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In this paper, a mathematical model is developed to simulate the activation of regulatory T lymphocytes dynamics. The model considers the adaptive immune response and consists of epithelial cells, infected cells, free virus particles, helper and cytotoxic T lymphocytes, B lymphocytes, and regulatory T lymphocytes. A mathematical analysis was carried out to discuss the conditions of existence and stability of equilibrium solutions in terms of the basic reproductive number. In addition, the definitions and properties necessary to preserve the positivity and stability of the model are shown. The precision of these mathematical models can be affected by numerous sources of uncertainty, partly due to the balance between the complexity of the model and its predictive capacity to depict the biological process accurately. Nevertheless, these models can provide remarkably perspectives on the dynamics of infection and assist in identification specific immunological traits that improve our comprehension of immune mechanisms. The theoretical results are validated by numerical simulations using data reported in the literature. The construction, analysis, and simulation of the developed models demonstrate that the increased induced regulatory T lymphocytes effectively suppress the inflammatory response in contrast to similar cells at lower contents, playing a key role in maintaining self-tolerance and immune homeostasis. [ABSTRACT FROM AUTHOR]

The 80+ existing autoimmune disorders (ADs) affect billions with little prevention or treatment options, except for temporary symptomatic management, leading to enormous human suffering and a monumental financial burden. The autoantibodies formed in most ADs have been identified, allowing the development of novel anti-idiotypic antibodies to mute the autoantibodies using vaccines. Nucleoside vaccines have been successfully tested as antigen-specific immunotherapies (ASI), with mRNA technology offering multi-epitope targeting to mute multiple autoantibodies. This paper proposes using mRNA technology to produce anti-idiotypic antibodies with broad effectiveness in preventing and treating them. This paper delves into the state-of-the-art mRNA design strategies used to develop novel ASIs by selecting appropriate T cell and B cell epitopes to generate anti-idiotypic antibodies. The low cost and fast development of mRNA vaccines make this technology the most affordable for the global control of ADs. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) is a common malignant tumour. Despite advancements in surgery, radiotherapy and chemotherapy, which have improved the prognosis of most patients, a subset of patients with poor prognoses still exist due to loss of surgical opportunities, postoperative recurrence, and metastasis, among other reasons. The tumour microenvironment (TME) is a complex organization composed of tumour, stromal, and endothelial cells. Communication and interaction between tumours and immune cells within the TME are increasingly being recognized as pivotal in inhibiting or promoting tumour development. Previous studies on T cells in the TME of HNSCC have yielded novel therapeutic possibilities. However, the function of B cells, another adaptive immune cell type, in the TME of HNSCC patients has yet to be determined. Recent studies have revealed various distinct subtypes of B cells and tertiary lymphoid structures (TLSs) in the TME of HNSCC patients, which are believed to impact the efficacy of immune checkpoint inhibitors (ICIs). Therefore, this paper focuses on B cells in the TME to explore potential directions for future immunotherapy for HNSCC. [ABSTRACT FROM AUTHOR]

Helminths are multicellular parasites that are a substantial problem for both human and veterinary medicine. According to estimates, 1.5 billion people suffer from their infection, resulting in decreased life quality and burdens for healthcare systems. On the other hand, these infections may alleviate autoimmune diseases and allergy symptoms. The immune system is programmed to combat infections; nevertheless, its effector mechanisms may result in immunopathologies and exacerbate clinical symptoms. This review summarizes the role of the immune response against worms, with an emphasis on the Th2 response, which is a hallmark of helminth infections. We characterize non-immune cells (enteric tuft cells—ETCs) responsible for detecting parasites, as well as the role of hematopoietic-derived cells (macrophages, basophils, eosinophils, neutrophils, innate lymphoid cells group 2—ILC2s, mast cells, T cells, and B cells) in initiating and sustaining the immune response, as well as the functions they play in granulomas. The aim of this paper is to review the existing knowledge regarding the immune response against helminths, to attempt to decipher the interactions between cells engaged in the response, and to indicate the gaps in the current knowledge. [ABSTRACT FROM AUTHOR]

Simple Summary: This article addresses the topic of primary immunodeficiencies, with particular emphasis on antibody deficiencies with near-normal immunoglobulin levels or hyperimmunoglobulinemia. This paper goes beyond genetics and emphasizes the importance of the immune system and particularly immune checkpoints and Epstein–Barr virus (EBV) reactivation in the context of these disorders. The article delves into the immune dysregulations occurring in the course of this type of disease and the potential role of EBV reactivation, which affects the clinical picture of patients and, in the future, may contribute to the development of cancer, especially those related to hematological malignancies. Disturbances observed in the immunopathogenesis of the presented diseases go beyond the accepted scheme, with the development of PID largely associated only with genetic disorders, and the article emphasizes that the regulation of immunity and virus reactivation also contributes to the progression of PID. This study delves into the intricate landscape of primary immunodeficiencies, with a particular focus on antibody deficiencies characterized by near-normal immunoglobulin levels or hyperimmunoglobulinemia. Contrary to the conventional focus on genetic dysregulation, these studies investigate the key roles of immune checkpoints, such as PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200, on selected subpopulations of T and B lymphocytes and their serum concentrations of soluble forms in patients recruited for the studies in healthy volunteers. In addition, the studies also show the role of Epstein–Barr virus (EBV) reactivation and interactions with tested pathways of immune checkpoints involved in the immunopathogenesis of this disease. By examining the context of antibody deficiencies, this study sheds light on the nuanced interplay of factors beyond genetics, particularly the immune dysregulations that occur in the course of this type of disease and the potential role of EBV reactivation, which affects the clinical presentation of patients and may contribute to the development of cancer in the future, especially related to hematological malignancies. [ABSTRACT FROM AUTHOR]

Astragaloside IV (AS-IV) is one of the main active components extracted from the Chinese medicinal herb Astragali and serves as a marker for assessing the herb's quality. AS-IV is a tetracyclic triterpenoid saponin in the form of lanolin ester alcohol and exhibits various biological activities. This review article summarizes the chemical structure of AS-IV, its pharmacological effects, mechanism of action, applications, future prospects, potential weaknesses, and other unexplored biological activities, aiming at an overall analysis. Papers were retrieved from online electronic databases, such as PubMed, Web of Science, and CNKI, and data from studies conducted over the last 10 years on the pharmacological effects of AS—IV as well as its impact were collated. This review focuses on the pharmacological action of AS-IV, such as its anti-inflammatory effect, including suppressing inflammatory factors, increasing T and B lymphocyte proliferation, and inhibiting neutrophil adhesion-associated molecules; antioxidative stress, including scavenging reactive oxygen species, cellular scorching, and regulating mitochondrial gene mutations; neuroprotective effects, antifibrotic effects, and antitumor effects. [ABSTRACT FROM AUTHOR]

It is very important to understand the communication and interaction mechanisms between the host and its resident microorganisms on host physiology and for precise diagnosis and treatment. Although intestinal fungi and bacteria dysbiosis is increasingly linked to ankylosing spondylitis (AS), their mechanisms of action have been rarely illustrated. In this paper, fecal samples from 10 AS monkeys and 10 healthy controls were collected to systematically characterize the gut mycobiota and microbiota in AS monkeys by 16S rRNA and ITS2 DNA sequencing. Our results showed the gut fungi of Kazachstania pintolopesii, Saccharomycetaceae, Kazachstania, and Saccharomyceteles. Saccharomycetes were specially enriched in AS, and the microbiota of AS monkeys was characterized by an increased abundance of Clostridia, Clostridiales, Ruminococcaceae, and Prevotella 2, using Line Discriminant Analysis Effect Size. Compared to healthy controls, decreased ITS2/16S biodiversity ratios and altered bacterial--fungal interkingdom networks were observed in AS monkeys. Oral administration of K. pintolopesii activates IL-17RA pathway and induce inflammatory reaction in the colonic tissue of C57BL/6 mice, as well as multiple AS phenotypes, including fungal and bacterial dysbiosis, immune responses of NK cells, platelets, T cells, leukocytes, B-cell activation, rheumatoid arthritis, and inflammatory bowel disease. We also found the secreted products of K. pintolopesii could activate the IL-17RA pathway, which induces PANoptosis in macrophage RAW264.7 cells. Much worse, the PANoptosis products could promote the proliferation and morphological changes of K. pintolopesii, which resulted in much more K. pintolopesii and a severe inflammatory reaction. Interestingly, the inflammatory factor TNF-α can promote the morphological transformation of Candida albicans and K. pintolopesii, which is worthy of further study. The characteristic fungi in all these findings implied that fungal and bacterial dysbiosis have a close link to AS and that their communication and interaction indeed play an important role in autoimmune responses, and K. pintolopesii could be a potential marker microorganism in AS, although its specific mechanism is not fully elucidated. [ABSTRACT FROM AUTHOR]

