Management of persistent inflammation, immunosuppression, and catabolism syndrome (PICS) after sepsis remains challenging for patients in the intensive care unit, experiencing poor quality of life and death. However, immune-cell signatures in patients with PICS after sepsis remain unclear.

We determined immune-cell signatures of PICS after sepsis at single-cell resolution. Murine cecal ligation and puncture models of PICS were applied for validation.

Immune functions of two enriched monocyte subpopulations, Mono1 and Mono4, were suppressed substantially in patients with sepsis and were partially restored in patients with PICS after sepsis and exhibited immunosuppressive and pro-apoptotic effects on B and CD8T cells. Patients with PICS and sepsis had reduced naive and memory B cells and proliferated plasma cells. Besides, naive and memory B cells in patients with PICS showed an active antigen processing and presentation gene signature compared to those with sepsis. PICS patients with better prognoses exhibited more active memory B cells and IGHA1-plasma cells. CD8TEMRA displayed signs of proliferation and immune dysfunction in the PICS-death group in contrast with the PICS-alive group. Megakaryocytes proliferation was more pronounced in patients with PICS and sepsis than in healthy controls, with notable changes in the anti-inflammatory and immunomodulatory effects observed in patients with PICS and verified in mice models.

Our study evaluated PICS after sepsis at the single-cell level, identifying the heterogeneity present within immune-cell subsets, facilitating the prediction of disease progression and the development of effective intervention.

This work was supported by the National Natural Science Foundation of China, Shanghai Municipal Health Commission "Yiyuan New Star" Youth Medical Talent Cultivating Program, and Shanghai Clinical Research Center for Anesthesiology.

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.

CD11c+ B cells are an age-associated subset emerging in infections and autoimmune diseases. However, their role in sepsis is poorly clarified. This study identified a class of CD11c+ B cells with a proinflammatory phenotype that is expended in septic patients and mice. Notably, the transfer of these cells accelerates sepsis-induced lung injury and death in mice. Furthermore, the CD11c+ B cells were induced by the triggering receptor expressed on myeloid cells 2 (TREM2) signal, which promotes their generation via the interferon regulatory factor 4 (IRF4) pathway. Moreover, TREM2 directly participates in sepsis regulation mediated by CD11c+ B cells. This study reveals the proinflammatory role of CD11c+ B cells in sepsis and identifies TREM2 as a contributing factor in CD11c+ B-cell-mediated inflammatory injury during sepsis.

Group A Streptococcus (GAS) is a pathogen that is capable of colonizing various infection sites and can potentially elicit an inadequate immune response that will lead to sepsis. The processes underlying this misdirected immune reaction remain poorly understood, and reliable biomarkers for indicating impending organ failure during sepsis are still missing. The present study aims to identify parameters that can predict the onset of end-organ damage in the course of sepsis. To that extent, we investigated key aspects of the immune response in early-phase sepsis following infection of different tissues in a mouse model, using Brefeldin A to link cytokine production to specific cell types through multi-parameter flow cytometry. Subcutaneous and intravenous GAS infections resulted in clinical sepsis, which was paralleled by peripheral blood lymphopenia. Intravenous infection in particular was associated with a higher bacterial burden in the liver that strongly correlated with an increased granulocyte-to-lymphocyte ratio of the peripheral blood. Strikingly, IL-6 overexpression was more pronounced in intravenous infection and strongly correlated with hepatic stress, indicated by elevated bacterial loads in the liver. Collectively, our data highlight the potential utility of IL-6 in conjunction with an elevated granulocyte-to-lymphocyte ratio as promising early indicators of concomitant liver stress in sepsis.

