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The immune system has a vital, albeit complex, relationship with the microbes residing within us, one that we are only beginning to understand. We asked investigators what they felt were the fundamental challenges we currently face in unraveling the impacts of microbes and their metabolites on host immunity and to discuss key opportunities toward achieving future insights and innovation., Competing Interests: Declaration of interests E.E. is a scientific cofounder of BiomX and GutBiome and an advisor to Purposebio, Aposense, and Zoe in topics unrelated to this work. S.Z. is a cofounder of Ibiome, which studies microbial regulation of immune responses in topics unrelated to the subject of this work. F.M. is a scientific advisory board member at Neologics Bio. R.J.P. has patents related to this topic: “Non-invasive assessment of gut function with transcriptional recording sentinel cells,” EP22166075 (2022) and “Transcriptional recording by CRISPR spacer acquisition from RNA,” PCT/EP2019/074267 (2018)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Osteoporosis (OP) is a disease characterized by decreased bone mass, deteriorated microstructure, and increased fragility and fracture risk. The diagnosis and prevention of OP and its complications have become major public health challenges. Therefore, exploring the complex ecological connections between the immune and skeletal systems may provide new insights for clinical prevention and treatment strategies., Methods: First, we performed single-cell RNA sequencing on human lumbar lamina tissue and conducted clustering and subgroup analysis of quality-controlled single-cell transcriptome data to identify target subgroups. Subsequently, enrichment analysis and pseudotime analysis were performed. In addition, we conducted in-depth studies on the gene regulatory network between different cell subgroups and the communication between bone immune cells., Results: In this study, we identified several cell subgroups that may be involved in the progression of OP. For example, the CCL4 + NKT and CXCL8 + neutrophils subgroups promote OP progression by mediating an inflammatory environment that disrupts bone homeostasis, and the MNDA + Mac subgroup promotes osteoclast differentiation to promote OP. Moreover, the TNFAIP6 + Obl, NR4A2 + B and HMGN2 + erythrocyte subgroups promoted the balance of bone metabolism and suppressed OP. In the cell communication network, Obl closely interacts with immune cell subgroups through the CXCR4-CXCL12, CTGF-ITGB2, and TNFSF14-TNFRSF14 axes., Conclusion: Our research revealed specific subgroups and intercellular interactions that play crucial roles in the pathogenesis of OP, providing potential new insights for more precise therapeutic interventions for OP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Liver failure profoundly affects the immune system, leading to dysregulation of innate and adaptive immune response. This review explores the intricate relationship between liver function and immune homeostasis. The role of the liver as a central hub in immune response initiation is elucidated, emphasizing its involvement in hepatic inflammation induction and subsequent systemic inflammation. Cytokines, chemokines, growth factors, and lipid mediators orchestrate these immune processes, serving as both prognostic biomarkers and potential therapeutic targets in liver failure-associated immune dysregulation, which might result from acute-on-chronic liver failure (ACLF) and cirrhosis. Furthermore, the review delves into the mechanisms underlying immunosuppression in liver failure, encompassing alterations in innate immune cell functions such as neutrophils, macrophages, and natural killer cells (NK cells), as well as perturbations in adaptive immune responses mediated by B and T cells. Conclusion: Understanding the immunological consequences of liver failure is crucial for developing targeted therapeutic interventions and improving patient outcomes in liver disease management.

Everyone knows that an infection can make you feel sick. Although we perceive infection-induced changes in metabolism as a pathology, they are a part of a carefully regulated process that depends on tissue-specific interactions between the immune system and organs involved in the regulation of systemic homeostasis. Immune-mediated changes in homeostatic parameters lead to altered production and uptake of nutrients in circulation, which modifies the metabolic rate of key organs. This is what we experience as being sick. The purpose of sickness metabolism is to generate a metabolic environment in which the body is optimally able to fight infection while denying vital nutrients for the replication of pathogens. Sickness metabolism depends on tissue-specific immune cells, which mediate responses tailored to the nature and magnitude of the threat. As an infection increases in severity, so do the number and type of immune cells involved and the level to which organs are affected, which dictates the degree to which we feel sick. Interestingly, many alterations associated with metabolic disease appear to overlap with immune-mediated changes observed following infection. Targeting processes involving tissue-specific interactions between activated immune cells and metabolic organs therefore holds great potential for treating both people with severe infection and those with metabolic disease. In this review, we will discuss how the immune system communicates in situ with organs involved in the regulation of homeostasis and how this communication is impacted by infection., (© 2024. The Author(s).)