This article, titled "Editorial: Pathogenic roles of T cells in autoimmunity," explores the role of T cells in autoimmune diseases. The immune system has mechanisms in place to prevent self-reactive T and B lymphocytes from causing autoimmune diseases, but these mechanisms are imperfect. Helper T cells, specifically CD4 T cells, play a crucial role in the development of autoimmune diseases. The article discusses the different subsets of helper T cells and their functions, as well as the potential for targeting pathogenic T cells in the treatment and prevention of autoimmune diseases. The research topic also includes papers on the pathogenic roles of T cells in specific autoimmune diseases such as vitiligo, idiopathic inflammatory myopathies, and primary Sjogren Syndrome. [Extracted from the article]

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ dysfunction resulting from the production of multiple autoantibodies and adaptive immune system abnormalities involving T and B lymphocytes. In recent years, inflammasomes have been recognized as an important component of innate immunity and have attracted increasing attention because of their pathogenic role in SLE. In short, inflammasomes regulate the abnormal differentiation of immune cells, modulate pathogenic autoantibodies, and participate in organ damage. However, due to the clinical heterogeneity of SLE, the pathogenic roles of inflammasomes are variable, and thus, the efficacy of inflammasome-targeting therapies is uncertain. To provide a foundation for the development of such therapeutic strategies, in this paper, we review the role of different inflammasomes in the pathogenesis of SLE and their correlation with clinical phenotypes and propose some corresponding treatment strategies. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR)-expressing T-cells are without a doubt a breakthrough therapy for hematological malignancies. Despite their success, clinical experience has revealed several challenges, which include relapse after targeting single antigens such as CD19 in the case of B-cell acute lymphoblastic leukemia (B-ALL), and the occurrence of side effects that could be severe in some cases. Therefore, it became clear that improved safety approaches, and targeting multiple antigens, should be considered to further improve CAR T-cell therapy for B-ALL. In this paper, we address both issues by investigating the use of CD10 as a therapeutic target for B-ALL with our switchable UniCAR system. The UniCAR platform is a modular platform that depends on the presence of two elements to function. These include UniCAR T-cells and the target modules (TMs), which cross-link the T-cells to their respective targets on tumor cells. The TMs function as keys that control the switchability of UniCAR T-cells. Here, we demonstrate that UniCAR T-cells, armed with anti-CD10 TM, can efficiently kill B-ALL cell lines, as well as patient-derived B-ALL blasts, thereby highlighting the exciting possibility for using CD10 as an emerging therapeutic target for B-cell malignancies. [ABSTRACT FROM AUTHOR]

This study described the interactions of different nutritional components with the immune system. A detailed search was carried out on Google Scholar and PubMed databases to find out the relevant research studies using different keywords, such as "Nutrients", "Micronutrients", and "Immune system and micronutrients". Only those papers that discussed the interactions between nutrients and the components of the immune system were included in the study. This research outlined the impact of different vitamins, trace elements or metals, amino acids, and fatty acids on different immune system components. It was found that vitamins, such as vitamin A, D, and C, tend to help immune cell differentiation and enhance the expression of different cytokines. Vitamins also contribute to the proliferation of T and B cells and impact the production of white blood cells. Similarly, trace elements or metals act as enzyme cofactors and control different immune response cycles by controlling the expression of cytokines, chemokines, and other signaling molecules. Moreover, different essential and non-essential amino acids play important roles in immune system development as they are primarily involved in protein synthesis. Amino acids, such as arginine, glutamine, and alanine, modulate the expression of cytokines and also control the migration and transmigration capabilities of macrophages. They also enhance the phagocytic properties of macrophages and neutrophils. In a similar way, fatty acids act as anti-inflammatory agents since they can decrease the expression of major histocompatibility complex class I (MHC-I) and MHCII. Furthermore, they inhibit the secretion of different inflammatory cytokines. In conclusion, all the components of our daily diet are associated with the development of the immune system, and understanding their interactions is important for future immune therapies and drug development. [ABSTRACT FROM AUTHOR]

The spleen is a complex secondary lymphoid organ that plays a crucial role in controlling blood‐stage infection with Plasmodium parasites. It is tasked with sensing and removing parasitized RBCs, erythropoiesis, the activation and differentiation of adaptive immune cells, and the development of protective immunity, all in the face of an intense inflammatory environment. This paper describes how these processes are regulated following infection and recognizes the gaps in our current knowledge, highlighting recent insights from human infections and mouse models. [ABSTRACT FROM AUTHOR]

An interesting inference drawn by some COVID-19 epidemiological models is that there exists a proportion of the population who are not susceptible to infection—even at the start of the current pandemic. This paper introduces a model of the immune response to a virus. This is based upon the same sort of mean-field dynamics as used in epidemiology. However, in place of the location, clinical status, and other attributes of people in an epidemiological model, we consider the state of a virus, B and T-lymphocytes, and the antibodies they generate. Our aim is to formalise some key hypotheses as to the mechanism of resistance. We present a series of simple simulations illustrating changes to the dynamics of the immune response under these hypotheses. These include attenuated viral cell entry, pre-existing cross-reactive humoral (antibody-mediated) immunity, and enhanced T-cell dependent immunity. Finally, we illustrate the potential application of this sort of model by illustrating variational inversion (using simulated data) of this model to illustrate its use in testing hypotheses. In principle, this furnishes a fast and efficient immunological assay—based on sequential serology—that provides a (1) quantitative measure of latent immunological responses and (2) a Bayes optimal classification of the different kinds of immunological response (c.f., glucose tolerance tests used to test for insulin resistance). This may be especially useful in assessing SARS-CoV-2 vaccines. [ABSTRACT FROM AUTHOR]

Introduction: Richter Syndrome (RS) is defined as the development of an aggressive lymphoma in the context of Chronic Lymphocytic Leukemia (CLL), with a Diffuse Large B-Cell Lymphoma (DLBCL) histology in 95% cases. RS genomic landscape shares only a few features with de novo DLBCLs and is marked by a wide spectrum of cytogenetic abnormalities. Little is known about RS microenvironment. Therapeutic options and efficacy are limited, leading to a 12 months median overall survival. The new targeted treatments usually effective in CLL fail to obtain long-term remissions in RS. Methods: We reviewed available PubMed literature about RS genomics, PD-1/PD-L1 (Programmed Death 1/Programmed Death Ligand 1) pathway triggering and subsequent new therapeutic options. Results: Data from about 207 patients from four landmark papers were compiled to build an overview of RS genomic lesions and point mutations. A number of these abnormalities may be involved in tumor microenvironment reshaping. T lymphocyte exhaustion through PD-L1 overexpression by tumor cells and subsequent PD-1/PD-L1 pathway triggering is frequently reported in solid cancers. This immune checkpoint inhibitor is also described in B lymphoid malignancies, particularly CLL: PD-1 expression is reported in a subset of prolymphocytes from the CLL lymph node proliferation centers. However, there is only few data about PD-1/PD-L1 pathway in RS. In RS, PD-1 expression is a hallmark of recently described « Regulatory B-cells », which interact with tumor microenvironment by producing inhibiting cytokines such as TGF-β and IL-10, impairing T lymphocytes anti-tumoral function. Based upon the discovery of high PD-1 expression on tumoral B lymphocyte from RS, immune checkpoint blockade therapies such as anti-PD-1 antibodies have been tested on small RS cohorts and provided heterogeneous but encouraging results. Conclusion: RS genetic landscape and immune evasion mechanisms are being progressively unraveled. New protocols using targeted treatments such as checkpoint inhibitors as single agents or in combination with immunochemotherapy are currently being evaluated. [ABSTRACT FROM AUTHOR]

