Multiple sclerosis (MS) is defined as an inflammatory disorder that chronically affects the central nervous system of young people mostly and is distributed globally. It is associated with degeneration and demyelination of the myelin sheath around the nerves, resulting in multiple neurological disability symptoms ranging from mild to severe cases that end with paralysis sometimes. MS is one of the rising diseases globally that is unfortunately associated with reduced quality of life and adding national economic burdens. The definite MS mechanism is not clearly defined; however, all the previous researches confirm the role of the immune system as the master contributor in the pathogenesis. Innate and adaptive immune cells are activated peripherally then attracted toward the central nervous system (CNS) due to the breakdown of the blood-brain barrier. Recently, the gut-brain axis was shown to depend on gut metabolites that are produced by different microorganisms in the colon. The difference in microbiota composition between individuals is responsible for diversity in secreted metabolites that affect immune responses locally in the gut or systemically when reach blood circulation to the brain. It may enhance or suppress immune responses in the central nervous system (CNS) (repeated short forms); consequently, it may exacerbate or ameliorate MS symptoms. Recent data showed that some metabolites can be used as adjuvant therapy in MS and other inflammatory diseases. This review sheds light on the nature of MS and the possible interaction between gut microbiota and immune system regulation through the gut-brain axis, hence contributing to MS pathogenesis.

In recent years, the discovery of IL-12 family cytokines, which includes IL-12, IL-23, IL-27, IL-35, and IL-39, whose biological functions directly or indirectly affect various autoimmune diseases. In autoimmune diseases, IL-12 family cytokines are aberrantly expressed to varying degrees. These cytokines utilize shared subunits to influence T-cell activation and differentiation, thereby regulating the balance of T-cell subsets, which profoundly impacts the onset and progression of autoimmune diseases. In such conditions, IL-12 family members are aberrantly expressed to varying degrees. By exploring their immunomodulatory functions, researchers have identified varying therapeutic potentials for each member. This review examines the physiological functions of the major IL-12 family members and their interactions, discusses their roles in several autoimmune diseases, and summarizes the progress of clinical studies involving monoclonal antibodies targeting IL-12 and IL-23 subunits currently available for treatment.

Regulatory B cells (Breg) are instrumental in protecting allografts in transplantation. Breg signatures are identified in operationally tolerant human kidney transplant recipients and can predict organ survival and acute rejection. Animal models of transplantation and autoimmunity support the use of Breg as an adoptive cellular therapy. Detailed mechanistic studies have identified multiple signaling pathways utilized by Breg in their induction, expansion, and downstream function. These preclinical studies provide the guiding principles, which will inform protocols by which to expand this crucial immunoregulatory population before clinical use. There is an urgent need for novel therapies to improve long-term transplant outcomes and to minimize immunosuppression-related morbidity including life-threatening infection and cancer. Systematic evaluation of the signals, which drive Breg expansion, will be key to transforming the as of yet unharnessed potential of this potent immunoregulatory cell. In this review, we explore the potential avenues of translating Breg subsets from cell culture at the laboratory bench to cell therapy at the patient's bedside. We will discuss the standardization of Breg phenotypes to aid in precursor population selection and quality control of a Breg-cell therapy product. We will evaluate avenues by which to optimize protocols to drive human Breg expansion to levels sufficient for cellular therapy. Finally, we will examine the steps required in process development including scalable culture systems and quality control measures to deliver a viable Breg-cell therapy product for administration to a transplant recipient.

The rapid onset of innate immune defenses is critical for early control of viral replication in an infected host and yet it can also lead to irreversible tissue damage, especially in the respiratory tract. Sensitive regulators must exist that modulate inflammation, while controlling the infection. In the present study, we identified acetylcholine (ACh)-producing B cells as such early regulators. B cells are the most prevalent ACh-producing leukocyte population in the respiratory tract demonstrated with choline acetyltransferase (ChAT)-green fluorescent protein (GFP) reporter mice, both before and after infection with influenza A virus. Mice lacking ChAT in B cells, disabling their ability to generate ACh (ChatBKO), but not those lacking ChAT in T cells, significantly, selectively and directly suppressed α7-nicotinic-ACh receptor-expressing interstitial, but not alveolar, macrophage activation and their ability to secrete tumor necrosis factor (TNF), while better controlling virus replication at 1 d postinfection. Conversely, TNF blockade via monoclonal antibody treatment increased viral loads at that time. By day 10 of infection, ChatBKO mice showed increased local and systemic inflammation and reduced signs of lung epithelial repair despite similar viral loads and viral clearance. Thus, B cells are key participants of an immediate early regulatory cascade that controls lung tissue damage after viral infection, shifting the balance toward reduced inflammation at the cost of enhanced early viral replication.