Genital tract infections can cause a variety of harmful health outcomes, including endometritis, bacterial vaginosis, and pelvic inflammatory disease, in addition to infertility. Anaerobic bacteria, such as Gardnerella vaginalis, Megasphaera spp., and Atopobium vaginae, are more commonly identified in cases of bacterial vaginosis than lactobacilli. It is unknown how the microorganisms that cause pelvic inflammatory diseases and endometritis enter the uterus. Both prospective and retrospective research have connected pelvic inflammatory disorders, chronic endometritis, and bacterial vaginosis to infertility. Similar to bacterial vaginosis, endometritis-related infertility is probably caused by a variety of factors, such as inflammation, immune system recognition of sperm antigens, bacterial toxins, and a higher risk of STDs. Preconception care for symptomatic women may include diagnosing and treating pelvic inflammatory disease, chronic endometritis, and bacterial vaginosis before conception to optimize the results of both natural and assisted reproduction., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

T cell receptor (TCR) is a kind of surface marker that are specific to T cells. The TCR regulates T cell function and participates in the body's immunological response to prevent immune dysregulation and inflammatory reactions by identifying and binding exogenous antigens. Due to its brief intracellular segment, TCR requires intracellular molecules to assist with signaling. Among these, the CD3 molecule is one of the most important. The CD3 molecule involves in TCR structural stability as well as T cell activation signaling. A TCR-CD3 complex is created when TCR and CD3 form a non-covalent bond. Antigen recognition and T cell signaling are both facilitated by the TCR-CD3 complex. When a CD3 subunit is absent, a TCR-CD3 complex cannot form, and none of the subunits is transported to the cell surface. Thus, T cells cannot develop. Consequently, research on the physiological functions and potential pathogenicity of CD3 subunits can clarify the pathogenesis of immune system diseases and can offer fresh approaches to the treatment of it. In this review, the structure and function of the TCR-CD3 complex in the immune system was summarized, the pathogenicity of each CD3 subunit and therapeutic approaches to related diseases was explored and research directions for the development of new targeted drugs was provided., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The first 1000 days of life is a critical period of development in which adverse circumstances can have long-term consequences for the child's health. Maternal immune activation is associated with increased risk of neurodevelopmental disorders in the child. Aberrant immune responses have been reported in individuals with neurodevelopmental disorders. Moreover, lasting effects of maternal immune activation on the offspring's immune system have been reported. Taken together, this indicates that the effect of maternal immune activation is not limited to the central nervous system. Here, we explore the impact of maternal immune activation on the immune system of the offspring. We first describe the development of the immune system and provide an overview of reported alterations in the cytokine profiles, immune cell profiles, immune cell function, and immune induction in pre-clinical models. Additionally, we highlight recent research on the impact of maternal COVID-19 exposure on the neonatal immune system and the potential health consequences for the child. Our review shows that maternal immune activation alters the offspring's immune system under certain conditions, but the reported effects are conflicting and inconsistent. In general, epigenetic modifications are considered the mechanism for fetal programming. The available data was insufficient to identify specific pathways that may contribute to immune programming. As a consequence of the COVID-19 pandemic, more research now focuses on the possible health effects of maternal immune activation on the offspring. Future research addressing the offspring's immune response to maternal immune activation can elucidate specific pathways that contribute to fetal immune programming and the long-term health effects for the offspring., (© 2024. The Author(s).)

Competing Interests: GH receives a share of the royalty received on sales of the CTD 110.6 antibody, managed by JHU. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that they were editorial board members of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Giardia lamblia , the cause of giardiasis, significantly impacts patients with metabolic disorders related to insulin resistance (IR). Both giardiasis and metabolic disorders share elements such as chronic inflammation and intestinal dysbiosis, which substantially affect the metabolic and cytokine profiles of patients. This review discusses the mechanisms of virulence of G. lamblia , its influence on the immune system, and its association with metabolic disorders. The review aims to show how G. lamblia invasion acts on the immune system and the glucose and lipid metabolism. Key findings reveal that G. lamblia infection, by disrupting intestinal permeability, alters microbiota composition and immune responses, potentially impairing metabolic status. Future research should focus on elucidating the specific mechanisms by which G. lamblia influences the metabolism, exploring the long-term consequences of chronic infection, and developing targeted therapeutic strategies that include both parasitic and metabolic aspects. These insights underscore the need for a multidisciplinary approach to the treatment of giardiasis in patients with metabolic disorders.

Ageing as a natural irreversible process inherently results in the functional deterioration of numerous organ systems and tissues, including the skeletal and immune systems. Recent studies have elucidated the intricate bidirectional interactions between these two systems. In this review, we provide a comprehensive synthesis of molecular mechanisms of cell ageing. We further discuss how age-related skeletal changes influence the immune system and the consequent impact of immune system alterations on the skeletal system. Finally, we highlight the clinical implications of these findings and propose potential strategies to promote healthy ageing and reduce pathologic deterioration of both the skeletal and immune systems., (© 2024. The Author(s).)