Tofactinib is a JAK inhibitor approved for ulcerative colitis in humans. Despite of its' proven effectiveness in humans, mechanistic data are scarce on the effectiveness of Tofactinib in experimental colitis in mice. We induced experimental colitis by transfer of CD4+CD25− isolated T cells into RAG2−/− (T and B cell deficient) mice and treated these mice with tofacitinib for 5–6 weeks either with a dosage of 10 or 40 mg/kg body weight immediately after CD4+ transfer or started treatment after first symptoms of disease for several weeks. While treatment with tofacitinib immediately after transfer resulted in an enhanced expansion of CD4+ T cells and did not prevent occurrence of colitis, treatment after start of symptoms of colitis ameliorated disease activity on a clinical basis and in histological analyses. Tofacitinib is effective in the treatment of murine experimental T cell transfer colitis, however does not prevent occurrence of disease. [ABSTRACT FROM AUTHOR]

As the amount of biomedical information available in the literature continues to increase, databases that aggregate this information continue to grow in importance and scope. The population of databases can occur either through fully automated text mining approaches or through manual curation by human subject experts. We here report our experiences in populating the National Institute of Allergy and Infectious Diseases sponsored Immune Epitope Database and Analysis Resource ( IEDB, http://iedb.org), which was created in 2003, and as of 2012 captures the epitope information from approximately 99% of all papers published to date that describe immune epitopes (with the exception of cancer and HIV data). This was achieved using a hybrid model based on automated document categorization and extensive human expert involvement. This task required automated scanning of over 22 million PubMed abstracts followed by classification and curation of over 13 000 references, including over 7000 infectious disease-related manuscripts, over 1000 allergy-related manuscripts, roughly 4000 related to autoimmunity, and 1000 transplant/alloantigen-related manuscripts. The IEDB curation involves an unprecedented level of detail, capturing for each paper the actual experiments performed for each different epitope structure. Key to enabling this process was the extensive use of ontologies to ensure rigorous and consistent data representation as well as interoperability with other bioinformatics resources, including the Protein Data Bank, Chemical Entities of Biological Interest, and the NIAID Bioinformatics Resource Centers. A growing fraction of the IEDB data derives from direct submissions by research groups engaged in epitope discovery, and is being facilitated by the implementation of novel data submission tools. The present explosion of information contained in biological databases demands effective query and display capabilities to optimize the user experience. Accordingly, the development of original ways to query the database, on the basis of ontologically driven hierarchical trees, and display of epitope data in aggregate in a biologically intuitive yet rigorous fashion is now at the forefront of the IEDB efforts. We also highlight advances made in the realm of epitope analysis and predictive tools available in the IEDB. [ABSTRACT FROM AUTHOR]

The occurrence and development of tumors are closely associated with abnormalities in the immune system's structure and function, with tumor immunotherapy being intricately linked to the tumor microenvironment (TME). Early studies on lymphocytes within the TME primarily concentrated on T cells. However, as research has advanced, the multifaceted roles of tumor-infiltrating B cells (TIL-Bs) in tumor immunity, encompassing both anti-tumor and pro-tumor effects, have garnered increasing attention. This paper explored the composition of the TME and the biological characteristics of TIL-Bs, investigating the dual roles within the TME to offer new insights and strategies for tumor immunotherapy. [Display omitted] • Dual roles of tumor-infiltrating B cells in tumor microenvironment: anti-tumor and pro-tumor effects. • Tumor-infiltrating B cells boost anti-tumor immunity via antigen presentation, antibody production, cytokine secretion, etc. • Regulatory B cells aid tumor immune evasion by releasing suppressive cytokines, specific antibodies, and metabolites. • Insights into Tumor-infiltrating B cells may offer potential new targets for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Long COVID occurs in a small but important minority of patients following COVID-19, reducing quality of life and contributing to healthcare burden. Although research into underlying mechanisms is evolving, immunity is understudied. SARS-CoV-2-specific T cell responses are of key importance for viral clearance and COVID-19 recovery. However, in long COVID, the establishment and persistence of SARS-CoV-2-specific T cells are far from clear, especially beyond 12 mo postinfection and postvaccination. We defined ex vivo antigen-specific B cell and T cell responses and their T cell receptors (TCR) repertoires across 2 y postinfection in people with long COVID. Using 13 SARS-CoV-2 peptide-HLA tetramers, spanning 11 HLA allotypes, as well as spike and nucleocapsid probes, we tracked SARS-CoV-2-specific CD8+ and CD4+ T cells and B-cells in individuals from their first SARS-CoV-2 infection through primary vaccination over 24 mo. The frequencies of ORF1a-and nucleocapsid-specific T cells and B cells remained stable over 24 mo. Spike-specific CD8+ and CD4+ T cells and B cells were boosted by SARS-CoV-2 vaccination, indicating immunization, in fully recovered and people with long COVID, altered the immunodominance hierarchy of SARS-CoV-2 T cell epitopes. Meanwhile, influenza-specific CD8+ T cells were stable across 24 mo, suggesting no bystander-activation. Compared to total T cell populations, SARS-CoV-2-specific T cells were enriched for central memory phenotype, although the proportion of central memory T cells decreased following acute illness. Importantly, TCR repertoire composition was maintained throughout long COVID, including postvaccination, to 2 y postinfection. Overall, we defined ex vivo SARS-CoV-2-specific B cells and T cells to understand primary and recall responses, providing key insights into antigen-specific responses in people with long COVID. [ABSTRACT FROM AUTHOR]

Introduction: Leprosy is a chronic infectious condition and the main cause of neuropathy that occurs brought on by M. leprae. It is known that the biological characteristics of the human host, such as the immunological ones, have a higher influence on the pathology of this disease than the intrinsic mechanisms of the bacterium. The objective of this work was to review the scientific knowledge about the relationship between immunopathology and the severity of leprosy. Methods: A systematic review following the PRISMA 2020 recommendations was conducted in the PUBMED, LILACS, SciELO and Science Direct databases using articles in English, Portuguese or Spanish between January 2011 and May 2022 with the descriptors "Leprosy/Immunology", "Cytokines" and "Mycobacterium leprae". A methodological quality assessment was carried out using the JBI checklists. Results: A total of 49 articles were included. There is a relationship of greater severity of infection associated with lower release of MHC molecules in response to PGL-1 that inhibit the promotion of resolving T lymphocytes arising from dendritic cells (DCs) stimulation. In addition, the differentiation of macrophage phenotypes dependent on the activation of PRRs can define activation and the distinct type of T helper (Th) cells involved according to severity. Activated CD8+ T cells also have distinct types at the appropriate poles of the disease, and B cells show at the most severe pole of the LL, specific induction of IgA and more Treg-type CD8+ T cells that further contribute to T cell anergy. Conclusion: Therefore, the adaptive immune system aggravates nerve damage and defines the type of leprosy, while the innate immune system is considerably more significant in the onset of nerve damage, symptomatic of the initial presentation of illness and in several critical immune responses, including inflammation and elimination of dead M. leprae. [ABSTRACT FROM AUTHOR]

Background: Lymphocytes play a key role in the pathogenesis of inflammatory bowel disease (IBD) and are widely explored as promising prognostic indicators. We aimed to outline the existing evidences on the capability of lymphocyte subpopulations to predict disease progression and treatment response in patients with IBD. Methods: The protocol for this review was registered in PROSPERO (registration ID: CRD 42022364126). Systematic retrieval was conducted using PubMed, Embase, and Web of Science databases. Original articles on the prognostic value of lymphocyte subsets in IBD published up to April 8, 2023 were eligible for inclusion. The Newcastle–Ottawa Scale was used to evaluate the risk of bias. Results: Twenty studies were ultimately included: eight evaluated the prediction of disease progression and 12 focused on the prediction of treatment response. According to the Newcastle–Ottawa Scale, three studies were of high quality, 16 were of moderate quality, and only one was of low quality. T-cell subpopulations, including CD4+ T cells, CD8+ T cells, and gd T cells, are revealed to have prognostic capacity. Transmembrane tumor necrosis factor a-bearing lymphocytes, CD4+ T cells, CD8+ T cells, and Plasma cells are found to have the potential to predict the response to anti-TNFα agents. In contrast memory T cells, CD4+ T cells, and naïve B cells may predict the response to vedolizumab. Conclusions: This systematic review identified several potential lymphocyte subset-related predictors. If verified in large cohort prospective studies, these findings could aid clinical decision-making. [ABSTRACT FROM AUTHOR]