The spleen, the largest lymphatic organ, comprises a diverse array of immunocytes in approximately one quarter of the body, including T cells, B cells, natural killer cells, and myeloid cells (such as dendritic cells, neutrophils, myeloid-derived suppressor cells, and macrophages). These immune cells undergo dynamic transitions and mobilization, enabling the spleen to execute a wide range of immunological functions. The spleen's structural organization and multicellular composition, along with its reservoir of lymphocytes, facilitate the capture and clearance of blood-borne antigens while also orchestrating both innate and adaptive immune responses. Additionally, the spleen plays critical roles in hematopoiesis and the removal of aged or damaged red blood cells. Despite being innervated by sympathetic (catecholaminergic) nerve fibers, the spleen lacks parasympathetic (vagal or cholinergic) innervation. The neuroimmune axis, particularly the interplay between sympathetic and parasympathetic nervous system immune circuits, significantly influences disease onset and progression. Extensive research employing physical, genetic, and pharmacological approaches has sought to directly modulate splenic immunocytes and activate neuroimmune interactions to restore immune homeostasis and counteract disease. Two primary mechanisms underlie these immunomodulatory interventions: (1) the cholinergic anti-inflammatory pathway, wherein norepinephrine released by splenic catecholaminergic fibers binds to β2-adrenergic receptors on CD4⁺ T cells, triggering acetylcholine secretion, which in turn suppresses inflammatory cytokine production in macrophages via α7 nicotinic acetylcholine receptor signaling, and (2) direct immunomodulation of splenic immunocytes, which regulates key genes and signaling pathways, alters cytokine secretion, and modulates ion flux to influence cellular functions. Among various therapeutic strategies, physical methods, particularly electrical stimulation and splenic ultrasound stimulation, have demonstrated the greatest promise for clinical applications in splenic immunomodulation and disease management.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition that can be accompanied by alterations in immune markers. However, the intricate nature of the association between ADHD and immune markers remains insufficiently elucidated. To explore the currently ambiguous causal relationship between ADHD and the immune system, we performed a bidirectional Mendelian randomization (MR) analysis of immune cell traits and ADHD under the randomized inverse variance weighting (IVW) method based on genome-wide association study (GWAS) summary data. We found ADHD increased the level of 3 immune cell traits including myeloid dendritic cells (β = 0.28, P = 0.008), monocyte (β = 0.25, P = 0.024) and granulocyte (β = 0.2, P = 0.042). We also identified 1 trait which belongs to B cell panel was a risk factor (odds ratio (OR) = 1.07, P = 0.001) for ADHD onset. Other 5 traits including CD14+ monocyte (OR = 0.98, P = 0.002), immature myeloid-derived suppressor cells (MDSC) (OR = 0.98, P = 0.003), monocyte MDSC (OR = 0.95, P = 0.005), CD33br HLA DR+ (OR = 0.97, P = 0.021) and basophil (OR = 0.96, P = 0.022) were protective factors for ADHD. Here we identified a range of causal relationships extending from ADHD to immune cell traits, underscoring the complex interaction patterns between ADHD and the immune system. Enhanced interventions for protective and risk factors may be beneficial in the prevention and treatment of ADHD.

Sepsis is characterized by a concomitant early pro-inflammatory response by immune cells to an infection, and an opposing anti-inflammatory response that results in protracted immunosuppression. The primary pathological event in sepsis is widespread programmed cell death, or cellular self-sacrifice, of innate and adaptive immune cells, leading to profound immunological suppression. This severe immune dysfunction hampers effective primary pathogen clearance, thereby increasing the risk of secondary opportunistic infections, latent viral reactivation, multiple organ dysfunction, and elevated mortality. The types of cell death include apoptosis (type I programmed cell death), autophagy (type II programmed cell death), NETosis (a program for formation of neutrophil extracellular traps (NETs)) and other programmed cell deaths like pyroptosis, ferroptosis, necroptosis, each contributing to immunosuppression in distinct ways during the later phases of sepsis. Extensive apoptosis of lymphocytes, such as CD4+, CD8+ T cells, and B cells, is strongly associated with immunosuppression. Apoptosis of dendritic cells further compromises T and B cell survival and can induce T cell anergy or promote regulatory Treg cell proliferation. Moreover, delayed apoptosis and impaired neutrophil function contribute to nosocomial infections and immune dysfunction in sepsis. Interestingly, aberrant NETosis and the subsequent depletion of mature neutrophils also trigger immunosuppression, and neutrophil pyroptosis can positively regulate NETosis. The interaction between programmed cell death 1 (PD-1) or programmed cell death 1 ligand (PD-L1) plays a key role in T cell modulation and neutrophil apoptosis in sepsis. The dendritic cell growth factor, Fms-like tyrosine kinase (FLTEL), increases DC numbers, enhances CD 28 expression, attenuates PD-L1, and improves survival in sepsis. Recently, immunoadjuvant therapies have attracted attention for their potential to restore host physiological immunity and homeostasis in patients with sepsis. This review focuses on several potential immunotherapeutic agents designed to bolster suppressed innate and adaptive immune responses in the management of sepsis.

Lactate significantly impacts immune cell function in sepsis and septic shock, transcending its traditional view as just a metabolic byproduct. This review summarizes the role of lactate as a biomarker and its influence on immune cell dynamics, emphasizing its critical role in modulating immune responses during sepsis. Mechanistically, key lactate transporters like MCT1, MCT4, and the receptor GPR81 are crucial in mediating these effects. HIF-1α also plays a significant role in lactate-driven immune modulation. Additionally, lactate affects immune cell function through post-translational modifications such as lactylation, acetylation, and phosphorylation, which alter enzyme activities and protein functions. These interactions between lactate and immune cells are central to understanding sepsis-associated immune dysregulation, offering insights that can guide future research and improve therapeutic strategies to enhance patient outcomes.

In sepsis, the relationship between lymphocyte counts and patient outcomes is complex. Lymphocytopenia and lymphocytosis significantly influence survival, illustrating the dual functionality of lymphocytes in responding to infections. This study investigates this complex interaction, focusing on how variations in lymphocyte counts correlate with all-cause hospital mortality among sepsis patients.