Systemic lupus erythematosus is a complex autoimmune disease resulting from a dysregulation of the immune system that involves gut dysbiosis and an altered host cellular metabolism. This review highlights novel insights and expands on the interactions between the gut microbiome and the host immune metabolism in lupus. Pathobionts, invasive pathogens, and even commensal microbes, when in dysbiosis, can all trigger and modulate immune responses through metabolic reprogramming. Changes in the microbiota's global composition or individual taxa may trigger a cascade of metabolic changes in immune cells that may, in turn, reprogram their functions. Factors contributing to dysbiosis include changes in intestinal hypoxia, competition for glucose, and limited availability of essential nutrients, such as tryptophan and metal ions, all of which can be driven by host metabolism changes. Conversely, the accumulation of some host metabolites, such as itaconate, succinate, and free fatty acids, could further influence the microbial composition and immune responses. Overall, mounting evidence supports a bidirectional relationship between host immunometabolism and the microbiota in lupus pathogenesis., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose of Review: Solid organ transplantation recipients have an increased risk of infection, exacerbated by immunosuppressant medications that need to finely balance suppression of the immune system to prevent allograft rejection while avoiding over-suppression leading to infections and malignancy. Exercise modulates immune functions, with moderate-intensity activities particularly associated with enhanced antiviral immunity and reduced infection incidence. However, investigations of the effects of exercise and physical activity on immune function and infection risk posttransplantation are scarce. This review highlights areas where the relationship between exercise, immune function and infection risk has greatest potential for benefit for solid organ transplantation and therefore greatest need for investigation., Recent Findings: Moderate and higher intensity exercise do not appear to cause adverse immunological effects in kidney transplantation recipients, although evidence from other organ transplantation is lacking. Evidence from healthy younger and older adults suggests that regular exercise can reduce risk of respiratory infections and latent herpesvirus reactivation and improves antibody responses to vaccination, which is of great importance for organ transplantation recipients., Summary: There is a strong need for research to investigate the role of exercise on immune function and infection risk in solid organ transplantation to improve both allograft survival and long-term health of the recipient., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The gut microbiota is a system of microorganisms in the human gastrointestinal (GI) system, consisting of trillions of microorganisms residing in epithelial surfaces of the body. Gut microbiota are exposed to various external and internal factors and form a unique gut-associated immunity maintained through a balancing act among diverse groups of microorganisms. The role of microbiota in dysbiosis of the gut in aiding prostate cancer development has created an urgency for extending research toward comprehension and preventative measures. The gut microbiota varies among persons based on diet, race, genetic background, and geographic location. Bacteriome, mainly, has been linked to GI complications, metabolism, weight gain, and high blood sugar. Studies have shown that manipulating the microbiome (bacteriome, virome, and mycobiome) through the dietary intake of phytochemicals positively influences physical and emotional health, preventing and delaying diseases caused by microbiota. In this review, we discuss the wealth of knowledge about the GI tract and factors associated with dysbiosis-mediated compromised gut immunity. This review also focuses on the relationship of dysbiosis to prostate cancer, the impact of microbial metabolites short-chain fatty acids (SCFAs) on host health, and the phytochemicals improving health while inhibiting prostate cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence this work., (Copyright © 2024 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

An essential prerequisite for evolution by natural selection is variation among individuals in traits that affect fitness 1 . The ability of a system to produce selectable variation, known as evolvability 2 , thus markedly affects the rate of evolution. Although the immune system is among the fastest-evolving components in mammals 3 , the sources of variation in immune traits remain largely unknown 4,5 . Here we show that an important determinant of the immune system's evolvability is its organization into interacting modules represented by different immune cell types. By profiling immune cell variation in bone marrow of 54 genetically diverse mouse strains from the Collaborative Cross 6 , we found that variation in immune cell frequencies is polygenic and that many associated genes are involved in homeostatic balance through cell-intrinsic functions of proliferation, migration and cell death. However, we also found genes associated with the frequency of a particular cell type that are expressed in a different cell type, exerting their effect in what we term cyto-trans. The vertebrate evolutionary record shows that genes associated in cyto-trans have faced weaker negative selection, thus increasing the robustness and hence evolvability 2,7,8 of the immune system. This phenomenon is similarly observable in human blood. Our findings suggest that interactions between different components of the immune system provide a phenotypic space in which mutations can produce variation with little detriment, underscoring the role of modularity in the evolution of complex systems 9 ., (© 2024. The Author(s).)

Mother and child are immunologically interconnected by mechanisms that we are only beginning to understand. During pregnancy, multiple molecular and cellular factors of maternal origin are transferred across the placenta and influence the development and function of the fetal and newborn immune system. Altered maternal immune states arising from pregnancy-associated infections or immunizations have the potential to program offspring immune function in ways that may have long-term health consequences. In this study, we review current literature on the impact of prenatal infection and vaccination on the developing immune system, highlight knowledge gaps, and look to the horizon to envision maternal interventions that could benefit both the mother and her child., (Copyright © 2024 The Authors.)

Aging is associated with changes in the immune system and the gut microbiota. Immunosenescence may lead to a low-grade, sterile chronic inflammation in a multifactorial and dynamic way, which plays a critical role in most age-related diseases. Age-related changes in the gut microbiota also shape the immune and inflammatory responses. Nutrition is a determinant of immune function and of the gut microbiota. Immunonutrion has been regarded as a new strategy for disease prevention and management, including many age-related diseases. However, the understanding of the cause-effect relationship is required to be more certain about the role of immunonutrition in supporting the immune homeostasis and its clinical relevance in elderly individuals. Herein, we review the remarkable quantitative and qualitative changes during aging that contribute to immunosenescence, inflammaging and microbial dysbiosis, and the effects on late-life health conditions. Furthermore, we discuss the clinical significance of immunonutrition in the treatment of age-related diseases by systematically reviewing its modulation of the immune system and the gut microbiota to clarify the effect of immunonutrition-based interventions on the healthy aging.