Regulatory B cells (Bregs) are crucial for maintaining homeostasis and controlling inflammation. Although interleukin (IL)-10 has been traditionally suggested as the primary suppressive mechanism of Bregs in both mice and humans, the key functional differences between Bregs in these two species, particularly in the context of disease, is still largely unresolved. IL-37, the latest described immunosuppressive cytokine, is produced in humans but not in mice. Herein we identified the characteristics and functions of IL-37-producing Bregs, that naturally exist in human and can be induced by recombinant IL-37 (rIL-37) and/or Toll-like receptor 9 agonist CpG via different mechanisms. rIL-37 alone is sufficient to prompt IL-37, but not IL-10, production and proliferation of Bregs, whereas CpG elicits IL-37 expression in Bregs independently of IL-10, but dependent on HIF-1α which binds on the enhancer/promoter of the IL-37 gene. Functionally, IL-37+ Bregs exhibit superior anti-inflammatory efficacy than IL-37- Bregs in vitro, as well as in psoriasis and colitis models. However, the frequency of IL-37+ Bregs is reduced in patients with psoriasis. Thus, IL-37+ Bregs hold significant therapeutic potential for treating various inflammatory disorders, including psoriasis and colitis.

Gut microbiota can significantly alter the risk or progression of cancer by maintaining gut immune system homeostasis. However, the exact mechanism by which the gut microbiota and its metabolites influence colorectal tumorigenesis is unclear.

The roles of tryptophan metabolite indole-3-acetic acid (IAA) in inflammation and tumor development were investigated in dextran sodium sulfate (DSS) and azoxymethane (AOM)-DSS mouse models with or without IAA supplementation and with or without Lactobacillus reuteri-produced IAA. Pregnane X receptor (PXR) knockout (KO) mice and aryl hydrocarbon receptor KO mice were used to explore the mechanism by which IAA regulates interleukin (IL)-35 expression. IL-35+ immune cells were stimulated in vitro and analyzed by flow cytometry. Additionally, metabolites were analyzed by liquid chromatography-mass spectrometry.

We found that IAA, a metabolite of tryptophan produced in the gut by L. reuteri, can inhibit the development of colitis by inducing IL-35 expression in immunosuppressant cells. HuREG3αIECtg mice had high levels of intestinal microbiota-derived IAA, and these mice were resistant to AOM-DSS-induced cancer. Patients with colorectal cancer also had low peripheral blood levels of IAA. Further studies revealed that IAA-producing L. reuteri alleviated colitis symptoms and inhibited colon tumors by inducing macrophages, T cells, and B cells to produce IL-35. Finally, PXR KO completely abolished the effects of IAA on immune cells.

We demonstrate that gut microbiota-derived IAA can improve the precancerous colon inflammatory environment through IL-35, thereby inhibiting tumorigenesis, suggesting that IAA may be a preventive factor for colitis-related cancers.

Mounting evidence shows that gut microbiota communities and the human immune system coexist and influence each other, and there are a number of reports of a correlation between specific changes in gut microbiota and the occurrence of autoimmune diseases. B lymphocytes play a central role in the regulation of both gut microbiota communities and in autoimmune diseases. Here, we summarize evidence of the influence of gut microbiota-B cell pathways on autoimmune diseases and how B cells regulate microorganisms, which provides mechanistic insights with relevance for identification of potential therapeutic targets and related fields.

Neuroinflammation is an inflammatory response occurring within the central nervous system (CNS). The process is marked by the production of pro-inflammatory cytokines, chemokines, small-molecule messengers, and reactive oxygen species. Microglia and astrocytes are primarily involved in this process, while endothelial cells and infiltrating blood cells contribute to neuroinflammation when the blood-brain barrier (BBB) is damaged. Neuroinflammation is increasingly recognized as a pathological hallmark of several neurological diseases, including amyotrophic lateral sclerosis (ALS), and is closely linked to neurodegeneration, another key feature of ALS. In fact, neurodegeneration is a pathological trigger for inflammation, and neuroinflammation, in turn, contributes to motor neuron (MN) degeneration through the induction of synaptic dysfunction, neuronal death, and inhibition of neurogenesis. Importantly, resolution of acute inflammation is crucial for avoiding chronic inflammation and tissue destruction. Inflammatory processes are mediated by soluble factors known as cytokines, which are involved in both promoting and inhibiting inflammation. Cytokines with anti-inflammatory properties may exert protective roles in neuroinflammatory diseases, including ALS. In particular, interleukin (IL)-10, transforming growth factor (TGF)-β, IL-4, IL-13, and IL-9 have been shown to exert an anti-inflammatory role in the CNS. Other recently emerging immune regulatory cytokines in the CNS include IL-35, IL-25, IL-37, and IL-27. This review describes the current understanding of neuroinflammation in ALS and highlights recent advances in the role of anti-inflammatory cytokines within CNS with a particular focus on their potential therapeutic applications in ALS. Furthermore, we discuss current therapeutic strategies aimed at enhancing the anti-inflammatory response to modulate neuroinflammation in this disease.