This retrospective cohort study analyzed data from two extensive critical care databases: the Medical Information Mart for Intensive Care IV 2.0 (MIMIC-IV 2.0) from Beth Israel Deaconess Medical Center, Boston, Massachusetts, and the eICU Collaborative Research Database (eICU-CRD), which was Multi-center database from over 200 hospitals across the United States conducted by Philips eICU Research Institute. We included adult patients aged 18 years and older who met the Sepsis-3 criteria, characterized by documented or suspected infection and a Sequential Organ Failure Assessment (SOFA) score of 2 or higher. Sepsis patients were categorized into quartiles based on lymphocyte counts. The primary outcome was all-cause mortality in the hospital, with 90 and 60-day all-cause mortality as the secondary outcomes. Univariable and multivariable Cox proportional hazard regressions were utilized to assess lymphocyte counts' impact on hospital mortality. An adjusted restricted cubic spline (RCS) analysis was performed to elucidate this relationship further. Subgroup analyses were also conducted to explore the association across various comorbidity groups among sepsis and septic shock patients.

Our study included 37,054 patients, with an observed in-hospital mortality rate of 16.6%. Univariable and multivariable Cox proportional hazard regression models showed that lymphocyte counts were independently associated with in-hospital mortality (HR = 1.04, P < 0.01; HR = 1.06, P < 0.01). RCS regression analysis revealed a U-shaped relationship between lymphocyte levels and hospital mortality risk in sepsis and septic shock patients (P for overall < 0.001, P for nonliner < 0.01; P for overall = 0.002, P for nonliner = 0.014). Subgroup analyses revealed that elevated lymphocyte counts correlated with increased hospital mortality among sepsis patients with liver disease and requiring renal replacement therapy (P for overall = 0.021, P for nonliner = 0.158; P for overall = 0.025, P for nonliner = 0.759). These findings suggest that lymphocytes may have enhanced prognostic value in specific subsets of critically ill sepsis patients.

Our findings demonstrate that lymphocyte counts are a significant independent predictor of hospital mortality in sepsis and septic shock patients. We observed a U-shaped association between lymphocyte levels and mortality risk, indicating that high and low counts are linked to increased mortality. This result highlights the complex role of lymphocytes in sepsis outcomes and suggests the need for further investigation into the underlying mechanisms and potential therapeutic approaches. Integrating lymphocyte count assessment into risk stratification algorithms and clinical decision support tools could enhance the early identification of high-risk sepsis patients.

Sepsis is a life-threatening condition caused by dysregulated host responses to infection. Myeloid cell accumulation and lymphocyte decline are widely recognized phenomena in septic patients. However, the fate of specific immune cells remains unclear. Here, we report the results of a human explorative study of patients with septic peritonitis and patients undergoing abdominal surgery without sepsis. We analyzed pairwise peritoneal fluid and peripheral blood taken 24 h after surgery to characterize immediate immune cell changes. Our results show that myeloid cell expansion and lymphocyte loss occur in all patients undergoing open abdominal surgery, indicating that these changes are not specific to sepsis. However, B1-like lymphocytes were specifically increased in the peritoneal fluid of septic patients, correlating positively with sequential organ failure assessment (SOFA) and acute physiology and chronic health evaluation II (APACHE-II) clinical severity scores. In support of this notion, we identified an accumulation of peritoneal B1b lymphocytes in septic mice.

Sepsis poses a health challenge globally owing to markedly high rates of morbidity and mortality. Despite employing bundle therapy over two decades, approaches including transient organ supportive therapy and clinical trials focusing on signaling pathways have failed in effectively reversing multiple organ failure in patients with sepsis. Prompt and appropriate perioperative management for surgical patients with concurrent sepsis is urgent. Consequently, innovative therapies focusing on remedying organ injuries are necessitated. Cell therapy has emerged as a promising therapeutic avenue for repairing local damage to vital organs and restoring homeostasis during perioperative treatment for sepsis. Given the pivotal role of immune cell responses in the pathogenesis of sepsis, stem cell-based interventions that primarily modulate immune responses by interacting with multiple immune cells have progressed into clinical trials. The strides made in single-cell sequencing and gene-editing technologies have advanced the understanding of disease-specific immune responses in sepsis. Chimeric antigen receptor (CAR)-immune cell therapy offers an intriguing option for the treatment of sepsis. This review provides a concise overview of immune cell therapy, its current status, and the strides made in the context of sepsis research, discussing potential strategies for the management of patients with sepsis during perioperative stages.

The rapid onset of innate immune defenses is critical for early control of viral replication in an infected host, yet it can also lead to irreversible tissue damage, especially in the respiratory tract. Intricate regulatory mechanisms must exist that modulate inflammation, while controlling the infection. Here, B cells expressing choline acetyl transferase (ChAT), an enzyme required for production of the metabolite and neurotransmitter acetylcholine (ACh) are identified as such regulators of the immediate early response to influenza A virus. Lung tissue ChAT + B cells are shown to interact with a7 nicotinic Ach receptor-expressing lung interstitial macrophages in mice within 24h of infection to control their production of TNFa, shifting the balance towards reduced inflammation at the cost of enhanced viral replication. Thus, innate-stimulated B cells are key participants of an immediate-early regulatory cascade that controls lung tissue damage after viral infection.