Millions of microorganisms make up the complex microbial ecosystem found in the human gut. The immune system's interaction with the gut microbiota is essential for preventing inflammation and maintaining intestinal homeostasis. Numerous metabolic products that can cross-talk between immune cells and the gut epithelium are metabolized by the gut microbiota. Traumatic injury elicits a great and multifaceted immune response in the minutes after the initial offense, containing simultaneous pro- and anti-inflammatory responses. The development of innovative therapies that improve patient outcomes depends on the gut microbiota and immunological responses to trauma. The altered makeup of gut microbes, or gut dysbiosis, can also dysregulate immunological responses, resulting in inflammation. Major human diseases may become more common as a result of chronic dysbiosis and the translocation of bacteria and the products of their metabolism beyond the mucosal barrier. In this review, we briefly summarize the interactions between the gut microbiota and the immune system and human disease and their therapeutic probiotic formulations. We also discuss the immune response to traumatic injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ullah, Arbab, Tian, Chen, Liu, Li and Li.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

The cells presented in this work are not classified as cells that make up the immune system. They, however, present functions and molecules, which are characteristic of immune cells. These characteristic functions are, for example, sensing threat, performing phagocytosis, presentation of foreign antigens, cytokine release or enhancing immune memory. The enlisted immune response mechanisms are carried out by the possession of molecules such as Toll-like receptors, receptors for the Fc fragment of IgG, major histocompatibility complex class II molecules, costimulatory CD80/CD86 proteins and molecules needed for NLRP3 (NOD-like family pyrin domain containing 3) inflammasome activation. Thanks to these properties, the described nonimmune cells play an important role in the local immune response and support of the entire body in the fight against pathogens. They constitute the first line of defense of tissues and organs against pathogens and molecules recognized as harmful. The cells described in this article are particularly important in immunologically privileged places (e.g. the Bowman's capsule in the kidney), where "typical" immune cells normally do not have access. In this paper, we present immune-like functions and molecule suites of resident kidney cells (podocytes and mesangial cells), cochlear resident cells, fibrocytes and fibroblasts, as well as some stem cells (mesenchymal stem cells and umbilical cord Wharton's jelly-derived cells)., (© 2024 the Australian and New Zealand Society for Immunology, Inc.)

Patients with chronic liver disease (CLD) often present with significant frailty, sarcopenia, and impaired immune function. However, the mechanisms driving the development of these age-related phenotypes are not fully understood. To determine whether accelerated biological aging may play a role in CLD, epigenetic, transcriptomic, and phenotypic assessments were performed on the skeletal muscle tissue and immune cells of CLD patients and age-matched healthy controls. Accelerated biological aging of the skeletal muscle tissue of CLD patients was detected, as evidenced by an increase in epigenetic age compared with chronological age (mean +2.2 ± 4.8 years compared with healthy controls at -3.0 ± 3.2 years, p = 0.0001). Considering disease etiology, age acceleration was significantly greater in both the alcohol-related (ArLD) (p = 0.01) and nonalcoholic fatty liver disease (NAFLD) (p = 0.0026) subgroups than in the healthy control subgroup, with no age acceleration observed in the immune-mediated subgroup or healthy control subgroup (p = 0.3). The skeletal muscle transcriptome was also enriched for genes associated with cellular senescence. Similarly, blood cell epigenetic age was significantly greater than that in control individuals, as calculated using the PhenoAge (p < 0.0001), DunedinPACE (p < 0.0001), or Hannum (p = 0.01) epigenetic clocks, with no difference using the Horvath clock. Analysis of the IMM-Age score indicated a prematurely aged immune phenotype in CLD patients that was 2-fold greater than that observed in age-matched healthy controls (p < 0.0001). These findings suggested that accelerated cellular aging may contribute to a phenotype associated with advanced age in CLD patients. Therefore, therapeutic interventions to reduce biological aging in CLD patients may improve health outcomes., (© 2024. The Author(s).)