The polarization of the monocyte/macrophage compartment toward an anti-inflammatory profile is considered detrimental in tuberculosis (TB), but the factors controlling M2 polarization in this context are still poorly understood. Here, we found that B cells promote the differentiation of human monocytes toward an M2-like activation program through a process primarily dependent on IL-6 and the activation of STAT3 signaling in monocytes. This confers monocytes with immunomodulatory properties characterized by a reduced ability to produce proinflammatory cytokines and to stimulate IFNγ secretion by allogeneic T cells. Our findings were validated using B cells from TB patients, which constitutively produce high levels of IL-6, underscoring the clinical relevance of our experimental observations. Collectively, our results indicate that human B-cell-derived IL-6 might impair TB immunity by driving monocyte polarization toward an anti-inflammatory phenotype.

Sepsis, a leading cause of death in intensive care units, is associated with immune alterations that increase the patients' risk of secondary infections and mortality, so better understandings of the pathophysiology of sepsis-induced immunosuppression is essential for the development of therapeutic strategies. In a murine model of sepsis that recapitulates immune alterations observed in patients, here we demonstrate that PD-L1+CD44+B220LowCD138+IgM+ regulatory plasma cells are induced in spleen and regulate ex vivo proliferation and IFNɣ secretion induced by stimulation of T splenocytes. This effect is mediated both by cell-cell contact through increased PD-L1 expression on plasma cells and by production of a soluble factor. These observations are recapitulated in three cohorts of critically ill patients with bacterial and viral sepsis in association with increased mortality. Our findings thus reveal the function of regulatory plasma cells in the pathophysiology of sepsis-induced immune alterations, and present a potential therapeutic target for improving immune cell function impaired by sepsis.

Osteoarthritis (OA) is a chronic disease primarily characterized by degenerative changes in articular cartilage and synovitis, for which there are currently no targeted or curative therapies available in clinical practice. In recent years, the in-depth analysis of OA using single-cell sequencing and immunomics technologies has revealed the presence of multiple immune cell subsets, as well as different differentiation states within the same subset, in OA. Through immune-immune and immune-joint tissue interactions, these cells collectively promote or inhibit the progression of arthritis. This complex immune network, where "friends and foes coexist," has made targeted therapeutic strategies aimed at directly eliminating immune cells challenging, highlighting the urgent need for a detailed review of the composition, distribution, functional heterogeneity, therapeutic potential, and potential risks of immune subsets within the joint. Additionally, the similarities and differences between OA and rheumatoid arthritis (RA) in terms of diagnosis and immunotherapy need to be precisely understood, in order to draw lessons from or reject RA-based immunotherapies. To this end, this review summarizes the major triggers of inflammation in OA, the differentiation characteristics of key immune cell subsets, and compares the similarities and differences between OA and RA in diagnosis and treatment. It also outlines the current immunomodulatory strategies for OA and their limitations. Furthermore, we provide a detailed and focused discussion on immune cells that act as "friends or foes" in arthritis, covering the M1/M2 polarization of macrophages, functional heterogeneity of neutrophils, unique roles of dendritic cells at different maturation states, the balance between pro-inflammatory T cells and regulatory T cells (Tregs), and the diverse functions of B cells, plasma cells, and regulatory B cells (Bregs) in OA. By interpreting the roles of these immune cells, this review clarifies the dynamic changes and interactions of immune cells in OA joints, providing a theoretical foundation for more precise targeted interventions in future clinical practice.

Cytokines influence cell-fate decisions of naïve lymphocytes and determine outcome of immune responses by transducing signals that regulate the initiation, intensity and duration of immune responses. However, aberrant regulation of physiological levels of cytokines contribute to the development of autoimmune and other inflammatory diseases. The Interleukin 6 (IL-6)/IL-12 superfamily of cytokines have a profound influence on all aspects of host immunity and our focus in this review is on the signaling pathways that mediate their functions, with emphasis on how this enigmatic family of cytokines promote or suppress inflammation depending on the physiological context. We also describe regulatory lymphocyte populations that suppress neuroinflammatory diseases by producing cytokines, such as IL-27 (i27-Breg) or IL-35 (i35-Breg and iTR35). We conclude with emerging immunotherapies like STAT-specific Nanobodies, Exosomes and Breg therapy that ameliorate CNS autoimmune diseases in preclinical studies.