Psoriasis, an immune-mediated inflammatory skin disorder, seriously affects the quality of life of nearly four percent of the world population. Euphorbia helioscopia L. is the monarch constituent of Chinese ZeQi powder preparation for psoriasis, so it is necessary to illustrate its active ingredients. Thus, twenty-three diterpenoids, including seven new ones, were isolated from the whole herb of E. helioscopia L. Compounds 1 and 2, each featuring a 2,3-dicarboxylic functionality, are the first examples in the ent-2,3-sceo-atisane or the ent-2,3-sceo-abietane family. Extensive spectroscopic analysis (1D, 2D NMR, and HRMS data) and computational methods were used to confirm their structures and absolute configurations. According to the previous study and NMR data from the jatropha diterpenes obtained in this study, some efficient 1H NMR spectroscopic rules for assigning the relative configurations of 3α-benzyloxy-jatroph-11E-ene and 7,8-seco-3α-benzyloxy-jatropha-11E-ene were summarized. Moreover, the hyperproliferation of T cells and keratinocytes is considered a key pathophysiology of psoriasis. Anti-proliferative activities against induced T/B lymphocytes and HaCaT cells were tested, and IC50 values of some compounds ranged from 6.7 to 31.5 μM. Compounds 7 and 11 reduced the secretions of IFN-γ and IL-2 significantly. Further immunofluorescence experiments and a docking study with NF-κB P65 showed that compound 13 interfered with the proliferation of HaCaT cells by inhibiting the NF-κB P65 phosphorylation at the protein level. [ABSTRACT FROM AUTHOR]

Background: Immunoglobulin G subclass deficiencies (IgGsd) comprise a wide clinical spectrum from no symptoms to repeated respiratory infections and risk for the development of lung damage. Our aims were to investigate whether the immunological phenotype of IgGsd patients on and off immunoglobulin replacement therapy (IgRT) was reflected in the clinical features of IgGsd. Method: Thirty patients with IgGsd were included in this prospective study of 18 months of IgRT, followed by 7-18 months of IgRT discontinuation. Blood samples were collected when patients were on and off IgRT and compared with samples from 34 cross-sectional healthy controls. An in-depth lymphocyte phenotyping was performed by flow cytometry and plasma levels of immune checkpoints were assessed. Results: IgG3 subclass deficiency was most common. Patients with IgGsd had decreased levels of activated T cells and B cells and plasma levels of negative immune checkpoint molecules correlated negatively with T cell and B cell activation. The decreased T cell activation level was unaffected by IgRT, while the B cell activation was partly restored. Of note, decreased levels of activated regulatory T cells (Tregs) were found in IgGsd patients and was partly restored during IgRT. The profile of comorbidities did not associate with Treg levels. Discussion: IgGsd is associatedwith decreased B cell and T cell activation including Tregs, and increased plasma levels of negative immune checkpoint molecules. The consequence of reduced activated Tregs in IgGsd remains unclear. Decreased immune cell activation was partly restored during IgRT, demonstrating that IgRT may contribute to improved immune function in patients with IgGsd. [ABSTRACT FROM AUTHOR]

Foot and mouth disease (FMD) is a highly contagious infection caused by FMDvirus (FMDV) that affects livestock worldwide with significant economic impact. The main strategy for the control is vaccination with FMDV chemically inactivated with binary ethylenimine (FMDVi). In FMDV infection and vaccination, B cell response plays a major role by providing neutralizing/protective antibodies in animal models and natural hosts. Extracellular vesicles (EVs) and small EVs (sEVs) such as exosomes are important in cellular communication. EVs secreted by antigen-presenting cells (APC) like dendritic cells (DCs) participate in the activation of B and T cells through the presentation of native antigen membrane-associated to B cells or by transferring MHC-peptide complexes to T cells and even complete antigens from DCs. In this study, we demonstrate for the first time that APC activated with the FMDVi O1 Campos vaccine-antigens secrete EVs expressing viral proteins/peptides that could stimulate FMDV-specific immune response. The secretion of EVs-FMDVi is a time-dependent process and can only be isolated within the first 24 h post-activation. These vesicles express classical EVs markers (CD9, CD81, and CD63), along with immunoregulatory molecules (MHC-II and CD86). With an average size of 155 nm, they belong to the category of EVs. Studies conducted in vitro have demonstrated that EVs-FMDVi express antigens that can stimulate a specific B cell response against FMDV, including both marginal zone B cells (MZB) and follicular B cells (FoB). These vesicles can also indirectly or directly affect T cells, indicating that they express both B and T epitopes. Additionally, lymphocyte expansion induced by EVs-FMDVi is greater in splenocytes that have previously encountered viral antigens in vivo. The present study sheds light on the role of EVs derived fromAPC in regulating the adaptive immunity against FMDV. This novel insight contributes to our current understanding of the immune mechanisms triggered by APC during the antiviral immune response. Furthermore, these findings may have practical implications for the development of new vaccine platforms, providing a rational basis for the design of more effective vaccines against FMDV and other viral diseases. [ABSTRACT FROM AUTHOR]

The occurrence and progression of skin cutaneous melanoma (SKCM) is strongly associated with immune cells infiltrating the tumor microenvironment (TME). This study examined the expression, prognosis, and immune relevance of SIGLEC9 in SKCM using multiple online databases. Analysis of the GEPIA2 and Ualcan databases revealed that SIGLEC9 is highly expressed in SKCM, and patients with high SIGLEC9 expression had improved overall survival (OS). Furthermore, the mutation rate of SIGLEC9 in SKCM patients was found to be 5.41%, the highest observed. The expression of SIGLEC9 was positively correlated with macrophages, neutrophils and B cells, CD8 + T cells, CD4 + T cells, and dendritic cells, according to TIMER. Based on TCGA-SKCM data, we verified that high SIGLEC9 expression is closely associated with a good prognosis for SKCM patients, including overall survival, progression-free interval, and disease-specific survival. This positive prognosis could be due to the infiltration of immune cells into the TME. Additionally, our analysis of single-cell transcriptome data revealed that SIGLEC9 not only played a role in the normal skin immune microenvironment, but is also highly expressed in immune cell subpopulations of SKCM patients, regulating the immune response to tumors. Our findings suggest that the close association between SIGLEC9 and SKCM prognosis is primarily mediated by its effect on the tumor immune microenvironment. [ABSTRACT FROM AUTHOR]

Ligation of the B cell antigen receptor (BCR) initiates humoral immunity. However, BCR signaling without appropriate co-stimulation commits B cells to death rather than to differentiation into immune effector cells. How BCR activation depletes potentially autoreactive B cells while simultaneously primes for receiving rescue and differentiation signals from cognate T lymphocytes remains unknown. Here, we use a mass spectrometry-based proteomic approach to identify cytosolic/nuclear shuttling elements and uncover transcription factor EB (TFEB) as a central BCR-controlled rheostat that drives activation-induced apoptosis, and concurrently promotes the reception of co-stimulatory rescue signals by supporting B cell migration and antigen presentation. CD40 co-stimulation prevents TFEB-driven cell death, while enhancing and prolonging TFEB's nuclear residency, which hallmarks antigenic experience also of memory B cells. In mice, TFEB shapes the transcriptional landscape of germinal center B cells. Within the germinal center, TFEB facilitates the dark zone entry of light-zone-residing centrocytes through regulation of chemokine receptors and, by balancing the expression of Bcl-2/BH3-only family members, integrates antigen-induced apoptosis with T cell-provided CD40 survival signals. Thus, TFEB reprograms antigen-primed germinal center B cells for cell fate decisions. B cell receptor activation leads to contrary outcomes in the absence and presence of co-stimulation. Here, the authors show transcription factor EB acts as a B cell receptor-controlled rheostat that balances activation-induced cell death with co-stimulatory rescue signals, collectively reprograming antigen-primed germinal center B cells for fate decisions. [ABSTRACT FROM AUTHOR]