Due to the ongoing global warming, the risk of heatwaves in the oceans is continuously increasing while our understanding of the physiological response of Litopenaeus vannamei under extreme temperature conditions remains limited. Therefore, this study aimed to evaluate the physiological responses of L. vannamei under heat stress. Our results indicated that as temperature rose, the structure of intestinal and hepatopancreatic tissues was damaged sequentially. Activity of immune-related enzymes (acid phosphatase/alkaline phosphatase) initially increased before decreased, while antioxidant enzymes (superoxide dismutase and glutathione-S transferase) activity and malondialdehyde content increased with rising temperature. In addition, the total antioxidant capacity decreased with rising temperature. With the rising temperature, there was a significant increase in the expression of caspase-3, heat shock protein 70, lipopolysaccharide-induced tumor necrosis factor-α, transcriptional enhanced associate domain and yorkie in intestinal and hepatopancreatic tissues. Following heat stress, the number of potentially beneficial bacteria (Rhodobacteraceae and Gemmonbacter) increased which maintain balance and promote vitamin synthesis. Intestinal transcriptome analysis revealed 852 differentially expressed genes in the heat stress group compared with the control group. KEGG functional annotation results showed that the endocrine system was the most abundant in Organismal systems followed by the immune system. These results indicated that heat stress leads to tissue damage in shrimp, however the shrimp may respond to stress through a coordinated interaction strategy of the endocrine system, immune system and gut microbiota. This study revealed the response mechanism of L. vannamei to acute heat stress and potentially provided a theoretical foundation for future research on shrimp environmental adaptations., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Multiple epidemiologic studies have revealed that gender is considered one of the important factors in the frequency and severity of certain infectious diseases, in which estrogens may play a vital role. There is growing evidence that estrogens as female sex hormone can modulate multiple biological functions outside of the reproductive system, such as in brain and cardiovascular system. However, it is largely unknown about the roles and mechanisms of estrogens/estrogen receptors in immune health and infection disease. Thence, by reading a lot of literature, we summarized the regulatory mechanisms of estrogens/estrogen receptors in immune cells and their roles in certain infectious diseases with gender differences. Therefore, estrogens may have therapeutic potentials to prevent and treat these infectious diseases, which needs further clinical investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Phenuiviruses are a class of segmented negative-sense single-stranded RNA viruses, typically consisting of three RNA segments that encode four distinct proteins. The emergence of pathogenic phenuivirus strains, such as Rift Valley fever phlebovirus (RVFV) in sub-Saharan Africa, Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV) in East and Southeast Asia, and Heartland Virus (HRTV) in the United States has presented considerable challenges to global public health in recent years. The innate immune system plays a crucial role as the initial defense mechanism of the host against invading pathogens. In addition to continued research aimed at elucidating the epidemiological characteristics of phenuivirus, significant advancements have been made in investigating its viral virulence factors (glycoprotein, non-structural protein, and nucleoprotein) and potential host-pathogen interactions. Specifically, efforts have focused on understanding mechanisms of viral immune evasion, viral assembly and egress, and host immune networks involving immune cells, programmed cell death, inflammation, nucleic acid receptors, etc. Furthermore, a plethora of technological advancements, including metagenomics, metabolomics, single-cell transcriptomics, proteomics, gene editing, monoclonal antibodies, and vaccines, have been utilized to further our understanding of phenuivirus pathogenesis and host immune responses. Hence, this review aims to provide a comprehensive overview of the current understanding of the mechanisms of host recognition, viral immune evasion, and potential therapeutic approaches during human pathogenic phenuivirus infections focusing particularly on RVFV and SFTSV.

Historically, amphibians have been essential to our understanding of vertebrate biology and animal development. Because development from egg to tadpole to adult frog can be directly observed, amphibians contributed greatly to our understanding of not only vertebrate animal development but also the development of the immune system. The South African clawed frog (Xenopus laevis) has been key to many of these findings. For example, using Xenopus as a model, the comparative immunology community learned about the contribution of hematopoietic stem cells to development of the immune system and about the diversity of antibodies, B cells, T cells and antigen presenting cells. Amphibians offer many advantages as unique potential model systems to address questions about immune skin interactions, host responses to mycobacteria, the diverse functions of interferons, and immune and mucosal interactions. However, there are also many challenges to advance the research including the lack of specific reagents and well annotated genomes of diverse species. While much is known, many important questions remain. The aim of this short commentary is to look to the future of comparative immunology of amphibians as a group. By identifying some important questions or "information-deficit" areas of research, I hope to pique the interest of younger developing scientists and persuade funding agencies to continue to support comparative immunology studies including those of amphibians., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Viral infections significantly impact the immune system, and impact will persist until recovery. However, the influence of severe acute respiratory syndrome coronavirus 2 infection on the homeostatic immune status and secondary immune response in recovered patients remains unclear. To investigate these persistent alterations, we employed five feature-ranking algorithms (LASSO, MCFS, RF, CATBoost, and XGBoost), incremental feature selection, synthetic minority oversampling technique and two classification algorithms (decision tree and k-nearest neighbors) to analyze multi-omics data (surface proteins and transcriptome) from coronavirus disease 2019 (COVID-19) recovered patients and healthy controls post-influenza vaccination. The single-cell multi-omics dataset was divided into five subsets corresponding to five immune cell subtypes: B cells, CD4+ T cells, CD8+ T cells, Monocytes, and Natural Killer cells. Each cell was represented by 28,402 scRNA-seq (RNA) features, 3 Hash Tag Oligo (HTO) features, 138 Cellular indexing of transcriptomes and epitopes by sequencing (CITE) features and 23,569 Single Cell Transform (SCT) features. Some multi-omics markers were identified and effective classifiers were constructed. Our findings indicate a distinct immune status in COVID-19 recovered patients, characterized by low expression of ribosomal protein (RPS26) and high expression of immune cell surface proteins (CD33, CD48). Notably, TMEM176B, a membrane protein, was highly expressed in monocytes of COVID-19 convalescent patients. These observations aid in discerning molecular differences among immune cell subtypes and contribute to understanding the prolonged effects of COVID-19 on the immune system, which is valuable for treating infectious diseases like COVID-19., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Melatonin is the major product both synthesized and secreted by the pineal gland during the night period and it is the principal chronobiotic hormone that regulates the circadian rhythms and seasonal changes in vertebrate biology. Moreover, melatonin shows both a broad distribution along the phylogenetically distant organisms and a high functional versatility. At the present time, a significant amount of experimental evidence has been reported in scientific literature and has clearly shown a functional relationship between the endocrine, nervous, and immune systems. The biochemistry basis of the functional communication between these systems is the utilization of a common chemicals signals. In this framework, at present melatonin is considered to be a relevant member of the so-called neuro-endocrine-immunological network. Thus, both in vivo and in vitro investigations conducted in both experimental animals and humans, have clearly documented that melatonin has an important immunomodulatory role. However, most of the published results refer to information on T lymphocytes, i.e., cell-mediated immunity. On the contrary, fewer studies have been carried out on B lymphocytes, the cells responsible for the so-called humoral immunity. In this review, we have focused on the biological role of melatonin in the humoral immunity. More precisely, we report the actions of melatonin on B lymphocytes biology and on the production of different types of antibodies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Diabetes is associated with numerous comorbidities, one of which is increased vulnerability to infections. This review will focus on how diabetes mellitus (DM) affects the immune system and its various components, leading to the impaired proliferation of immune cells and the induction of senescence. We will explore how the pathology of diabetes-induced immune dysfunction may have similarities to the pathways of "inflammaging", a persistent low-grade inflammation common in the elderly. Inflammaging may increase the likelihood of conditions such as rheumatoid arthritis (RA) and periodontitis at a younger age. Diabetes affects bone marrow composition and cellular senescence, and in combination with advanced age also affects lymphopoiesis by increasing myeloid differentiation and reducing lymphoid differentiation. Consequently, this leads to a reduced immune system response in both the innate and adaptive phases, resulting in higher infection rates, reduced vaccine response, and increased immune cells' senescence in diabetics. We will also explore how some diabetes drugs induce immune senescence despite their benefits on glycemic control.