Dysregulated B cell cytokine production contributes to pathogenesis of immune-mediated diseases including multiple sclerosis (MS); however, the underlying mechanisms are poorly understood. In this study we investigated how cytokine secretion by pro-inflammatory (GM-CSF-expressing) and anti-inflammatory (IL-10-expressing) B cells is regulated. Pro-inflammatory human B cells required increased oxidative phosphorylation (OXPHOS) compared with anti-inflammatory B cells. OXPHOS reciprocally modulated pro- and anti-inflammatory B cell cytokines through regulation of adenosine triphosphate (ATP) signaling. Partial inhibition of OXPHOS or ATP-signaling including with BTK inhibition resulted in an anti-inflammatory B cell cytokine shift, reversed the B cell cytokine imbalance in patients with MS, and ameliorated neuroinflammation in a myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis mouse model. Our study identifies how pro- and anti-inflammatory cytokines are metabolically regulated in B cells and identifies ATP and its metabolites as a "fourth signal" that shapes B cell responses and is a potential target for restoring the B cell cytokine balance in autoimmune diseases.

Dysregulation of the hematopoietic niche during hyperlipidemia facilitates pathologic leukocyte production, driving atherogenesis. Although definitive hematopoiesis occurs primarily in the bone marrow, during atherosclerosis this also occurs in the spleen. Cells of the bone marrow niche, particularly endothelial cells, have been studied in atherosclerosis, although little is known about how splenic endothelial cells respond to the atherogenic environment. Here we show unique dysregulated pathways in splenic compared to bone marrow endothelial cells during atherosclerosis, including perturbations of lipid metabolism and endocytic trafficking pathways. As part of this response, we identify the mixed lineage kinase domain-like (MLKL) protein as a repressor of splenic, but not bone marrow, myelopoiesis. Silencing MLKL in splenic endothelial cells results in inefficient endosomal trafficking and lipid accumulation, ultimately promoting the production of myeloid cells that participate in plaque development. These studies identify endocytic trafficking by MLKL as a key mechanism of splenic endothelial cell maintenance, splenic hematopoiesis and, subsequently, atherosclerosis.

Sepsis is a life-threatening condition that occurs when the body responds to an infection but subsequently triggers widespread inflammation and impaired blood flow. These pathologic responses can rapidly cause multiple organ dysfunction or failure either one by one or simultaneously. The fundamental common mechanisms involved in sepsis-induced multiple organ dysfunction remain unclear. Here, employing quantitative global and phosphoproteomics, we examine the liver's temporal proteome and phosphoproteome changes after moderate sepsis induced by cecum ligation and puncture. In total, 4593 global proteins and 1186 phosphoproteins according to 3275 phosphosites were identified. To characterize the liver-kidney comorbidity after sepsis, we developed a mathematical model and performed cross-analyses of liver and kidney proteome data obtained from the same set of mice. Beyond immune response, we showed the commonly disturbed pathways and key regulators of the liver-kidney comorbidity are linked to energy metabolism and consumption. Our data provide open resources to understand the communication between the liver and kidney as they work to fight infection and maintain homeostasis.

Sepsis, a critical condition marked by systemic inflammation, profoundly impacts both innate and adaptive immunity, often resulting in lymphopenia. This immune alteration can spare regulatory T cells (Tregs) but significantly affects other lymphocyte subsets, leading to diminished effector functions, altered cytokine profiles, and metabolic changes. The complexity of sepsis stems not only from its pathophysiology but also from the heterogeneity of patient responses, posing significant challenges in developing universally effective therapies. This review emphasizes the importance of phenotyping in sepsis to enhance patient-specific diagnostic and therapeutic strategies. Phenotyping immune cells, which categorizes patients based on clinical and immunological characteristics, is pivotal for tailoring treatment approaches. Flow cytometry emerges as a crucial tool in this endeavor, offering rapid, low cost and detailed analysis of immune cell populations and their functional states. Indeed, this technology facilitates the understanding of immune dysfunctions in sepsis and contributes to the identification of novel biomarkers. Our review underscores the potential of integrating flow cytometry with omics data, machine learning and clinical observations to refine sepsis management, highlighting the shift towards personalized medicine in critical care. This approach could lead to more precise interventions, improving outcomes in this heterogeneously affected patient population.

RAS guanyl releasing protein 1 (RASGRP1) is a guanine nucleotide exchange factor (GEF) characterized by the presence of a RAS superfamily GEF domain. It functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor, specifically activating RAS through the exchange of bound GDP for GTP. Activation of RAS by RASGRP1 has a wide range of downstream effects at the cellular level. Thus, it is not surprising that many diseases are associated with RASGRP1 disorders. Here, we present an overview of the structure and function of RASGRP1, its crucial role in the development, expression, and regulation of immune cells, and its involvement in various signaling pathways. This review comprehensively explores the relationship between RASGRP1 and various diseases, elucidates the underlying molecular mechanisms of RASGRP1 in each disease, and identifies potential therapeutic targets. This study provides novel insights into the role of RASGRP1 in insulin secretion and highlights its potential as a therapeutic target for diabetes. The limitations and challenges associated with studying RASGRP1 in disease are also discussed.

Doxorubicin is an effective chemotherapeutic agent, but its use is limited by acute and chronic cardiotoxicity. Exercise training has been shown to protect against doxorubicin-induced cardiotoxicity, but the involvement of immune cells remains unclear. This study aimed to investigate the role of exercise-derived B cells in protecting against doxorubicin-induced cardiotoxicity and to further determine whether B cell activation and antibody secretion play a role in this protection.