Introduction: Cannabidiol (CBD) exhibits neuroprotective, anti-inflammatory, and immunomodulatory properties, making it a promising candidate for addressing inflammatory skin disorders like atopic dermatitis. Aim: This study aimed to (i) investigate CBD's impact on lymphocyte proliferation and lymphocyte viability; (ii) assess in vitro cytotoxicity U937 cells (a human promonocytic cell line) of CBD/cytotoxicity of CBD on U937 cells; (iii) provide insights into CBD immunomodulatory potential, and (iv) evaluate suitability of CBD for treating inflammatory skin conditions. Material and methods: To this aim PBMCs from healthy donors were cultured with mitogen and two different CBD doses (0.1 and 1 mg/ml), assessing B and T cell proliferation through flow cytometry. CBD inhibited mitogen-induced lymphocyte proliferation, reducing the percentage of proliferating T and B cells. Notably, both CBD doses did not exhibit cytotoxicity on lymphocytes as revealed by viability assessment. We also analysed the effect of CBD on U937 cells using an optical microscopy approach. Interestingly, the higher dose of CBD exerted a cytotoxic effect on U937 cells, while the lower dose was well tolerated. Results: We analysed the effect of an adjuvant treatment for atopic dermatitis with a CBD-containing cleansing cream in reducing itch. Notably, the treatment with the CBD-containing cleansing cream significantly reduced itch in patients suffering from atopic dermatitis. Conclusions: These findings affirm CBD's immunomodulatory characteristics, emphasizing its potential therapeutic application in inflammatory skin disorders. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) patients have an increased risk of infections and infection-related mortality. Therefore, during the global SARS-CoV-2 pandemic, SLE patients were particularly vulnerable to SARS-CoV-2 infections. Also, compared to other patients, SLE patients seem to develop more severe manifestations of coronavirus disease 2019 (COVID-19), with higher rates of hospitalization, invasive ventilation requirements, or death. This study evaluated the immune parameters after SARS-CoV-2 infection in SLE patients. We analyzed subpopulations of peripheral blood cells collected from patients with renal manifestation of SLE (lupus nephritis, LN). LN patients were divided into two subgroups: those unexposed to SARS-CoV-2 (LN CoV-2(−)) and those who had confirmed COVID-19 (LN-CoV-2(+)) six months earlier. We analyzed basic subpopulations of T cells, B cells, monocytes, dendritic cells (DCs), and serum cytokines using flow cytometry. All collected data were compared to a healthy control group without SARS-CoV-2 infection in medical history. LN patients were characterized by a decreased percentage of helper T (Th) cells and an increased percentage of cytotoxic T (Tc) cells regardless of SARS-CoV-2 infection. LN CoV-2(+) patients had a higher percentage of regulatory T cells (Tregs) and plasmablasts (PBs) and a lower percentage of non-switched memory (NSM) B cells compared to LN CoV-2(−) patients or healthy controls (HC CoV-2(−)). LN patients had a higher percentage of total monocytes compared with HC CoV-2(−). LN CoV-2(+) patients had a higher percentage of classical and intermediate monocytes than LN CoV-2(−) patients and HC CoV-2(−). LN CoV-2(+) patients had higher serum IL-6 levels than HC CoV-2(−), while LN CoV-2(−) patients had higher levels of serum IL-10. LN patients are characterized by disturbances in the blood's basic immunological parameters. However, SARS-CoV-2 infection influences B-cell and monocyte compartments. [ABSTRACT FROM AUTHOR]

Steering system of intelligent vehicle is very difficult to execute precise control in driving due to many known and unknown disturbances. Therefore, design of steering algorithm has to be feasible for uncertain external interference, such as uneven pavement and horizontal wind, with automatic correction function for changes in the location of intelligent cars caused by road tilt and horizontal wind. As traditional PID control is impossible to meet the control requirements, according to mechanism of biological immunity, an immune feedback control method was proposed to approximate nonlinearity of T and B cells by BP network. Joint simulations of serpentine condition were carried out by Carsim and Simulink. The results show that trajectory tracking error, operating load, risk of rollover and slip and control stability of control system are synthetically evaluated. The comprehensive evaluation index of automatic steering algorithm under high speed operation is fairly advantageous. Experimental results also show that the algorithm effectively realizes tracking of intelligent vehicle for marking lines and avoidance of obstacles. [ABSTRACT FROM AUTHOR]

Background: Amavata is a chronic immune-inflammatory systemic disorder caused by the formation of Ama and its association with Vata at Kaphasthana (joints) and can be simulated with rheumatoid arthritis (RA). Published evidences show that treatment indicated in Amavata is effective in RA. Increased inflammatory status in RA is suggestive of gut dysbiosis involving gut microbiota (GM). Aim: The aim of the present study was to analyze the influence of diet on GM of RA patients based on Pathya (dietary advice) mentioned for Amavata. Materials and Methods: Laghutrayis such as Bhavaprakasha Samhita, Madhava Nidana and Sharangadhara Samhita, Bhaishajya Ratnavali and Nighantus (Sanskrit glossary) such as Raja Nighantu, Bhavaprakasha Nighantu and Yogaratnakara, Ashtanga Hridaya also different databases were reviewed for Pathya of Amavata. Different databases such as PubMed, Scopus, DHARA, Google Scholar, Science Direct were searched with research papers establishing the role of nonnutritive bioactive components in horse gram, barley, garlic, ginger, drumstick leaves, cow urine and buttermilk in the management of RA were also reviewed. It was found that Pathya influences on the GM by lowering or inhibiting inflammatory markers such as interleukin-6 (IL-6), 17 and leukotrines through Bowman-Birk inhibitors and polyphenolic compounds. Among them, Takra is already a proven probiotic. Gomutra augments B and T lymphocytes, IL-1 and IL-2, strengthening the immune system. Conclusion: It was concluded that Pathya Ahara mentioned for Amavata have a direct link with GM of RA patients. Even though the pharmacological actions have been clinically proven/practised, this review creates evidence for its scientific basis. [ABSTRACT FROM AUTHOR]

Atlantic Cod (Gadus morhua) has lost the major histocompatibility complex class II presentation pathway. We recently identified CD8-positive T cells, B cells, and plasma cells in cod, but further characterisation of lymphocyte subsets is needed to elucidate immune adaptations triggered by the absence of CD4-positive T lymphocytes. Here, we use single-cell RNA sequencing to examine the lymphocyte heterogeneity in Atlantic cod spleen. We describe five T cell subsets and eight B cell subsets and propose a B cell trajectory of differentiation. Notably, we identify a subpopulation of T cells that are CD8-negative. Most of the CD8-negative T lymphocytes highly express the homologue of monocyte chemotactic protein 1b, and another subset of CD8-negative T lymphocytes express the homologue of the scavenger receptor m130. Uncovering the multiple lymphocyte cell sub-clusters reveals the different immune states present within the B and T cell populations, building a foundation for further work. Single-cell sequencing of naïve and vaccinated Atlantic Cod uncovers multiple B and T lymphocyte subsets including a subset of T lymphocytes expressing neither CD4 or CD8 and reveals different immune states present within B and T cell populations. [ABSTRACT FROM AUTHOR]

Abnormalities in glucose metabolism that precede the onset of type 2 diabetes (T2D) activate immune cells, leading to elevated inflammatory factors and chronic inflammation. However, no single-cell RNA sequencing (scRNA-seq) studies have characterized the properties and networks of individual immune cells in T2D. Here, we analyzed peripheral blood mononuclear cells (PBMCs) from non-diabetes and T2D patients by scRNA-seq. We found that CD14 monocytes in T2D patients were in a pro-inflammatory state and intermediate monocytes expressed more MHC class II genes. In T2D patients, cytotoxic CD4 T cells, effector memory CD8 T cells, and gd T cells have increased cytotoxicity and clonal expansion. B cells were characterized by increased differentiation into intermediate B cells, plasma cells, and isotype class switching with increased expression of soluble antibody genes. These results suggest that monocytes, T cells, and B cells could interact to induce chronic inflammation in T2D patients with pro-inflammatory characteristics. [ABSTRACT FROM AUTHOR]

The study explored the role of circadian rhythm genes (CRGs) in lower grade glioma (LGG) development and found that certain genes, such as CRY1, NPAS2, and RORB, were associated with increased or decreased risk of LGG. The study also investigated the correlation between CRGs and immune cell infiltration, revealing a negative association with macrophage infiltration and a positive correlation with B cell and CD8 + T cell infiltration. Additionally, the study identified major mutated CRGs, including PER2, BMAL1, CLOCK, and BMAL2, and their potential interaction with other CNS-associated genes. The study suggests that CRGs play a crucial role in immune response and tumorigenesis in LGG patients and warrants further investigation. [ABSTRACT FROM AUTHOR]

