Therapeutic targeting of gut‐originating regulatory B cells in neuroinflammatory diseases
Tradite Neziraj,
Lena Siewert,
Elisabeth Pössnecker
et al.
Abstract:Regulatory B cells (Bregs) are immunosuppressive cells that support immunological tolerance by the production of interleukin (IL)‐10, IL‐35, and transforming growth factor β (TGF‐β). Bregs arise from different developmental stages in response to inflammatory stimuli. In that regard, mounting evidence points towards a direct influence of gut microbiota on mucosal B cell development, activation, and regulation in health and disease. While an increasing number of diseases are associated with alterations in gut mi… Show more
“…Antigen sampling within the gut is likely to stimulate immunotolerance because of regulatory cytokine ratios present in the healthy intestine. This propensity for tolerance is extended to other areas of the body, as the immune cells trained in the GIT migrate to other parts of the body [69]. Peyer's Patches are also the most prominent areas for T-cell dependent class switching, while T-cell independent class switching takes place within the laminal propria [17,63].…”
Section: Mechanisms By Which the Microbiome Provides Colonization Res...mentioning
The gut microbiome is intimately intertwined with the host immune system, having effects on the systemic immune system. Dysbiosis of the gut microbiome has been linked not only to gastrointestinal disorders but also conditions of the skin, lungs, and brain. Commensal bacteria can affect the immune status of the host through a stimulation of the innate immune system, training of the adaptive immune system, and competitive exclusion of pathogens. Commensal bacteria improve immune response through the production of immunomodulating compounds such as microbe-associated molecular patterns (MAMPs), short-chain fatty acids (SCFAs), and secondary bile acids. The microbiome, especially when in dysbiosis, is plastic and can be manipulated through the introduction of beneficial bacteria or the adjustment of nutrients to stimulate the expansion of beneficial taxa. The complex nature of the gastrointestinal tract (GIT) ecosystem complicates the use of these methods, as similar treatments have various results in individuals with different residential microbiomes and differential health statuses. A more complete understanding of the interaction between commensal species, host genetics, and the host immune system is needed for effective microbiome interventions to be developed and implemented in a clinical setting.
“…Antigen sampling within the gut is likely to stimulate immunotolerance because of regulatory cytokine ratios present in the healthy intestine. This propensity for tolerance is extended to other areas of the body, as the immune cells trained in the GIT migrate to other parts of the body [69]. Peyer's Patches are also the most prominent areas for T-cell dependent class switching, while T-cell independent class switching takes place within the laminal propria [17,63].…”
Section: Mechanisms By Which the Microbiome Provides Colonization Res...mentioning
The gut microbiome is intimately intertwined with the host immune system, having effects on the systemic immune system. Dysbiosis of the gut microbiome has been linked not only to gastrointestinal disorders but also conditions of the skin, lungs, and brain. Commensal bacteria can affect the immune status of the host through a stimulation of the innate immune system, training of the adaptive immune system, and competitive exclusion of pathogens. Commensal bacteria improve immune response through the production of immunomodulating compounds such as microbe-associated molecular patterns (MAMPs), short-chain fatty acids (SCFAs), and secondary bile acids. The microbiome, especially when in dysbiosis, is plastic and can be manipulated through the introduction of beneficial bacteria or the adjustment of nutrients to stimulate the expansion of beneficial taxa. The complex nature of the gastrointestinal tract (GIT) ecosystem complicates the use of these methods, as similar treatments have various results in individuals with different residential microbiomes and differential health statuses. A more complete understanding of the interaction between commensal species, host genetics, and the host immune system is needed for effective microbiome interventions to be developed and implemented in a clinical setting.
“…Regulatory B cells (Bregs) represent a specialized subset of B cells renowned for their immunosuppressive properties, which are crucial in maintaining immune tolerance and regulating inflammation [ 9 , 10 ]. Initially identified in the context of autoimmunity, Bregs have now been acknowledged for their significant roles in infection, allergy, and transplant tolerance [ 11 ]. In the realm of tumor biology, Bregs have been found to impede anti-tumor immune responses, thereby promoting tumorigenesis.…”
Background
Regulatory B cells (Bregs), a specialized subset of B cells that modulate immune responses and maintain immune tolerance in malignant tumors, have not been extensively investigated in the context of bladder cancer (BLCA). This study aims to elucidate the roles of Bregs and Breg-related genes in BLCA.
Methods
We assessed Breg infiltration levels in 34 pairs of BLCA and corresponding paracancerous tissues using immunohistochemical staining. We conducted transwell and wound healing assays to evaluate the impact of Bregs on the malignant phenotype of SW780 and T24 cells. Breg-related genes were identified through gene sets and transcriptional analysis. The TCGA-BLCA cohort served as the training set, while the IMvigor210 and 5 GEO cohorts were used as external validation sets. We employed LASSO regression and random forest for feature selection and developed a risk signature using Cox regression. Primary validation of the risk signature was performed through immunohistochemical staining and RT-qPCR experiments using the 34 local BLCA samples. Additionally, we employed transfection assays and flow cytometry to investigate Breg expansion ability and immunosuppressive functions.
Results
Breg levels in BLCA tissues were significantly elevated compared to paracancerous tissues (P < 0.05) and positively correlated with tumor malignancy (P < 0.05). Co-incubation of SW780 and T24 cells with Bregs resulted in enhanced invasion and migration abilities (all P < 0.05). We identified 27 Breg-related genes, including CD96, OAS1, and CSH1, which were integrated into the risk signature. This signature demonstrated robust prognostic classification across the 6 cohorts (pooled HR = 2.25, 95% CI = 1.52–3.33). Moreover, the signature exhibited positive associations with advanced tumor stage (P < 0.001) and Breg infiltration ratios (P < 0.05) in the local samples. Furthermore, the signature successfully predicted immunotherapeutic sensitivity in three cohorts (all P < 0.05). Knockdown of CSH1 in B cells increased Breg phenotype and enhanced suppressive ability against CD8 + T cells (all P < 0.05).
Conclusions
Bregs play a pro-tumor role in the development of BLCA. The Breg-related gene signature established in this study holds great potential as a valuable tool for evaluating prognosis and predicting immunotherapeutic response in BLCA patients.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.