Mice that were administered with doxorubicin (5 mg/kg per week, 20 mg/kg cumulative dose) received treadmill running exercise. The adoptive transfer of exercise-derived splenic B cells to μMT-/- (B cell-deficient) mice was performed to elucidate the mechanism of B cell regulation that mediated the effect of exercise.

Doxorubicin-administered mice that had undergone exercise training showed improved cardiac function, and low levels of cardiac apoptosis, atrophy, and fibrosis, and had reduced cardiac antibody deposition and proinflammatory responses. Similarly, B cell pharmacological and genetic depletion alleviated doxorubicin-induced cardiotoxicity, which phenocopied the protection of exercise. In vitro performed coculture experiments confirmed that exercise-derived B cells reduced cardiomyocyte apoptosis and fibroblast activation compared with control B cells. Importantly, the protective effect of exercise on B cells was confirmed by the adoptive transfer of splenic B cells from exercised donor mice to μMT-/- recipient mice. However, blockage of Fc gamma receptor IIB function using B cell transplants from exercised Fc gamma receptor IIB-/- mice abolished the protection of exercise-derived B cells against doxorubicin-induced cardiotoxicity. Mechanistically, we found that Fc gamma receptor IIB, an important B cell inhibitory receptor, responded to exercise and increased B cell activation threshold, which participated in exercise-induced protection against doxorubicin-induced cardiotoxicity.

Our results demonstrate that exercise training protects against doxorubicin-induced cardiotoxicity by upregulating Fc gamma receptor IIB expression in B cells, which plays an important anti-inflammatory role and participates in the protective effect of exercise against doxorubicin-induced cardiotoxicity.

CD8+ T cells are classically recognized as adaptive lymphocytes based on their ability to recognize specific foreign antigens and mount memory responses. However, recent studies indicate that some antigen-inexperienced CD8+ T cells can respond to innate cytokines alone in the absence of cognate T cell receptor stimulation, a phenomenon referred to as bystander activation. Here, we demonstrate that neonatal CD8+ T cells undergo a robust and diverse program of bystander activation, which corresponds to enhanced innate-like protection against unrelated pathogens. Using a multi-omics approach, we found that the ability of neonatal CD8+ T cells to respond to innate cytokines derives from their capacity to undergo rapid chromatin remodeling, resulting in the usage of a distinct set of enhancers and transcription factors typically found in innate-like T cells. We observed that the switch between innate and adaptive functions in the CD8+ T cell compartment is mediated by changes in the abundance of distinct subsets of cells. The innate CD8+ T cell subset that predominates in early life was also present in adult mice and humans. Our findings provide support for the layered immune hypothesis and indicate that the CD8+ T cell compartment is more functionally diverse than previously thought.

Sepsis remains a global challenge, especially in low- and middle-income countries, where there is an urgent need for easily accessible and cost-effective biomarkers to predict the occurrence and prognosis of sepsis. Lymphocyte counts are easy to measure clinically, and a large body of animal and clinical research has shown that lymphocyte counts are closely related to the incidence and prognosis of sepsis. This review extensively collected experimental articles related to lymphocyte counts since the unification of the definition of sepsis. The article categorizes and discusses the relationship between absolute lymphocyte counts, intrinsic lymphocyte subsets, effector T-lymphocytes, B-lymphocytes, dendritic cells, and the incidence and prognosis of sepsis. The results indicate that comparisons of absolute lymphocyte counts alone are meaningless. However, in addition to absolute lymphocyte counts, innate lymphocyte subsets, effector T-cells, B-lymphocytes, and dendritic cells have shown certain research value in related studies.

B cells play a central role in humoral immunity but also have antibody-independent functions. Studies to date have focused on B cells in blood and secondary lymphoid organs but whether B cells reside in non-lymphoid organs (NLO) in homeostasis is unknown. Here we identify, using intravenous labeling and parabiosis, a bona-fide tissue-resident B cell population in lung, liver, kidney and urinary bladder, a substantial proportion of which are B-1a cells. Tissue-resident B cells are present in neonatal tissues and also in germ-free mice NLOs, albeit in lower numbers than in specific pathogen-free mice and following co-housing with 'pet-store' mice. They spatially co-localise with macrophages and regulate their polarization and function, promoting an anti-inflammatory phenotype, in-part via interleukin-10 production, with effects on bacterial clearance during urinary tract infection. Thus, our data reveal a critical role for tissue-resident B cells in determining the homeostatic 'inflammatory set-point' of myeloid cells, with important consequences for tissue immunity.

Nonalcoholic fatty liver disease (NAFLD) is an expanding worldwide health concern, and the underlying mechanisms contributing to its progression still need further exploration. Neutrophil extracellular traps (NETs) are intricate formations comprised of nuclear constituents and diverse antimicrobial granules that are released into the extracellular milieu by activated neutrophils upon various triggers, which play a pivotal part in the onset and advancement of NAFLD. NETs actively participate in the genesis of NAFLD by fostering oxidative stress and inflammation, ultimately resulting in hepatic fat accumulation and the escalation of liver injury. Recent insights into the interaction with other hepatic immune populations and mediators, such as macrophages and T regulatory cells, have revealed several important mechanisms that can trigger further liver injury. In conclusion, the formation of NETs emerged as an important factor in the development of NAFLD, offering a promising target for innovative therapeutic approaches against this debilitating condition. This comprehensive review seeks to compile existing studies exploring the involvement of NETs in the genesis of NAFLD and their influence on the immune response throughout the progression of NAFLD.

