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Common variable immunodeficiency (CVID) is the most frequent form of primary hypogammaglobulinemia in adults. In addition to recurrent infections and respiratory manifestations, CVID patients may present several non-infection complications such as autoimmune diseases. The mechanisms that lead to immune dysregulation in CVID are not completely understood. Given the role of IgD on naïve B cells in the maintenance of tolerance and secreted IgD in the respiratory mucosa, we evaluated the frequency of IgD+ naïve and IgD+ memory B cells in CVID patients. Here, no differences were observed in the percentages and proliferative responses of anergic IgD+IgM-CD27- B cells between CVID patients, with or without autoimmune disease, and the control group. Interestingly, in the compartment of memory B cells, the percentage of IgD+IgM- cells was higher only in CVID patients with allergic rhinitis/allergic asthma. Our results may indicate that anergic IgD+IgM-CD27- B cells may not be compromised in our CVID cohort. However, IgD+IgM- memory B cells may play a role in the immunopathogenesis of allergic rhinitis/allergic asthma in CVID patients. Further studies are needed to better understand the participation of IgD+IgM- memory B cells in the immunopathogenesis of allergic rhinitis/allergic asthma in CVID patients.

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

Most high grade serous ovarian cancers (HGSOC) originate in the fallopian tube but spread to the ovary and peritoneal cavity, highlighting the need to understand antitumor immunity across HGSOC sites. Using spatial analyses, we discover that tertiary lymphoid structures (TLSs) within ovarian tumors are less developed compared with TLSs in fallopian tube or omental tumors. We reveal transcriptional differences across a spectrum of lymphoid structures, demonstrating that immune cell activity increases when residing in more developed TLSs and produce a prognostic, spatially derived TLS signature from HGSOC tumors. We interrogate TLS-adjacent stroma and assess how normal mesenchymal stem cells MSCs (nMSCs) may support B cell function and TLS, contrary to cancer-educated MSCs (CA-MSCs) which negate the prognostic benefit of our TLS signature, suggesting that pro-tumorigenic stroma could limit TLS formation. [Display omitted] • TLS activity varies by HGSOC anatomical site • An in situ -derived TLS signature from ovarian tumors is prognostic • TLS state governs B cell immunity • Cancer reprogrammed stroma blunts B cell function and is implicated in TLS regulation Therapies that harness the immune response are lacking for ovarian cancer patients. MacFawn et al. utilize spatial transcriptomics to understand how tumor site, stroma, and cellular interactions govern the activity of tertiary lymphoid structures. These studies reveal how we may promote development of these prognostic structures to bolster adaptive antitumor immunity. [ABSTRACT FROM AUTHOR]

Bidirectional exchange of cells between mother and fetus occurs during pregnancy, and persistence of these genetically foreign cells establishes long-term microchimerism in both individuals after parturition. Since women can have multiple pregnancies, and all mothers were once daughters themselves, the microchimeric milieu in each woman could theoretically contain cells from a variety of origins, including from their own mothers as well as their babies from each pregnancy. Interestingly and in sharp contrast to this prediction, we recently showed preexisting populations of microchimeric cells are lost following pregnancy and associated with seeding of new fetal microchimeric cells. Complete loss of preexisting microchimeric cells in this context draws parallels to immunological rejection with synchronized elimination of cells and tissues that express defined discordant antigens. This perspective evaluates this provocative hypothesis regarding pregnancy induced rejection of microchimeric cells, including new experimental data comparing microchimerism levels in mice simultaneously lacking B and T cells before pregnancy, and after parturition with primary and secondary pregnancies. [ABSTRACT FROM AUTHOR]

The avian bursa of Fabricius (BF) is a primary lymphoid organ, where B-cell development occurs within bursal follicles of epithelial origin. During embryogenesis the epithelial anlage of the BF emerges as a diverticulum of the cloaca surrounded by undifferentiated tail bud mesenchyme. While it is believed that the epithelial-mesenchymal BF primordium provides a selective microenvironment for developing B cells, the initial events inducing lymphoid follicle formation are not fully elucidated. Using wild type and CSF1R- eGFP transgenic chick embryos, we find that separate B cell, macrophage and dendritic cell precursors enter the BF mesenchyme, migrate to the surface epithelium, and colonize the lymphoid follicle buds. Detailed immunocytochemical characterization revealed a novel EIV-E12+ blood-borne cell type, colonizing the surface epithelium of the BF rudiment before the entry of myeloid and lymphoid lineages and the appearance of this cell type coincides with the onset of follicle bud formation. Chick-duck chimeras and chick-quail tissue recombination experiments suggest that EIV-E12+ cells represent a transient lymphoid inducer cell population. They are not dendritic or B cells precursors, and they are capable of follicle bud induction in both dendritic cell- and B cell-depleted bursae. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) is a complex and heterogeneous tissue composed of various cell types, including tumor cells, stromal cells, and immune cells, as well as non-cellular elements. Given their pivotal role in humoral immunity, B cells have emerged as promising targets for anti-tumor therapies. The dual nature of B cells, exhibiting both tumor-suppressive and tumor-promoting functions, has garnered significant attention. Understanding the distinct effects of various B cell subsets on different tumors could pave the way for novel targeted tumor therapies. This review provides a comprehensive overview of the heterogeneous B cell subsets and their multifaceted roles in tumorigenesis, as well as the therapeutic potential of targeting B cells in cancer treatment. To develop more effective cancer immunotherapies, it is essential to decipher the heterogeneity of B cells and their roles in shaping the TME. [ABSTRACT FROM AUTHOR]