Elevated levels of miR-155 in solid and liquid malignancies correlate with aggressiveness of the disease. In this manuscript, we show that miR-155 targets transcripts encoding IcosL, the ligand for Inducible T-cell costimulator (Icos), thus impairing the ability of T cells to recognize and eliminate malignant cells. We specifically found that overexpression of miR-155 in B cells of Eµ-miR-155 mice causes loss of IcosL expression as they progress toward malignancy. Similarly, in mice where miR-155 expression is controlled by a Cre-Tet-OFF system, miR-155 induction led to malignant infiltrates lacking IcosL expression. Conversely, turning miR-155 OFF led to tumor regression and emergence of infiltrates composed of IcosL-positive B cells and Icos-positive T cells forming immunological synapses. Therefore, we next engineered malignant cells to express IcosL, in order to determine whether IcosL expression would increase tumor infiltration by cytotoxic T cells and reduce tumor progression. Indeed, overexpressing an IcosL-encoding cDNA in MC38 murine colon cancer cells before injection into syngeneic C57BL6 mice reduced tumor size and increased intratumor CD8+ T cell infiltration, that formed synapses with IcosL-expressing MC38 cells. Our results underscore the fact that by targeting IcosL transcripts, miR-155 impairs the infiltration of tumors by cytotoxic T cells, as well as the importance of IcosL on enhancing the immune response against malignant cells. These findings should lead to the development of more effective anticancer treatments based on maintaining, increasing, or restoring IcosL expression by malignant cells, along with impairing miR-155 activity. [ABSTRACT FROM AUTHOR]

Infection is the leading cause of death in multiple myeloma (MM). However, the cellular composition associated with immune dysfunction is not defined. We analyzed immune profiles in the peripheral blood of patients with MM (n = 28) and B-cell chronic lymphoproliferative disorders (n = 53) vs. health care practitioners (n = 96), using multidimensional and computational flow cytometry. MM patients displayed altered distribution of most cell types (41/56, 73%), particularly within the B-cell (17/17) and T-cell (20/30) compartments. Using COVID-19 as a case study, we compared the immune response to vaccination based on 64,304 data points generated from the analysis of 1099 longitudinal samples. MM patients showed limited B-cell expansion linked to lower anti-RBD and anti-S antibody titers after the first two doses and booster. The percentages of B cells and CD4+ T cells in the blood, as well as the absolute counts of B cells and dendritic cells, predicted vaccine immunogenicity at different time points. In contrast with the humoral response, the percentage and antigen-dependent differentiation of SARS-CoV-2-specific CD8+ T cells was not altered in MM patients. Taken together, this study defined the cellular composition associated with immune dysfunction in MM and provided biomarkers such as the B-cell percentage and absolute count to individualize vaccination calendars. [ABSTRACT FROM AUTHOR]

Background: High-risk human papillomavirus (HR-HPV) infection is an important factor for the development of cervical cancer. HPV18 is the second most common HR-HPV after HPV16. Methods: In this study, MEGA11 software was used to analyze the variation and phylogenetic tree of HPV18 E6-E7 and L1 genes. The selective pressure to E6, E7 and L1 genes was estimated using pamlX. In addition, the B cell epitopes of L1 amino acid sequences and T cell epitopes of E6-E7 amino acid sequences in HPV18 were predicted by ABCpred server and IEDB website, respectively. Results: A total of 9 single nucleotide variants were found in E6-E7 sequences, of which 2 were nonsynonymous variants and 7 were synonymous variants. Twenty single nucleotide variants were identified in L1 sequence, including 11 nonsynonymous variants and 9 synonymous variants. Phylogenetic analysis showed that E6-E7 and L1 sequences were all distributed in A lineage. In HPV18 E6, E7 and L1 sequences, no positively selected site was found. The nonconservative substitution R545C in L1 affected hypothetical B cell epitope. Two nonconservative substitutions, S82A in E6, and R53Q in E7, impacted multiple hypothetical T cell epitopes. Conclusion: The sequence variation data of HPV18 may lay a foundation for the virus diagnosis, further study of cervical cancer and vaccine design in central China. [ABSTRACT FROM AUTHOR]

B cells and T cells collaborate in multiple sclerosis (MS) pathogenesis. IgH[MOG] mice possess a B cell repertoire skewed to recognize myelin oligodendrocyte glycoprotein (MOG). Here, we show that upon immunization with the T cell-obligate autoantigen, MOG[35-55], IgH[MOG] mice develop rapid and exacerbated experimental autoimmune encephalomyelitis (EAE) relative to wildtype (WT) counterparts, characterized by aggregation of T and B cells in the IgH[MOG] meninges and by CD4+ T helper 17 (Th17) cells in the CNS. Production of the Th17 maintenance factor IL-23 is observed from IgH[MOG] CNS-infiltrating and meningeal B cells, and in vivo blockade of IL-23p19 attenuates disease severity in IgH[MOG] mice. In the CNS parenchyma and dura mater of IgH[MOG] mice, we observe an increased frequency of CD4+PD-1+CXCR5- T cells that share numerous characteristics with the recently described T peripheral helper (Tph) cell subset. Further, CNS-infiltrating B and Tph cells from IgH[MOG] mice show increased reactive oxygen species (ROS) production. Meningeal inflammation, Tph-like cell accumulation in the CNS and B/Tph cell production of ROS were all reduced upon p19 blockade. Altogether, MOG-specific B cells promote autoimmune inflammation of the CNS parenchyma and meninges in an IL-23-dependent manner. B cells are crucial in multiple sclerosis (MS) pathology but the mechanisms are incompletely understood. In a mouse model of MS, the authors show that B cells make IL-23, and that IL-23 invokes meningeal inflammation and CNS presence of T peripheral helper cells. [ABSTRACT FROM AUTHOR]

Transgenic mice expressing human major histocompatibility complex class II (MHCII) risk alleles are widely used in autoimmune disease research, but limitations arise due to non‐physiologic expression. To address this, physiologically relevant mouse models are established via knock‐in technology to explore the role of MHCII in diseases like rheumatoid arthritis. The gene sequences encoding the ectodomains are replaced with the human DRB1*04:01 and 04:02 alleles, DRA, and CD74 (invariant chain) in C57BL/6N mice. The collagen type II (Col2a1) gene is modified to mimic human COL2. Importantly, DRB1*04:01 knock‐in mice display physiologic expression of human MHCII also on thymic epithelial cells, in contrast to DRB1*04:01 transgenic mice. Humanization of the invariant chain enhances MHCII expression on thymic epithelial cells, increases mature B cell numbers in spleen, and improves antigen presentation. To validate its functionality, the collagen‐induced arthritis (CIA) model is used, where DRB1*04:01 expression led to a higher susceptibility to arthritis, as compared with mice expressing DRB1*04:02. In addition, the humanized T cell epitope on COL2 allows autoreactive T cell‐mediated arthritis development. In conclusion, the humanized knock‐in mouse faithfully expresses MHCII, confirming the DRB1*04:01 alleles role in rheumatoid arthritis and being also useful for studying MHCII‐associated diseases. [ABSTRACT FROM AUTHOR]

The tumor microenvironment is closely linked to the initiation, promotion, and progression of solid tumors. Among its constitutions, immunologic cells emerge as critical players, facilitating immune evasion and tumor progression. Apart from their indirect impact on anti-tumor immunity, immunocytes directly influence neoplastic cells, either bolstering or impeding tumor advancement. However, current therapeutic modalities aimed at alleviating immunosuppression from regulatory cells on effector immune cell populations may not consistently yield satisfactory results in various solid tumors, such as breast carcinoma, colorectal cancer, etc. Therefore, this review outlines and summarizes the direct, dualistic effects of immunocytes such as T cells, innate lymphoid cells, B cells, eosinophils, and tumor-associated macrophages on tumor cells within the tumor microenvironment. The review also delves into the underlying mechanisms involved and presents the outcomes of clinical trials based on these direct effects, aiming to propose innovative and efficacious therapeutic strategies for addressing solid tumors. [ABSTRACT FROM AUTHOR]

Kaposi sarcoma associated herpesvirus (KSHV) is associated with around 1% of all human tumors, including the B cell malignancy primary effusion lymphoma (PEL), in which co-infection with the Epstein Barr virus (EBV) can almost always be found in malignant cells. Here, we demonstrate that KSHV/EBV co-infection of mice with reconstituted human immune systems (humanized mice) leads to IgM responses against both latent and lytic KSHV antigens, and expansion of central and effector memory CD4+ and CD8+ T cells. Among these, KSHV/EBV dual-infection allows for the priming of CD8+ T cells that are specific for the lytic KSHV antigen K6 and able to kill KSHV/EBV infected B cells. This suggests that K6 may represent a vaccine antigen for the control of KSHV and its associated pathologies in high seroprevalence regions, such as Sub-Saharan Africa. Kaposi sarcoma associated herpesvirus (KSHV) and Epstein Barr virus often co-infect hosts and some malignancies, such as primary effusion lymphoma, are typically arising from dual-infected cells. Here authors recapitulate dual infection in a humanized mouse model, and find that under these conditions, an efficient and specific CD8+ T cell response is mounted against the lytic KSHV antigen K6. [ABSTRACT FROM AUTHOR]