B lymphocytes were originally described as a cell type uniquely capable of secreting Abs. The importance of T cell help in Ab production was revealed soon afterward. Following these seminal findings, investigators made great strides in delineating steps in the conventional pathway that B cells follow to produce high-affinity Abs. These studies revealed generalized, or canonical, features of B cells that include their developmental origin and paths to maturation, activation, and differentiation into Ab-producing and memory cells. However, along the way, examples of nonconventional B cell populations with unique origins, age-dependent development, tissue localization, and effector functions have been revealed. In this brief review, features of B-1a, B-1b, marginal zone, regulatory, killer, NK-like, age-associated, and atypical B cells are discussed. Emerging work on these noncanonical B cells and functions, along with the study of their significance for human health and disease, represents an exciting frontier in B cell biology.

Ascorbic acid is a redox regulator in many physiological processes. Besides its antioxidant activity, many intriguing functions of ascorbic acid in the expression of immunoregulatory genes have been suggested. Ascorbic acid acts as a co-factor for the Fe+2 -containing α-ketoglutarate-dependent Jumonji-C domain-containing histone demethylases (JHDM) and Ten eleven translocation (TET) methylcytosine dioxygenasemediated epigenetic modulation. By influencing JHDM and TET, ascorbic acid facilitates the differentiation of double negative (CD4- CD8- ) T cells to double positive (CD4+ CD8+ ) T cells and of T-helper cells to different effector subsets. Ascorbic acid modulates plasma cell differentiation and promotes early differentiation of hematopoietic stem cells (HSCs) to NK cells. These findings indicate that ascorbic acid plays a significant role in regulating both innate and adaptive immune cells, opening up new research areas in Immunonutrition. Being a water-soluble vitamin and a safe micro-nutrient, ascorbic acid can be used as an adjunct therapy for many disorders of the immune system.

To date, studies of tissue-resident immunity have mainly focused on innate immune cells and T cells, with limited data on B cells. B-1 B cells are a unique subset of B cells with innate-like properties, enriched in murine pleural and peritoneal cavities and distinct from conventional B-2 cells in their ontogeny, phenotype and function. Here we discuss how B-1 cells represent exemplar tissue-resident immune cells, summarizing the evidence for their long-term persistence & self-renewal within tissues, differential transcriptional programming shaped by organ-specific environmental cues, as well as their tissue-homeostatic functions. Finally, we review the emerging data supporting the presence and homeostatic role of B-1 cells across non-lymphoid organs (NLOs) both in mouse and human.

Sepsis is a life-threatening disease caused by a systemic infection that triggers a dysregulated immune response. Sepsis is an important cause of death in intensive care units (ICUs), poses a major threat to human health, and is a common cause of death in ICUs worldwide. The pathogenesis of sepsis is intricate and involves a complex interplay of pro- and anti-inflammatory mechanisms that can lead to excessive inflammation, immunosuppression, and potentially long-term immune disorders. Recent evidence highlights the importance of immunosuppression in sepsis. Immunosuppression is recognized as a predisposing factor for increased susceptibility to secondary infections and mortality in patients. Immunosuppression due to sepsis increases a patient's chance of re-infection and increases organ load. In addition, antibiotics, fluid resuscitation, and organ support therapy have limited impact on the prognosis of septic patients. Therapeutic approaches by suppressing excessive inflammation have not achieved the desired results in clinical trials. Research into immunosuppression has brought new hope for the treatment of sepsis, and a number of therapeutic approaches have demonstrated the potential of immunostimulatory therapies. In this article, we will focus on the mechanisms of immunosuppression and markers of immune monitoring in sepsis and describe various targets for immunostimulatory therapy in sepsis.

Plasma cells are the antibody secretors of the immune system. Continuous antibody secretion over years can provide long-term immune protection but could also be held responsible for long-lasting autoimmunity in case of self-reactive plasma cells. Systemic autoimmune rheumatic diseases (ARD) affect multiple organ systems and are associated with a plethora of different autoantibodies. Two prototypic systemic ARDs are systemic lupus erythematosus (SLE) and Sjögren's disease (SjD). Both diseases are characterized by B-cell hyperactivity and the production of autoantibodies against nuclear antigens. Analogues to other immune cells, different subsets of plasma cells have been described. Plasma cell subsets are often defined dependent on their current state of maturation, that also depend on the precursor B-cell subset from which they derived. But, a universal definition of plasma cell subsets is not available so far. Furthermore, the ability for long-term survival and effector functions may differ, potentially in a disease-specific manner. Characterization of plasma cell subsets and their specificity in individual patients can help to choose a suitable targeting approach for either a broad or more selective plasma cell depletion. Targeting plasma cells in systemic ARDs is currently challenging because of side effects or varying depletion efficacies in the tissue. Recent developments, however, like antigen-specific targeting and CAR-T-cell therapy might open up major benefits for patients beyond current treatment options.