B cells are essential components of the immune response, primarily recognized for their ability to produce antibodies. However, emerging research reveals their important roles in regulating immune responses and influencing tumor development, independent of antibodies. The connection between tumor progression and alterations in the tumor microenvironment is well-established, as immune infiltrating cells can enhance the survival of tumor cells by modifying their surroundings. Despite this, the majority of studies have focused on T cells and macrophages, creating a gap in our understanding of B cells. Regulatory B cells (Bregs) represent a crucial subpopulation that plays a significant role in maintaining immune balance. They may have a substantial impact on tumor immunity by negatively regulating tumor-infiltrating immune cells. This paper reviews the existing literature on Bregs, examining their development, phenotypes, functions, and the mechanisms through which they exert their regulatory effects. Furthermore, we highlight their potential interventional roles and prognostic significance in cancer therapy. By addressing the current gaps in knowledge regarding Bregs within tumors, we hope to inspire further research that could lead to innovative cancer treatments and improved outcomes for patients.

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for aggressive hematologic malignancies. However, the risk of developing graft-versus-host disease (GVHD) is a significant barrier to allo-HSCT. GVHD is a debilitating condition with high mortality rates and current therapeutic options for GVHD are limited, with corticosteroids being the standard treatment. However, the adverse effects of steroids make prolonged use difficult, necessitating the development of safer therapies. IL-35-producing B-cells (i35-Bregs) have emerged as critical regulators of immunity during autoimmune diseases. In this study, we investigated whether i35-Bregs immunotherapy can suppress and mitigate GVHD. Methods: We administered a single dose of i35-Bregs (1.5×106) to mice undergoing allo-HSCT and monitored disease severity and survival of GVHD mice over 90 days post-transplantation. We discovered that i35-Bregs secrete exosomes containing membrane-bound IL-35 (i35-Exosomes) and investigated whether ex-vivo generated i35-exosomes can be used as stand-alone immunotherapy for GVHD. i35-Breg-induced expression of cytokines or checkpoint proteins (PD-1, LAG-3, CTLA-4) was analyzed by Flow cytometry, ELISA, and RNA-seq analysis. Characterization of membrane-bound IL-35 was by Proximity ligation assay (PLA), immunohistochemistry/Confocal microscopy and Alpha Fold-Multimer modeling. Results: A single dose of 1.5×106 i35-Breg reduced severity of GVHD and prolonged GVHD survival, with more than 70% i35-Breg-treated mice surviving beyond day-90 post-transplantation while observing 100% mortality among untreated mice by day-45. Contrary to the view that IL-35 is secreted cytokine, we show here that i35-Bregs mitigate GVHD via membrane-bound IL-35 and by secreting i35-exosomes. Furthermore, i35-Bregs or ex-vivo generated i35-exosomes induce alloreactive T-cells to upregulate checkpoint proteins associated with T-cell exhaustion and anergy, inhibiting alloreactive responses and propagating infectious-tolerance mechanisms that suppress GVHD. Importantly, i35-Bregs or i35-exosomes suppresses GVHD by increasing bystander lymphocytes coated with immunosuppressive i35-exosomes. Conclusions: This study demonstrates that i35-Bregs and i35-exosomes play a critical role in mitigating GVHD. The combination of i35-Breg and i35-exosome immunotherapy may be an effective strategy for treating GVHD and other inflammatory diseases.

Endothelial dysfunction is a significant factor in the pathogenesis of various diseases. In pathological states, endothelial cells (ECs) undergo activation, resulting in dysfunction characterized by the stimulation of inflammatory responses, oxidative stress, cell proliferation, blood coagulation, and vascular adhesions. Interleukin-35 (IL-35), a novel member of the IL-12 family, is primarily secreted by regulatory T cells (Tregs) and regulatory B cells (Bregs). The role of IL-35 in immunomodulation, antioxidative stress, resistance to apoptosis, control of EC activation, adhesion, and angiogenesis in ECs remains incompletely understood, as the specific mechanisms of IL-35 action and its regulation have yet to be fully elucidated. Therefore, this systematic review aims to comprehensively investigate the impact of IL-35 on ECs and their physiological roles in a range of conditions, including cardiovascular diseases, tumors, sepsis, and rheumatoid arthritis (RA), with the objective of elucidating the potential of IL-35 as a therapeutic target for these ailments.

The host-microbiome axis has been implicated in promoting anti-inflammatory immune responses. Yet, the underlying molecular mechanisms of commensal-mediated IL-10 production by regulatory B cells (Bregs) are not fully elucidated. Here, we demonstrate that bacterial CpG motifs trigger the signaling downstream of TLR9 promoting IκBNS-mediated expression of Blimp-1, a transcription regulator of IL-10. Surprisingly, this effect was counteracted by the NF-κB transcription factor c-Rel. A functional screen for intestinal bacterial species identified the commensal Clostridium sporogenes, secreting high amounts of short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs), as an amplifier of IL-10 production by promoting sustained mTOR signaling in B cells. Consequently, enhanced Breg functionality was achieved by combining CpG with the SCFA butyrate or the BCFA isovalerate thereby synergizing TLR- and mTOR-mediated pathways. Collectively, Bregs required two bacterial signals (butyrate and CpG) to elicit their full suppressive capacity and ameliorate T cell-mediated intestinal inflammation. Our study has dissected the molecular pathways induced by bacterial factors, which might contribute not only to better understanding of host-microbiome interactions, but also to exploration of new strategies for improvement of anti-inflammatory cellular therapy.