In recent years, there has been a growing realization of intricate interactions between the nervous and immune systems, characterized by shared humoral factors and receptors. This interplay forms the basis of the neuroimmune system, the understanding of which will provide insights into the pathogenesis of neurological diseases, in which the involvement of the immune system has been overlooked. Kynurenine and its derivatives derived from tryptophan have long been implicated in the pathogenesis of various neurological diseases. Recent studies have revealed their close association not only with neurological disorders but also with sepsis-related deaths. This review provides an overview of the biochemistry of kynurenine and its derivatives, followed by a discussion of their role via the modulation of the neuroimmune system in various diseases.

The process of thyroid autoimmunization develops against the background of genetic predispositions associated with class II human leukocyte antigens (HLA-DR), as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), protein tyrosine phosphatase non-receptor type 22 (PTPN22), and forkhead transcription box protein P3 (FOXP3). Environmental factors, such as vitamin D deficiency, Zn, Se, and Mg, as well as infections, chronic stress, pregnancy, smoking, alcohol, medications, intestinal dysbiosis, and malnutrition, also play an important role. The first stage of autoimmunization involves the accumulation of macrophages and dendritic cells, as well as plasma cells. In the second stage, the mutual interactions of individual cells in the immune system lead to a decrease in the level of CD8+ in favor of CD4+, which intensifies the synthesis of T lymphocyte derivatives, especially Th1, Th17, Tfh, and Tc, reducing the level of Treg. Consequently, the number of the anti-inflammatory cytokines IL10 and IL2 decreases, and the synthesis of the pro-inflammatory cytokines IL-2, Il-12, Il-17, IL-21, IL-22, IFN-γ, and TNF-α increases. The latter two especially trigger the pyroptosis process involving the inflammasome. Activation of the inflammasome by IL-β and IL-18 produced by macrophages is one of the mechanisms of pyroptosis in the course of Hashimoto's thyroiditis, involving Gram-negative bacteria and NLRC4. In the next step, the apoptosis of thyroid cells is initiated by the intensification of perforin, granzyme, and proteoglycan synthesis by Tc and NK cells. The current findings raise many possibilities regarding interventions related to the inhibition of pro-inflammatory cytokines and the stimulation of anti-inflammatory cytokines produced by both T and B lymphocytes. Furthermore, since there is currently no effective method for treating thyroid autoimmunity, a summary of the review may provide answers regarding the treatment of not only Hashimoto's thyroiditis, but also other autoimmune diseases associated with autoimmunity.

The immune system comprises a complex yet tightly regulated network of cells and molecules that play a critical role in protecting the body from infection and disease. The activity and development of each immune cell is regulated in a myriad of ways including through the cytokine milieu, the availability of key receptors, via tailored intracellular signalling cascades, dedicated transcription factors and even by directly modulating gene accessibility and expression; the latter is more commonly known as epigenetic regulation. In recent years, epigenetic regulators have begun to emerge as key players involved in modulating the immune system. Among these, the lysine methyltransferase DOT1L has gained significant attention for its involvement in orchestrating immune cell formation and function. In this review we provide an overview of the role of DOT1L across the immune system and the implications of this role on health and disease. We begin by elucidating the general mechanisms of DOT1L-mediated histone methylation and its impact on gene expression within immune cells. Subsequently, we provide a detailed and comprehensive overview of recent studies that identify DOT1L as a crucial regulator of immune cell development, differentiation, and activation. Next, we discuss the potential mechanisms of DOT1L-mediated regulation of immune cell function and shed light on how DOT1L might be contributing to immune cell homeostasis and dysfunction. We then provide food for thought by highlighting some of the current obstacles and technical limitations precluding a more in-depth elucidation of DOT1L's role. Finally, we explore the potential therapeutic implications of targeting DOT1L in the context of immune-related diseases and discuss ongoing research efforts to this end. Overall, this review consolidates the current paradigm regarding DOT1L's role across the immune network and emphasises its critical role in governing the healthy immune system and its potential as a novel therapeutic target for immune-related diseases. A deeper understanding of DOT1L's immunomodulatory functions could pave the way for innovative therapeutic approaches which fine-tune the immune response to enhance or restore human health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kealy, Runting, Thiele and Scheer.)