Whole blood, as one of the most significant biological fluids, provides critical information for health management and disease monitoring. Over the past 10 years, advances in nanotechnology, microfluidics, and biomarker research have spurred the development of powerful miniaturized diagnostic systems for whole blood testing toward the goal of disease monitoring and treatment. Among the techniques employed for whole-blood diagnostics, electrochemical biosensors, as known to be rapid, sensitive, capable of miniaturization, reagentless and washing free, become a class of emerging technology to achieve the target detection specifically and directly in complex media, e.g., whole blood or even in the living body. Here we are aiming to provide a comprehensive review to summarize advances over the past decade in the development of electrochemical sensors for whole blood analysis. Further, we address the remaining challenges and opportunities to integrate electrochemical sensing platforms.

Historically, the immune system was believed to develop along a linear axis of maturity from fetal life to adulthood. Now, it is clear that distinct layers of immune cells are generated from unique waves of hematopoietic progenitors during different windows of development. This model, known as the layered immune model, has provided a useful framework for understanding why distinct lineages of B cells and γδ T cells arise in succession and display unique functions in adulthood. However, the layered immune model has not been applied to CD8+ T cells, which are still often viewed as a uniform population of cells belonging to the same lineage, with functional differences between cells arising from environmental factors encountered during infection. Recent studies have challenged this idea, demonstrating that not all CD8+ T cells are created equally and that the functions of individual CD8+ T cells in adults are linked to when they were created in the host. In this review, we discuss the accumulating evidence suggesting there are distinct ontogenetic subpopulations of CD8+ T cells and propose that the layered immune model be extended to the CD8+ T cell compartment.

Since their discovery nearly 40 years ago, B-1 cells have continued to challenge the boundaries between innate and adaptive immunity, as well as myeloid and lymphoid functions. This B-cell subset ensures early immunity in neonates before the development of conventional B (B-2) cells and respond to immune injuries throughout life. B-1 cells are multifaceted and serve as natural- and induced-antibody-producing cells, phagocytic cells, antigen-presenting cells, and anti-/pro-inflammatory cytokine-releasing cells. This review retraces the origin of B-1 cells and their different roles in homeostatic and infectious conditions before focusing on pollutants comprising contact-sensitivity-inducing chemicals, endocrine disruptors, aryl hydrocarbon receptor (AHR) ligands, and reactive particles.

Inflammation contributes to Parkinson's disease pathogenesis. We hypothesized that B lymphocytes are involved in Parkinson's disease progression. We measured antibodies to alpha-synuclein and tau in serum from patients with rapid eye movement sleep behaviour disorder (n = 79), early Parkinson's disease (n = 50) and matched controls (n = 50). Rapid eye movement sleep behaviour disorder cases were stratified by risk of progression to Parkinson's disease (low risk = 30, high risk = 49). We also measured B-cell activating factor of the tumour necrosis factor receptor family, C-reactive protein and total immunoglobulin G. We found elevated levels of antibodies to alpha-synuclein fibrils in rapid eye movement sleep behaviour disorder patients at high risk of Parkinson's disease conversion (ANOVA, P < 0.001) and lower S129D peptide-specific antibodies in those at low risk (ANOVA, P < 0.001). An early humoral response to alpha-synuclein is therefore detectable prior to the development of Parkinson's disease. Peripheral B lymphocyte phenotyping using flow cytometry in early Parkinson's disease patients and matched controls (n = 41 per group) revealed reduced B cells in Parkinson's disease, particularly in those at higher risk of developing an early dementia [t(3) = 2.87, P = 0.01]. Patients with a greater proportion of regulatory B cells had better motor scores [F(4,24) = 3.612, P = 0.019], suggesting they have a protective role in Parkinson's disease. In contrast, B cells isolated from Parkinson's disease patients at higher risk of dementia had greater cytokine (interleukin 6 and interleukin 10) responses following in vitro stimulation. We assessed peripheral blood lymphocytes in alpha-synuclein transgenic mouse models of Parkinson's disease: they also had reduced B cells, suggesting this is related to alpha-synuclein pathology. In a toxin-based mouse model of Parkinson's disease, B-cell deficiency or depletion resulted in worse pathological and behavioural outcomes, supporting the conclusion that B cells play an early protective role in dopaminergic cell loss. In conclusion, we found changes in the B-cell compartment associated with risk of disease progression in rapid eye movement sleep behaviour disorder (higher alpha-synuclein antibodies) and early Parkinson's disease (lower levels of B lymphocytes that were more reactive to stimulation). Regulatory B cells play a protective role in a mouse model, potentially by attenuating inflammation and dopaminergic cell loss. B cells are therefore likely to be involved in the pathogenesis of Parkinson's disease, albeit in a complex way, and thus warrant consideration as a therapeutic target.