The amazing diversity of B cells within the tumor microenvironment is the basis for the diverse development of B cell-based immunotherapies. Here, we focus on elucidating the mechanisms of tumor intervention mediated by four tumor-infiltrating B lymphocytes. Naive B cells present the initial antigen, germinal center B cell subsets enhance antibody affinity, and immunoglobulin subtypes exert multiple immune effects, while regulatory B cells establish immune tolerance. Together they reflect the complexity of the changing dynamics of cancer immunity. Additionally, we have investigated the dynamic effects of tumor-infiltrating B lymphocytes in immunotherapy and their relationship to prognosis, providing new insights into potential treatment strategies for patients.

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.

B cell immunity carries the inherent risk of deviating into autoimmunity and malignancy, which are both strongly associated with genetic variants or alterations that increase immune signaling. Here, we investigated the interplay of autoimmunity and lymphoma risk factors centered around the archetypal negative immune regulator TNFAIP3/A20 in mice. Counterintuitively, B cells with moderately elevated sensitivity to stimulation caused fatal autoimmune pathology, while those with high sensitivity did not. We resolved this apparent paradox by identifying a rheostat-like cytotoxic T cell checkpoint. Cytotoxicity was instructed by and directed against B cells with high intrinsic hyperresponsiveness, while less reactive cells were spared. Removing T cell control restored a linear relationship between intrinsic B cell reactivity and lethal lymphoproliferation, lymphomagenesis, and autoinflammation. We thus identify powerful T cell-mediated negative feedback control of inherited and acquired B cell pathogenicity and define a permissive window for autoimmunity to emerge.

Gastric cancer is a common malignant tumor of the digestive tract, and its treatment remains a significant challenge. In recent years, the role of various immune cells in the tumor microenvironment in cancer progression and treatment has gained increasing attention. Immunotherapy, primarily based on immune checkpoint inhibitors, has notably improved the prognosis of patients with gastric cancer; however, challenges regarding therapeutic efficacy persist. Histological features within the tumor microenvironment, such as tertiary lymphoid structures (TLSs), tumor-infiltrating lymphocytes, and the proportion of intratumoral stroma, are emerging as potentially effective prognostic factors. In gastric cancer, TLSs may serve as local immune hubs, enhancing the ability of immune cells to interact with and recognize tumor antigens, which is closely linked to the effectiveness of immunotherapy and improved survival rates in patients. However, the specific cell type driving TLS formation in tumors has not yet been elucidated. Mature TLSs are B-cell regions containing germinal centers. During germinal center formation, B cells undergo transformations to become mature cells with immune function, exerting anti-tumor effects. Therefore, targeting B cells within TLSs could provide new avenues for gastric cancer immunotherapy. This review, combined with current research on TLSs and B cells in gastric cancer, elaborates on the relationship between TLSs and B cells in the prognosis and immunotherapy of patients with gastric cancer, aiming to provide effective guidance for precise immunotherapy.

Tumorigenesis embodies the formation of a heterotypic tumour microenvironment (TME) that, among its many functions, enables the evasion of T cell-mediated immune responses. Remarkably, most TME cell types, including cancer cells, fibroblasts, myeloid cells, vascular endothelial cells and pericytes, can be stimulated to deploy immunoregulatory programmes. These programmes involve regulatory inducers (signals-in) and functional effectors (signals-out) that impair CD8+ and CD4+ T cell activity through cytokines, growth factors, immune checkpoints and metabolites. Some signals target specific cell types, whereas others, such as transforming growth factor-β (TGFβ) and prostaglandin E2 (PGE2), exert broad, pleiotropic effects; as signals-in, they trigger immunosuppressive programmes in most TME cell types, and as signals-out, they directly inhibit T cells and also modulate other cells to reinforce immunosuppression. This functional diversity and redundancy pose a challenge for therapeutic targeting of the immune-evasive TME. Fundamentally, the commonality of regulatory programmes aimed at abrogating T cell activity, along with paracrine signalling between cells of the TME, suggests that many normal cell types are hard-wired with latent functions that can be triggered to prevent inappropriate immune attack. This intrinsic capability is evidently co-opted throughout the TME, enabling tumours to evade immune destruction.