Influenza A virus (IAV) causes significant morbidity and mortality worldwide due to seasonal epidemics and periodic pandemics. The antigenic drift/shift of IAV continually gives rise to new strains and subtypes, aiding IAV in circumventing previously established immunity. As a result, there has been substantial interest in developing a broadly protective IAV vaccine that induces, durable immunity against multiple IAVs. Previously, a polyanhydride nanoparticle-based vaccine or nanovaccine (IAV-nanovax) encapsulating H1N1 IAV antigens was reported, which induced pulmonary B and T cell immunity and resulted in cross-strain protection against IAV. A key feature of IAV-nanovax is its ability to easily incorporate diverse proteins/payloads, potentially increasing its ability to provide broad protection against IAV and/or other pathogens. Due to human susceptibility to both H1N1 and H3N2 IAV, several H3N2 nanovaccines were formulated herein with multiple IAV antigens to examine the "plug-and-play" nature of the polyanhydride nanovaccine platform and determine their ability to induce humoral and cellular immunity and broad-based protection similar to IAV-nanovax. The H3N2-based IAV nanovaccine formulations induced systemic and mucosal B cell responses which were associated with antigen-specific antibodies. Additionally, systemic and lung-tissue resident CD4 and CD8 T cell responses were enhanced post-vaccination. These immune responses corresponded with protection against both homologous and heterosubtypic IAV infection. Overall, these results demonstrate the plug-and-play nature of the polyanhydride nanovaccine platform and its ability to generate immunity and protection against IAV utilizing diverse antigenic payloads. [ABSTRACT FROM AUTHOR]

Increasing evidence supports a role for small extracellular vesicles (sEV, including exosomes) in Diffuse Large B-cell lymphoma (DLBCL) progression and resistance to treatment. CD20 and PD-L1 are found on DLBCL-derived sEV, but little is known about their patient-level heterogeneity. Moreover, the capacity of PD-L1+ sEV to modulate T cells needs to be clarified. Herein we analyzed sEV produced by human DLBCL cell lines and EBV-transformed B cell-lymphoblastoid cell lines (LCLs), a model allowing autologous T cell co-cultures. We determined CD20 and PD-L1 levels on plasma sEV from patient samples vs healthy volunteers (HV). sEV functional relevance was also investigated on CD4+ and CD8+ T cells. sEV derived from all cell lines showed an enrichment of CD20 and a high glycosylated PD-L1 expression when compared to cell lysates. High PD-L1 expression on LCL-derived sEV was associated with higher CD4+ and CD8+ T cell apoptosis. In patients, plasma sEV concentration was higher vs HV. Compared to sEV-CD20 level that seemed higher in patients, PD-L1 level in sEV was not different from those of HV. A high glycosylated PD-L1 level was shown in sEV from both patients and HV plasma samples, that was associated with the same inhibiting effect on activated T cells. We conclude that sEV derived from EBV-transformed B cells realize an immunosuppressive role that involved cell–cell interaction and probably at least PD-L1. Furthermore, our findings suggest the potential of circulating sEV as a source of biomarkers in DLBCL, notably to have information on immunotherapeutic target levels of parental tumor cells. [ABSTRACT FROM AUTHOR]

Toll-like receptor 9 (TLR9) recognizes bacterial, viral and self DNA and play an important role in immunity and inflammation. However, the role of TLR9 in obesity is less well-studied. Here, we generate B-cell-specific Tlr9-deficient (Tlr9fl/fl/Cd19Cre+/-, KO) B6 mice and model obesity using a high-fat diet. Compared with control mice, B-cell-specific-Tlr9-deficient mice exhibited increased fat tissue inflammation, weight gain, and impaired glucose and insulin tolerance. Furthermore, the frequencies of IL-10-producing-B cells and marginal zone B cells were reduced, and those of follicular and germinal center B cells were increased. This was associated with increased frequencies of IFNγ-producing-T cells and increased follicular helper cells. In addition, gut microbiota from the KO mice induced a pro-inflammatory state leading to immunological and metabolic dysregulation when transferred to germ-free mice. Using 16 S rRNA gene sequencing, we identify altered gut microbial communities including reduced Lachnospiraceae, which may play a role in altered metabolism in KO mice. We identify an important network involving Tlr9, Irf4 and Il-10 interconnecting metabolic homeostasis, with the function of B and T cells, and gut microbiota in obesity. Although the function of Toll-like receptor 9 (TLR9) in immunity and inflammation is well-established, its role in obesity is less well-studied. In this study, the authors demonstrate that TLR9 deficiency in B cells is associated with obesity in mice and results in altered frequencies of T and B lymphocyte subsets and gut microbiome dysbiosis. [ABSTRACT FROM AUTHOR]

The absence of stimulator of interferon genes (STING) in 129.B6.Fcgr2b-deficient mice rescue lupus phenotypes. The administration of a STING inhibitor (ISD017) into the young 129.B6.Fcgr2b-deficient mice prevents lupus nephritis development. This study mainly aimed to evaluate the effects of STING inhibition (ISD107) on established SLE in mice to prove that ISD017 could be a good therapeutic drug to reverse the already set-up autoimmunity and kidney impairment. Twenty-four-week-old Fcgr2b-deficient mice were treated with cyclophosphamide (25 mg/kg, intraperitoneal, once per week), ISD017 (10 mg/kg, intraperitoneal, three times per week), or control vehicle for 8 weeks, and were analyzed for phenotypes. Both ISD017 and cyclophosphamide treatment increased long-term survival and reduced the severity of glomerulonephritis in Fcgr2b-deficient mice. While cyclophosphamide reduced activated B cells (B220+GL-7+), ISD017 decreased activated T cells (CD4+CD69+) and neutrophils (Ly6c+Ly6g+) in Fcgr2b-deficient mice. In addition, ISD017 reduced IL-1β and interferon-inducible genes. In summary, ISD017 treatment in symptomatic 129.B6.Fcgr2b-deficient mice reduced the severity of glomerulonephritis and increased long-term survival. ISD017 worked comparably to cyclophosphamide for treating lupus nephritis in 129.B6.Fcgr2b-deficient mice. ISD017 reduced activated T cells and neutrophils, while cyclophosphamide targeted activated B cells. These results suggested that STING inhibitors can potentially be a new therapeutic drug for treating lupus. [ABSTRACT FROM AUTHOR]

Introduction: In toxicology, steps are being taken towards more mechanismfocused and human relevant approaches to risk assessment, requiring new approaches and methods. Additionally, there is increasing emphasis by regulators on risk assessment of immunotoxicity. Methods: Here we present data from a peripheral blood mononuclear cell (PBMC) system whereby a varied set of stimuli, including those against the TCR and Toll-like receptors, enable readouts of cytokine and prostaglandin E2 (PGE2) production with monocyte, T cell and B cell viability, proliferation, and associated activation markers. In addition to results on the impact of the stimuli used, initial profiling data for a case study chemical, curcumin, is presented, illustrating how the system can be used to generate information on the impact of exogenous materials on three major constituent immune cell subsets for use in risk assessment and to direct follow-on studies. Results: The different stimuli drove distinct responses, not only in relation to the "quantity" of the response but also the "quality". Curcumin had a limited impact on the B cell parameters measured, with the stimuli used, and it was noted that in contrast to T cells where there was either no impact or a reduction in viability and proliferation with increasing concentration, for B cells there was a small but significant increase in both measurements at curcumin concentrations below 20 µM. Similarly, whilst expression of activation markers by T cells was reduced by the highest concentration of curcumin, they were increased in B cells. Curcumin only impacted the viability of stimulated monocytes at the highest concentration and had differential impact on different activation markers. Levels of all cytokines and PGE2 were reduced at higher concentrations. Discussion: Although the platform has certain limitations, it nevertheless enables assessment of healthy baseline monocyte, T-, and B-cell responses, and scrutiny of the impact of different stimuli to detect potential immune suppression or enhancement from exogenous materials. In the case of curcumin, a pattern of responses indicative of immune suppressive / anti-inflammatory effects was detected. It is an accessible, highly modifiable system that can be used to screen materials and guide further studies, providing a holistic, integrated picture of effects. [ABSTRACT FROM AUTHOR]