Sepsis is a life-threatening disorder disease defined as infection-induced dysregulated immune responses and multiple organ dysfunction. The imbalance between hyperinflammation and immunosuppression is a crucial feature of sepsis immunity. Epigenetic modifications, including histone modifications, DNA methylation, chromatin remodeling, and non-coding RNA, play essential roles in regulating sepsis immunity through epi-information independent of the DNA sequence. In recent years, the mechanisms of histone modification in sepsis have received increasing attention, with ongoing discoveries of novel types of histone modifications. Due to the capacity for prolonged effects on immune cells, histone modifications can induce immune cell reprogramming and participate in the long-term immunosuppressed state of sepsis. Herein, we systematically review current mechanisms of histone modifications involved in the regulation of sepsis, summarize their role in sepsis from an immune perspective and provide potential therapeutic opportunities targeting histone modifications in sepsis treatment.

Sepsis is a life-threatening yet common disease, still posing high mortality worldwide. Sepsis-related deaths primarily occur during immunosuppression; the disease can hamper the numbers and function of B cells, which mediate innate and adaptive immune responses to maintain immune homeostasis. Dysfunction of B cells, along with aggravated immunosuppression, are closely related to poor prognosis. However, B cells in patients with sepsis have garnered little attention. This article focuses on the significance of B-cell subsets, including regulatory B cells, in sepsis and how the counts and function of circulating B cells are affected in patients with sepsis. Finally, potential B-cell-related immunotherapies for sepsis are explored.

B cells are classically considered solely as antibody-producing cells driving humoral immune responses to foreign antigens in infections and vaccinations as well as self-antigens in pathological settings such as autoimmunity. However, it has now become clear that B cells can also secrete a vast array of cytokines, which influence both pro- and anti-inflammatory immune responses. Indeed, similarly to T cells, there is significant heterogeneity in cytokine-driven responses by B cells, ranging from the production of pro-inflammatory effector cytokines such as IL-6, through to the release of immunosuppressive cytokines such as IL-10. In this review, focusing on human B cells, we summarize the key findings that have revealed that cytokine-producing B cell subsets have critical functions in healthy immune responses and contribute to the pathophysiology of autoimmune diseases.

The sequestering of oxidation-modified low-density lipoprotein by macrophages results in the accumulation of fatty deposits within the walls of arteries. Necrosis of these cells causes a release of intercellular epitopes and the activation of the adaptive immune system, which we predict leads to robust autoantibody production. T cells produce cytokines that act in the plaque environment and further stimulate B cell antibody production. B cells in atherosclerosis meanwhile have a mixed role based on subclass. The current model is that B-1 cells produce protective IgM antibodies in response to oxidation-specific epitopes that work to control plaque formation, while follicular B-2 cells produce class-switched antibodies (IgG, IgA, and IgE) which exacerbate the disease. Over the course of this review, we discuss further the validation of these protective antibodies while evaluating the current dogma regarding class-switched antibodies in atherosclerosis. There are several contradictory findings regarding the involvement of class-switched antibodies in the disease. We hypothesize that this is due to antigen-specificity, and not simply isotype, being important, and that a closer evaluation of these antibodies' targets should be conducted. We propose that specific antibodies may have therapeutical potential in preventing and controlling plaque development within a clinical setting.

Sepsis is a life-threatening syndrome caused by anomalous host response to infection. The pathogenesis of sepsis is complex, and immune dysfunction is the central link in its occurrence and development. The sepsis immune response is not a local and transient process but a complex and continuous process involving all major cell types of innate and adaptive immunity. B cells are traditionally studied for their ability to produce antibodies in the context of mediating humoral immunity. However, over the past few years, B cells have been increasingly recognized as key modulators of adaptive and innate immunity, and they can participate in immune responses by presenting antigens, producing cytokines, and modulating other immune cells. Recently, increasing evidence links B-cell dysfunction to mechanisms of immune derangement in sepsis, which has drawn attention to the powerful properties of this unique immune cell type in sepsis. Here, we reviewed the dynamic alterations of B cells and their novel roles in animal models and patients with sepsis, and provided new perspectives for therapeutic strategies targeting B cells in sepsis.

Myriad clinical findings provide links between chronic stressors, inflammation, and mood disorders. Furthermore, traumatic or chronic exposure to psychological stressors may promote stress sensitization, in which individuals have long-term complications, including increased vulnerability to subsequent stressors. Post-traumatic stress disorder (PTSD) is a clinically relevant example of stress sensitization. PTSD alters neuronal circuitry and mood; however, the mechanisms underlying long-term stress sensitization within this disorder are unclear. Rodent models of chronic social defeat recapitulate several key physiological, immunological, and behavioral responses associated with psychological stress in humans. Repeated social defeat (RSD) uniquely promotes the convergence of neuronal, central inflammatory (microglial), and peripheral immune (monocyte) pathways, leading to prolonged anxiety, social withdrawal, and cognitive impairment. Moreover, RSD promotes stress sensitization, in which mice are highly sensitive to subthreshold stress exposure and recurrence of anxiety weeks after the cessation of stress. Therefore, the purpose of this Review is to discuss the influence of social-defeat stress on the immune system that may underlie stress sensitization within three key cellular compartments: neurons, microglia, and monocytes. Delineating the mechanisms of stress sensitization is critical in understanding and treating conditions such as PTSD.