One vision-threatening side effect of systematic diabetes mellitus is diabetic retinopathy (DR). Recent studies have revealed that the development and progression of DR depend critically on inflammation resulting from diabetes. By attracting leukocytes to endothelium, the higher production of the inflammatory mediators induces degeneration of retinal capillaries, hence increasing vascular permeability and thrombosis probability. The leukocytes that are recruited eventually generate additional proinflammatory and proangiogenic substances, resulting in the increased infiltration of leukocytes in the retina. This process also leads to changes in the blood retinal barrier and the formation of new blood vessels, which helps to counteract the damage caused by the blockage of blood flow. IL-12 family members, IL-12, IL-23, IL-27, and IL-35, play a crucial role in regulating the responses of T helper (Th)1 and Th17 cell populations. The collected data from studies investigating the levels of IL-12 family members in the blood and eye tissues suggest that IL-12 is linked to DR, indicating that it may have a role in the development of DR as a sequential component of the immune response. This review specifically examines the possibility of using IL-12 family cytokines as a therapeutic approach for diabetes, taking into consideration their involvement in the development of DR.

Alzheimer's disease (AD) is a complex neurodegenerative disorder and the major cause of dementia. Amyloid-β (Aβ) and tau aggregation, mitochondrial dysfunction, and microglial dysregulation are key contributors to AD pathogenesis. Impairments in the blood-brain barrier have unveiled the contribution of the immune system, particularly B cells, in AD pathology. B cells, a crucial component of adaptive immunity, exhibit diverse functions, including antigen presentation and antibody production. While their role in neuroinflammatory disorders has been well-documented, their specific function in AD lacks adequate data. This review examines the dual role of the B cells and humoral immunity in modulating brain inflammation in AD and explores recent advancements in passive and active immunotherapeutic strategies targeting AD pathobiology. We summarize preclinical and clinical studies investigating B cell frequency, altered antibody levels, and their implications in neuroinflammation and immunotherapy. Notably, B cells demonstrate protective and pathological roles in AD, influencing neurodegeneration through antibody-mediated clearance of toxic aggregates and inflammatory activation inflammation. Passive immunotherapies targeting Aβ have shown potential in reducing amyloid plaques, while active immunotherapies are emerging as promising strategies, requiring further validation. Understanding the interplay between B cells, humoral immunity, microglia, and mitochondrial dysfunction is critical to unraveling AD pathogenesis. Their dual nature in disease progression underscores the need for precise therapeutic interventions to optimize immunotherapy outcomes and mitigate neuroinflammation effectively.

Type 1 diabetes (T1D) is a metabolic disorder caused by a complete lack of insulin, primarily manifested by hyperglycemia. The mechanisms underlying the onset of T1D are complex, involving genetics, environment, and various unknown factors, leading to the infiltration of various immune components into the islets. Besides T cells, B cells are now considered important contributors to the pathogenesis of T1D, according to recent studies. In non-obese diabetic (NOD) mice, the absence of B cells prevents the development of T1D, and B-cell depletion can even restore the function of pancreatic β cells, emphasizing their involvement in the development of T1D. Naturally, besides pathogenic B cells, regulatory B cells (Bregs) might have a protective function in T1D. This article examines the mechanisms behind B-cell tolerance and the defects in B-cell tolerance checkpoints in T1D. We explored possible functions of B cells in T1D, including the role of islet autoantibodies in T1D, T-B cell interactions, and the role of Bregs in the pathogenesis of T1D. We also summarized the advances of B cell-targeted therapy, exploring new methods for intervention and treatment of T1D.

In 2024, the United States was projected to experience 2 million new cancer diagnoses and approximately 611,720 cancer-related deaths, reflecting a broader global trend in which cancer cases are anticipated to exceed 35 million by 2050. This increasing burden highlights ongoing challenges in cancer treatment despite significant advances that have reduced cancer mortality by 31% since 1991. Key obstacles include the disease's inherent heterogeneity and complexity, such as treatment resistance, cancer stem cells, and the multifaceted tumor microenvironment (TME). The TME-comprising various tumor and immune cells, blood vessels, and biochemical factors-plays a crucial role in tumor growth and resistance to therapies. Recent innovations in cancer treatment, particularly in the field of immuno-oncology, have leveraged insights into TME interactions. An emerging example is the FDA-approved therapy using tumor-infiltrating lymphocytes (TILs), demonstrating the potential of cell-based approaches in solid tumors. However, TIL therapy is just one of many strategies being explored. This review provides a comprehensive overview of the emerging field of immuno-oncology, focusing on how novel therapies targeting or harnessing components of the TME could enhance treatment efficacy and address persistent challenges in cancer care.