Pathogenic adenovirus (Ad) infections are widespread but typically mild and transient, except in the immunocompromised. As vectors for gene therapy, vaccine, and oncology applications, Ad-based platforms offer advantages, including ease of genetic manipulation, scale of production, and well-established safety profiles, making them attractive tools for therapeutic development. However, the immune system often poses a significant challenge that must be overcome for adenovirus-based therapies to be truly efficacious. Both pre-existing anti-Ad immunity in the population as well as the rapid development of an immune response against engineered adenoviral vectors can have detrimental effects on the downstream impact of an adenovirus-based therapeutic. This review focuses on the different challenges posed, including pre-existing natural immunity and anti-vector immunity induced by a therapeutic, in the context of innate and adaptive immune responses. We summarise different approaches developed with the aim of tackling these problems, as well as their outcomes and potential future applications.

Cellular mechanisms mediating immunotherapy resistances are incompletely understood. In this issue, Li et al. reveal how breast cancer hijacks neuronal mechanisms of neuroprotection to shield itself from the immune system. Secretion of N-acetylaspartate impairs immune synapse formation in both neuroinflammation and breast cancer models, paving the way for novel therapeutic approaches., Competing Interests: Declaration of interests L.B. is an inventor on the patent for T cell receptor-derived binding polypeptides PCT/EP2023/061716. L.B. received honoraria from Adaptive Biotechnologies., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Multiple sclerosis (MS), a prevalent neurological disorder, predominantly affects young adults and is characterized by chronic autoimmune activity. The study explores the immune system dysregulation in MS, highlighting the crucial roles of immune and non-neuronal cells in the disease's progression. This review examines the dual role of cytokines, with some like IL-6, TNF-α, and interferon-gamma (IFN-γ) promoting inflammation and CNS tissue injury, and others such as IL-4, IL-10, IL-37, and TGF-β fostering remyelination and protecting against MS. Elevated chemokine levels in the cerebrospinal fluid (CSF), including CCL2, CCL5, CXCL10, CXCL13, and fractalkine, are analyzed for their role in facilitating immune cell migration across the blood-brain barrier (BBB), worsening inflammation and neurodegeneration. The study also delves into the impact of auto-antibodies targeting myelin components like MOG and AQP4, which activate complement cascades leading to further myelin destruction. The article discusses how compromised BBB integrity allows immune cells and inflammatory mediators to infiltrate the CNS, intensifying MS symptoms. It also examines the involvement of astrocytes, microglia, and oligodendrocytes in the disease's progression. Additionally, the effectiveness of immunomodulatory drugs such as IFN-β and CD20-targeting monoclonal antibodies (e.g., rituximab) in modulating immune responses is reviewed, highlighting their potential to reduce relapse rates and delaying MS progression. These insights emphasize the importance of immune system dysfunction in MS development and progression, guiding the development of new therapeutic strategies. The study underscores recent advancements in understanding MS's molecular pathways, opening avenues for more targeted and effective treatments., (Copyright © 2024 IBRO. Published by Elsevier Inc. All rights reserved.)

Chronic inflammation drives the growth of colorectal cancer through the dysregulation of molecular pathways within the immune system. Infiltration of immune cells, such as macrophages, into tumoral regions results in the release of proinflammatory cytokines (IL-6; IL-17; TNF-α), fostering tumor proliferation, survival, and invasion. Tumors employ various mechanisms to evade immune surveillance, effectively 'cloaking' themselves from detection and subsequent attack. A comprehensive understanding of these intricate molecular interactions is paramount for advancing novel strategies aimed at modulating the immune response against cancer.

Ten-eleven translocation (TET) proteins are iron-dependent and α-ketoglutarate-dependent dioxygenases that sequentially oxidize the methyl group of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). All three epigenetic modifications are intermediates in DNA demethylation. TET proteins are recruited by transcription factors and by RNA polymerase II to modify 5mC at enhancers and gene bodies, thereby regulating gene expression during development, cell lineage specification, and cell activation. It is not yet clear, however, how the established biochemical activities of TET enzymes in oxidizing 5mC and mediating DNA demethylation relate to the known association of TET deficiency with inflammation, clonal hematopoiesis, and cancer. There are hints that the ability of TET deficiency to promote cell proliferation in a signal-dependent manner may be harnessed for cancer immunotherapy. In this review, we draw upon recent findings in cells of the immune system to illustrate established as well as emerging ideas of how TET proteins influence cellular function.

The immune system plays a key role in gastrointestinal (GI) pathologies, being responsible for protecting the body against infection, maintaining homeostasis, and regulating the inflammatory response in the GI tract [...].

