al. 2014). In parasitic infections, however, Bregs mainly exert their immunosuppressive effects through IL-10 secretion and the induction of Tregs proliferation to inhibit excessive immune responses. Recent research has also emphasized the pivotal role of Bregs in modulating immune responses to parasitic infections. Bregs have been found to perform multifaceted functions across various parasitic infections, including leishmaniasis, schistosomiasis, malaria, toxoplasmosis, filariasis, echinococcosis, babesiosis, and Chagas disease. These functions range from regulating cytokine production and modulating immune cells to potential therapeutic applications. In the field of parasitology, Breg cells primarily promote CD4+ T cell differentiation through the secretion of IL-10, IL-35, TGF-β, and granzyme B (GrB), while simultaneously suppressing Th1, Th17, and CD8+ T cell responses (Mengmeng et al. 2020; Veh et al. 2024). During parasitic infections, the role of Bregs extends beyond merely mitigating the host's immune response against itself and minimizing excessive damage caused by the parasite. Bregs also potentially assist parasites in evading the host's immune system for complete clearance. This delicate balance highlights the potential of Bregs as a strategy for controlling parasitic infections.

Furthermore, in conditions such as allergic and autoimmune diseases, as well as inflammatory bowel diseases, parasite-induced Breg cells help to suppress inflammation and regulate immune responses, thereby reducing body damage. This suppression is advantageous for both the prevention and treatment of these diseases. Bregs also contribute to the management of certain metabolic diseases. Currently, research on the therapeutic potential of parasite-induced regulatory B cells is predominantly limited to murine models. The existing experimental evidence primarily derives from adoptive transfer studies in mice, which demonstrate that parasite-induced Bregs exhibit significant immunosuppressive effects across various inflammatory disease models. These models include Heligmosomoides polygyrus-induced allergic airway inflammation (Wilson et al. 2010a), Hymenolepis diminuta-induced colitis (Reyes et al. 2015), and Schistosoma japonicum-induced metabolic disorder models (Li et al. 2022). However, direct evidence from human studies remains limited, with the most compelling clinical data coming from multiple sclerosis (MS) patients with helminth infections, who demonstrate persistently elevated Breg numbers accompanied by stable immunoregulatory function (Correale and Farez 2007). Investigating Bregs in the context of parasitic diseases enhances our comprehension of host-parasite interactions and reveals potential new strategies for disease intervention by manipulating Breg activity. Such insights are of crucial importance for the more effective control and treatment of related conditions.

Parasitic infections are effective inducers of Breg cell activation. However, compared to direct parasitic infections, parasitic-derived molecules are more readily accepted by patients, and their safety is easier to control. Currently, there are many studies on using parasitic immunogenic antigen molecules to stimulate Bregs to regulate diseases, such as schistosome soluble egg antigens (SEA) (Haeberlein et al. 2017; Tian et al. 2015), worm-released excretions (ESP) (Harnett 2014), exosomes, and specific antigen molecules selected from them (Bhargava et al. 2012; Rodgers et al. 2014; Zhu et al. 2012). However, most of these studies are based on animal experiments, and translating their results for human clinical application remains a challenge, requiring further research in this area. Consequently, future research should concentrate on elucidating the mechanisms by which antigen molecules activate Bregs, their impact on the progression of parasitic diseases, and their regulatory functions during such infections. An understanding of these mechanisms will provide a scientific foundation for the development of novel therapeutic approaches that target Breg activity, offering potential advancements in disease treatment and management.

Acknowledgements

We are grateful to our colleagues at Zunyi Medical University for their insightful comments and suggestions.

Author contributions

H.C. and B.Z. conceptualized and designed the study; H.C., Q.M., H.X., M.L., and F.Y. prepared the original draft; L.Z. and B.Z. reviewed and edited the manuscript; B.Z. acquired funding. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (No. 81960378 and No. 82460402).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval

Clinical trial number: not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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