Autoantibodies contribute to many autoimmune diseases, yet there is no approved therapy to neutralize them selectively. A popular mouse model, experimental autoimmune encephalomyelitis (EAE), could serve to develop such a therapy, provided we can better understand the nature and importance of the autoantibodies involved. Here we report the discovery of autoantibody-secreting extrafollicular plasmablasts in EAE induced with specific myelin oligodendrocyte glycoprotein (MOG) antigens. Single-cell RNA sequencing reveals that these cells produce non-affinity-matured IgG antibodies. These include pathogenic antibodies competing for shared binding space on MOG's extracellular domain. Interestingly, the synthetic anti-MOG antibody 8-18C5 can prevent the binding of pathogenic antibodies from either EAE mice or people with MOG antibody disease (MOGAD). Moreover, an 8-18C5 variant carrying the NNAS mutation, which inactivates its effector functions, can reduce EAE severity and promote functional recovery. In brief, this study provides not only a comprehensive characterization of the humoral response in EAE models, but also a proof of concept for a novel therapy to antagonize pathogenic anti-MOG antibodies.

With the rising morbidity of inflammatory bowel disease (IBD) year by year, conventional therapeutic drugs with systemic side effects are no longer able to meet the requirements of patients. Probiotics can improve gut microbiota, enhance intestinal barrier function, and regulate mucosal immunity, making them a potential complementary or alternative therapy for IBD. To compensate for the low potency of probiotics, genetic engineering technology has been widely used to improve their therapeutic function. In this review, we systematically summarize the genetically engineered probiotics used for IBD treatment, including probiotic chassis, genetic modification strategies, methods for controlling probiotics, and means of improving efficacy. Finally, we provide prospects on how genetically engineered probiotics can be extended to clinical applications.

Autoimmune diseases are characterized by the body's immune system attacking its own cells, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). In recent studies, regulatory B cells (Bregs), which play a vital role in maintaining peripheral tolerance and controlling persistent autoimmune diseases (ADs), have shown great potential in treating ADs. This review synthesizes the latest advancements in targeted therapies for ADs, with a particular emphasis on the subgroups, phenotypic markers, and signal pathways associated with Bregs. Following an examination of these elements, the discussion pivots to innovative Breg-based therapeutic approaches for the management of ADs.

Regulatory B cells (Bregs) are a key component in the regulation of the immune system. Their immunosuppressive function, which includes limiting the inflammatory cascade, occurs through interactions with other immune cells and the secretion of cytokines, primarily IL-10. As knowledge about B cells continues to expand, their diversity is becoming more recognized, with many subpopulations identified in both human and animal models. However, identifying specific transcription factors or markers that could definitively distinguish regulatory B cells remains a challenge. This review summarizes recent findings on the role of B regulatory cells in allergic diseases.

In patients with bronchial asthma, atopic dermatitis, and food allergies, the number of regulatory B cells is reduced, and disease severity is inversely proportional to the quantity of these cells. Furthermore, in patients with atopic dermatitis, the ability of regulatory B cells to produce IL-10 in response to IL-6 stimulation is diminished. However, allergen immunotherapy has been shown to induce the formation of regulatory T cells as well as regulatory B cells.

The success of future therapies based on B cells may depend on deepening our current understanding of their phenotypes, induction, differentiation, and function. Research in these areas is essential for understanding the mechanisms regulating Breg activity and for developing potential targeted therapies in the treatment of allergic diseases.

Hypoxic microenvironments induce widespread metabolic changes that have been shown to be critical in regulating innate and adaptive immune responses. Hypoxia-induced changes include the generation of extracellular adenosine followed by subsequent signaling through adenosine receptors on immune cells. This evolutionarily conserved "hypoxia-adenosinergic" pathway of hypoxia → extracellular adenosine → adenosine receptor signaling has been shown to be critical in limiting and redirecting T cell responses including in tumor microenvironments and the gut mucosa. However, the question of whether hypoxic microenvironments are involved in the development of B cell responses has remained unexplored until recently. The discovery that germinal centers (GC), the anatomic site in which B cells undergo secondary diversification and affinity maturation, develop a hypoxic microenvironment has sparked new interest in how this evolutionarily conserved pathway affects antibody responses. In this review we will summarize what is known about hypoxia-adenosinergic microenvironments in lymphocyte development and ongoing immune responses. Specific focus will be placed on new developments regarding the role of the hypoxia-adenosinergic pathway in regulating GC development and humoral immunity.

Regulatory B cells (Bregs) are a functionally distinct B-cell subset involved in the maintenance of homeostasis and inhibition of inflammation. Studies, from the last two decades, have increased our understanding of cellular and molecular mechanisms involved in their generation, function, and to a certain extent phenotype. Current research endeavours to unravel the causes and consequences of Breg defects in disease, with increasing evidence highlighting the relevance of Bregs in promoting tumorigenic responses. Here we provide historical and emerging findings of the significance of Bregs in autoimmunity and transplantation, and how these insights have translated into the cancer field.