Maternal obesity and over/undernutrition can have a long-lasting impact on offspring health during critical periods in the first 1000 days of life. Children born to mothers with obesity have reduced immune responses to stimuli which increase susceptibility to infections. Recently, maternal western-style diets (WSDs), high in fat and simple sugars, have been associated with skewing neonatal immune cell development, and recent evidence suggests that dysregulation of innate immunity in early life has long-term consequences on metabolic diseases and behavioral disorders in later life. Several factors contribute to abnormal innate immune tolerance or trained immunity, including changes in gut microbiota, metabolites, and epigenetic modifications. Critical knowledge gaps remain regarding the mechanisms whereby these factors impact fetal and postnatal immune cell development, especially in precursor stem cells in bone marrow and fetal liver. Components of the maternal microbiota that are transferred from mothers consuming a WSD to their offspring are understudied and identifying cause and effect on neonatal innate and adaptive immune development needs to be refined. Tools including single-cell RNA-sequencing, epigenetic analysis, and spatial location of specific immune cells in liver and bone marrow are critical for understanding immune system programming. Considering the vital role immune function plays in offspring health, it will be important to understand how maternal diets can control developmental programming of innate and adaptive immunity.

Dysregulation of the immune system in individuals with Down syndrome is thought to play a major role in the pathophysiology of many clinical presentations. This natural history of disease study took a comprehensive evaluation of the prevalence of different immune related diagnoses in a cohort of 1299 patients with Down syndrome compared to a 2605 patient control cohort at the Mount Sinai Health System in New York, NY over the past 18 years. We conducted a stepwise analysis of the odds of receiving a diagnosis at the Chapter, Sub-chapter and Diagnosis level of the ICD-CM-10 code system. Individuals in our Down syndrome cohort had higher odds of a diagnosis with inflammatory and autoimmune presentations such as Alopecia areata (OR 6.06, p = 0.01), Other sepsis (OR 4.79, p < 0.001, Purpura and other hemorrhagic conditions (OR 2.31, p < 0.001), and Rosacea (OR 3.11, p < 0.001). They also presented with lower odds of a diagnosis of Herpesviral infection (OR 0.42, p = 0.01), and Viral warts (OR 0.51, p = 0.04). We posit that dysregulation of the immune system in individuals with Down syndrome has impact on infectious diseases, including lowering the incidence of viral disease and increasing its severity. Our data also suggests inflammation and autoimmune mediated diseases, in particular of the skin, are exacerbated in individuals with Down syndrome. Finally, there may be a need for greater clinical attention to non-emergent conditions within the Down syndrome patient population as those can also greatly affect quality of life., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The rise of immunotherapy and mRNA vaccines has underscored the power of modulating the immune system for a desired response. In this Voices piece, the Cell Chemical Biology editors ask researchers from a range of backgrounds: what are some major challenges and opportunities facing the field in coming years?, Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

Excessive fluoride intake from residential environments may affect multiple tissues and organs; however, the specific pathogenic mechanisms are unclear. Researchers have recently focused on the damaging effects of fluoride on the immune system. Damage to immune function seriously affects the quality of life of fluoride-exposed populations and increases the incidence of infections and malignant tumors. Probing the mechanism of damage to immune function caused by fluoride helps identify effective drugs and methods to prevent and treat fluorosis and improve people's living standards in fluorosis-affected areas. Here, the recent literature on the effects of fluoride on the immune system is reviewed, and research on fluoride damage to the immune system is summarized in terms of three perspectives: immune organs, immune cells, and immune-active substances. We reviewed that excessive fluoride can damage immune organs, lead to immune cells dysfunction and interfere with the expression of immune-active substances. This review aimed to provide a potential direction for future fluorosis research from the perspective of fluoride-induced immune function impairment. In order to seek the key regulatory indicators of fluoride on immune homeostasis in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhu and Wei.)

Mutations in the gene for β-catenin cause liver cancer cells to release fewer exosomes, which reduces the number of immune cells infiltrating the tumor., Competing Interests: SS No competing interests declared, (© 2024, Schmieder.)

Objectives: This manuscript undertakes a systematic examination of the research landscape concerning global Cryptococcus species and their dynamism with the host immune system spanning the past decade. It furnishes a detailed survey of leading knowledge institutions and critical focal points in this area, utilizing bibliometric analysis., Methods: VOSviewer and CiteSpace software platforms were employed to systematically analyze and graphically depict the relevant literature indexed in the WoSCC database over the preceding ten years., Results: In the interval between October 1, 2013, and October 1, 2023, a corpus of 795 publications was amassed. The primary research institutions involved in this study include Duke University, the University of Minnesota, and the University of Sydney. The leading trio of nations, in terms of publication volume, comprises the United States, China, and Brazil. Among the most prolific authors are Casadevall, Arturo; Wormley, Floyd L., Jr.; and Olszewski, Michal A., with the most highly cited author being Perfect, Jr. The most esteemed journal is Mbio, while Infection and Immunity commands the highest citation frequency, and the Journal of Clinical Microbiology boasts the most significant impact factor. Present research foci encompass the intricate interactions between Cryptococcus pathogenesis and host immunity, alongside immune mechanisms, complications, and immunotherapies., Conclusion: This represents the first exhaustive scholarly review and bibliometric scrutiny of the evolving landscapes in Cryptococcus research and its interactions with the host immune system. The analyses delineated herein provide insights into prevailing research foci and trajectories, thus furnishing critical directions for subsequent inquiries in this domain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tang, Hao, Liu, He, Tian, Jing, Liu, Xu and Li.)