Background: In prostate cancer (PCa), well-established biomarkers such as MSI status, TMB high, and PDL1 expression serve as reliable indicators for favorable responses to immunotherapy. Recent studies have suggested a potential association between CDK12 mutations and immunotherapy response; however, the precise mechanisms through which CDK12 mutation may influence immune response remain unclear. A plausible explanation for immune evasion in this subset of CDK12-mutated PCa may be reduced MHC expression. Results: Using genomic data of CDK12-mutated PCa from 48 primary and 10 metastatic public domain samples and a retrospective cohort of 53 low-intermediate risk primary PCa, we investigated how variation in the expression of the MHC genes affected associated downstream pathways. We classified the patients based on gene expression quartiles of MHC-related genes and categorized the tumors into "High" and "Low" expression levels. CDK12-mutated tumors with higher MHC-expressed pathways were associated with the immune system and elevated PD-L1, IDO1, and TIM3 expression. Consistent with an inflamed tumor microenvironment (TME) phenotype, digital cytometric analyses identified increased CD8 + T cells, B cells, γδ T cells, and M1 Macrophages in this group. In contrast, CDK12-mutated tumors with lower MHC expression exhibited features consistent with an immune cold TME phenotype and immunoediting. Significantly, low MHC expression was also associated with chromosome 6 loss of heterozygosity (LOH) affecting the entire HLA gene cluster. These LOH events were observed in both major clonal and minor subclonal populations of tumor cells. In our retrospective study of 53 primary PCa cases from this Institute, we found a 4% (2/53) prevalence of CDK12 mutations, with the confirmation of this defect in one tumor through Sanger sequencing. In keeping with our analysis of public domain data this tumor exhibited low MHC expression at the RNA level. More extensive studies will be required to determine whether reduced HLA expression is generally associated with primary tumors or is a specific feature of CDK12 mutated PCa. Conclusions: These data show that analysis of CDK12 alteration, in the context of MHC expression levels, and LOH status may offer improved predictive value for outcomes in this potentially actionable genomic subgroup of PCa. In addition, these findings highlight the need to explore novel therapeutic strategies to enhance MHC expression in CDK12-defective PCa to improve immunotherapy responses. [ABSTRACT FROM AUTHOR]

One of priority issues of the present-day healthcare system is development of new vaccines and improvement of existing ones due to decreasing immunocompetence of the population, emergence of new infections and reemergence of old ones which were previously thought to be under control. Adjuvants have proven to be integral and important components of modern vaccines, as they enhance immune response to the vaccine antigen. However, despite a lot of effort put into their development, only a small number of adjuvants are currently used in clinical practice. The aim of the study was to systematise literature data on the adjuvants’ mechanisms of action, their specific structure, composition, and stimulation effects that mediate their immunoadjuvant properties. The paper summarises data on adjuvants used as components in licensed vaccines, describes their characteristics, analyses molecular mechanisms of their action in order to establish correlation between their structure and activity, which is important for the development of more efficacious and safe adjuvants. The paper cites advanced developments aimed at enhancing stimulation effects of existing adjuvants. It concludes by stating that the key research area aimed at improving vaccination efficacy is the study of mechanisms that contribute to the development of effective protection against infectious agents, as well as analysis of how to use adjuvants to stimulate the body’s defensive mechanisms, primarily by impacting the innate immunity.

In this paper, we propose a novel immune dominance selection multi-objective optimization algorithm (IDSMOA) to solve multi-objective numerical and engineering optimization problems in the real world. IDSMOA was inspired by the mechanism that controls how B cells and T cells differentiate, recombine, and mutate self-adjustably to produce new lymphocytes matching antigens with high affinity, then how lymphocytes cooperatively eliminate antigens. The main idea of IDSMOA is to promote 2 populations, population B and population T, to coevolve through an immune selection operator, immune clone operator, immune gen operator, and memory selection operator to produce satisfying Pareto front. Therefore, several operators enable IDSMOA to exploit and excavate the search space, and decrease the number of dominance resistant solutions (DRSs). We compared IDSMOA performance with 3 known multi-objective optimization algorithms and IDSMOA without the combination operator in simulation experiments optimizing 12 benchmark functions. Our simulations indicated that IDSMOA is a competitive optimization tool for multi-objective optimization problems. [ABSTRACT FROM AUTHOR]

Background: The B and T cells of the human adaptive immune system leverage a highly diverse repertoire of antigen-specific receptors to protect the human body from pathogens. The sequencing and analysis of immune repertoires is emerging as an important tool to understand immune responses, whether beneficial or harmful (in the case of autoimmunity). However, methods for studying these repertoires, and for directly comparing different immune repertoires, are lacking. Results: In this paper, we present a non-parametric method for directly comparing sequencing repertoires, with the goal of rigorously quantifying differences in V, D, and J gene segment utilization. This method, referred to as the Repertoire Dissimilarity Index (RDI), uses a bootstrapped subsampling approach to account for variance in sequencing depth, and, coupled with a data simulation approach, allows for direct quantification of the average variation between repertoires. We use the RDI method to recapitulate known differences in the formation of the CD4+ and CD8+ T cell repertoires, and further show that antigen-driven activation of naïve CD8+ T cells is more selective than in the CD4+ repertoire, resulting in a more specialized CD8+ memory repertoire. Conclusions: We prove that the RDI method is an accurate and versatile method for comparisons of immune repertoires. The RDI method has been implemented as an R package, and is available for download through Bitbucket. [ABSTRACT FROM AUTHOR]

Flow cytometry is a unique technology useful in the examination of effects of immunotoxic agents on target cells of the immune system. The purpose of this workshop was to provide an overview of the use of flow cytometry in new and established models of immunotoxicity, with emphasis on the potential applications, assay validation, and potential pitfalls. This overview begins with a discussion of methods useful in the assessment of Ca2+ -dependent mechanisms of lymphoid cell activation in surface marker-defined human B cells, T cells, and monocytes. A discussion of the use of flow cytometry in analysis of apoptosis is also presented in this paper. The second paper presents data on the development and use of flow cytometry as an alternative to a Cr51 release assay for an assessment of cytotoxic T cell activation. The use of surface markers for characterizing and distinguishing the effects of chemical irritants from sensitizers is next presented, followed by an overview of the use of fluorescent probes to assess cell thiol status and overall oxidant-induced injury to lymphoid cells. Finally, an interlaboratory study designed to compare and evaluate the use of flow cytometry procedures in rat splenic cell subtyping is presented. Overall, these studies demonstrate the utility of flow cytometry assays in immunotoxicologic research, but further efforts are needed in the validation of many of these assays for routine use in immunotoxicologic testing. [ABSTRACT FROM AUTHOR]

Global control of infectious diseases depends on the continuous development and deployment of diverse vaccination strategies. Currently available live-attenuated and killed virus vaccines typically take a week or longer to activate specific protection by the adaptive immunity. The mosquito-transmitted Nodamura virus (NoV) is attenuated in mice by mutations that prevent expression of the B2 viral suppressor of RNA interference (VSR) and consequently, drastically enhance in vivo production of the virus-targeting small-interfering RNAs. We reported recently that 2 d after immunization with live-attenuated VSR-disabled NoV (NoVB2), neonatal mice become fully protected against lethal NoV challenge and develop no detectable infection. Using Rag1-/- mice that produce no mature B and T lymphocytes as a model, here we examined the hypothesis that adaptive immunity is dispensable for the RNAi-based protective immunity activated by NoVB2 immunization. We show that immunization of both neonatal and adult Rag1-/- mice with live but not killed NoVB2 induces full protection against NoV challenge at 2 or 14 d postimmunization. Moreover, NoVB2-induced protective antiviral immunity is virus-specific and remains effective in adult Rag1-/- mice 42 and 90 d after a single-shot immunization. We conclude that immunization with the live-attenuated VSR-disabled RNA virus vaccine activates rapid and long-lasting protective immunity against lethal challenges by a distinct mechanism independent of the adaptive immunity mediated by B and T cells. Future studies are warranted to determine whether additional animal and human viruses attenuated by VSR inactivation induce similar protective immunity in healthy and adaptive immunity-compromised individuals. [ABSTRACT FROM AUTHOR]