Immune cells are critical in promoting neuroinflammation and neuropathic pain and in facilitating pain resolution, depending on their inflammatory and immunoregulatory cytokine response. Interleukin (IL)-35, secreted by regulatory immune cells, is a member of the IL-12 family with a potent immunosuppressive function. In this study, we investigated the effects of IL-35 on pain behaviors, spinal microglia phenotype following peripheral nerve injury, and in vitro microglial cultures in male and female mice. Intrathecal recombinant IL-35 treatment alleviated mechanical pain hypersensitivity prominently in male mice, with only a modest effect in female mice after sciatic nerve chronic constriction injury (CCI). IL-35 treatment resulted in sex-specific microglial changes following CCI, reducing inflammatory microglial markers and upregulating anti-inflammatory markers in male mice. Spatial transcriptomic analysis revealed that IL-35 suppressed microglial complement activation in the superficial dorsal horn in male mice after CCI. Moreover, in vitro studies showed that IL-35 treatment of cultured inflammatory microglia mitigated their hypertrophied morphology, increased their cell motility, and decreased their phagocytic activity, indicating a phenotypic shift towards homeostatic microglia. Further, IL-35 altered microglial cytokines/chemokines in vitro, suppressing the release of IL-9 and monocyte-chemoattractant protein-1 and increasing IL-10 in the supernatant of male microglial cultures. Our findings indicate that treatment with IL-35 modulates spinal microglia and alleviates neuropathic pain in male mice, suggesting IL-35 as a potential sex-specific targeted immunomodulatory treatment for neuropathic pain.

B cells constitute a diverse and adaptable immune cell population with functions that can vary according to the environment and circumstances. The involvement of B cells in pregnancy, as well as the associated molecular pathways, has yet to be investigated. This review consolidates current knowledge on B cell activities and regulation during pregnancy, with a particular focus on the roles of various B cell subsets and the effects of B cell-derived factors on pregnancy outcomes. Moreover, the review examines the significance of B cell-associated autoantibodies, cytokines, and signaling pathways in relation to pregnancy complications such as pregnancy loss, preeclampsia, and preterm birth.

Autoimmune diseases and cancers, two seemingly unrelated diseases, have been threatening human health, and many of them have no cure. By identifying pathological inflammation as the driving cause of uncontrolled cell proliferation in both classes of diseases, and differentiating autoimmune disorders and cancers by whether the cell death programs are under control, we propose the attenuation of prolonged inflammation via maintaining mitochondrial reduction-oxidation (redox) homeostasis being a possible cure of both diseases. Importantly, we propose the feasibility of applying cold atmospheric plasma (CAP) in treating autoimmune disorders and cancers given its redox-modulatory nature, which not only extends the medical utilities of CAP to autoimmune diseases and all other inflammation-driven disorders, but also positions the efficacy of CAP against cancer cells to its suppressive role on prolonged inflammation. Our insights may open an innovative avenue towards a unified view on the molecular mechanism driving the diversified types of medical miracles of CAP and what CAP can do in the field of plasma medicine.

Interleukin (IL)-12 is a heterodimeric pro-inflammatory cytokine. Our cryoelectron microscopy structure determination of human IL-12 in complex with IL-12Rβ1 and IL-12Rβ2 at a resolution of 3.75 Å reveals that IL-12Rβ2 primarily interacts with the IL-12p35 subunit via its N-terminal Ig-like domain, while IL-12Rβ1 binds to the p40 subunit with its N-terminal fibronectin III domain. This binding mode of IL-12 with its receptors is similar to that of IL-23 but shows notable differences with other cytokines. Through structural information and biochemical assays, we identified Y62, Y189, and K192 as key residues in IL-12p35, which bind to IL-12Rβ2 with high affinity and mediate IL-12 signal transduction. Furthermore, structural comparisons reveal two distinctive conformational states and structural plasticity of the heterodimeric interface in IL-12. As a result, our study advances our understanding of IL-12 signal initiation and opens up new opportunities for the engineering and therapeutic targeting of IL-12.

Pathophysiologic function of B cells in graft rejection has been well recognized in transplantation. B cells promote alloantigen-specific T-cell response and secrete antibodies that can cause antibody-mediated graft failures and rejections. Therefore, strategies targeting B cells, for example, B-cell depletion, have been used for the prevention of both acute and chronic rejections. Interestingly, however, recent mounting evidence indicates that subsets of B cells yet to be further identified can display potent immune regulatory functions, and they contribute to transplantation tolerance and operational tolerance in both experimental and clinical settings, respectively. In this review, we integrate currently available information on B-cell subsets, including T-cell Ig domain and mucin domain 1-positive transitional and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domain-positive memory B cells, displaying immune regulatory functions, with a focus on transplantation tolerance, by analyzing their mechanisms of action. In addition, we will discuss potential T-cell Ig domain and mucin domain 1-positive and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domain-positive B cell-based strategies for the enhancement of operational tolerance in transplantation patients.