The humoral response is complex and involves multiple cellular populations and signaling pathways. Bacterial and viral infections, as well as immunization regimens, can trigger this type of response, promoting the formation of microanatomical cellular structures called germinal centers (GCs). GCs formed in secondary lymphoid organs support the differentiation of high‐affinity plasma cells and memory B cells. There is growing evidence that the quality of the humoral response is influenced by genetic variants. Using 12 genetically divergent mouse strains, we assessed the impact of genetics on GC cellular traits. At steady state, in the spleen, lymph nodes and Peyer's patches, we quantified GC B cells, plasma cells and follicular helper T cells. These traits were also quantified in the spleen of mice following immunization with a foreign antigen, namely, sheep red blood cells, in addition to the number and size of GCs. We observed both strain‐ and organ‐specific variations in cell type abundance, as well as for GC number and size. Moreover, we find that some of these traits are highly heritable. Importantly, the results of this study inform on the impact of genetic diversity in shaping the GC response and identify the traits that are the most impacted by genetic background. [ABSTRACT FROM AUTHOR]

In immuno-oncology, the focus has traditionally been on αβ T cells, and immune checkpoint inhibitors that primarily target PD-1 or CTLA4 in these lymphocytes have revolutionized the management of multiple human malignancies. However, recent research highlights the crucial role of B cells and the antibodies they produce in antagonizing malignant progression, offering new avenues for immunotherapy. Our group has demonstrated that dimeric Immunoglobulin A can penetrate tumor cells, neutralize oncogenic drivers in endosomes, and expel them from the cytosol. This mechanistic insight suggests that engineered antibodies targeting this pathway may effectively reach previously inaccessible targets. Investigating antibody production within intratumoral germinal centers and understanding the impact of different immunoglobulins on malignant progression could furnish new tools for the therapeutic arsenal, including the development of tumor-penetrating antibodies. This review aims to elucidate the nature of humoral adaptive immune responses in human cancer and explore how they could herald a new era of immunotherapeutic modalities. By expanding the scope of antitumor immunotherapies, these approaches have the potential to benefit a broader range of cancer patients, particularly through the utilization of tumor cell–penetrating antibodies. [ABSTRACT FROM AUTHOR]

As one molecule related to cytotoxicity, surface expression of C-X3-C motif receptor 1 (CX3CR1) was highly correlated with intracellular granzyme B (GZMB) in natural killer and cytolytic T cells. However, the expression of CX3CR1 and GZMB in B cells has not been clarified, and their clinical significance in systemic lupus erythematosus (SLE) remains unclear. This study aimed to clarify the changes and clinical significance of peripheral blood B cells expressing GZMB and/or CX3CR1 in SLE. Peripheral blood was collected from 39 patients with SLE and 48 healthy controls. We found that GZMB and CX3CR1 expression varied in different B-cell subsets, with plasmablasts possessing the highest positive percentages, consistent with bioinformatics prediction. GZMB+ and CX3CR1+ percentages in circulating B cells and plasmablasts were increased in patients with SLE. CX3CR1 was upregulated on B cells after in vitro stimulation. Notch intracellular domain expression was significantly decreased in plasmablasts of patients with SLE, and CX3CR1 in plasmablasts was downregulated with the addition of JAG1. In conclusion, GZMB and CX3CR1 were increased in B cells and in plasmablasts of patients with SLE and CX3CR1 was negatively regulated by Notch signal in plasmablasts, which may be involved in SLE pathogenesis. [ABSTRACT FROM AUTHOR]

Immunity is a critical self-defense mechanism of the human body, wherein immune cells and immune molecules play a crucial role. Extracellular vesicles (EVs), derived from immune cells or other cells, play a significant role in tumors, autoimmune diseases and other immune-related disorders by serving as carriers and facilitating intercellular communication through the transfer of cargoes. Numerous studies have revealed that EVs can exacerbate disease development by modulating immune responses. Therefore, this paper focuses on the effects of EVs on the number, activity and function of different types of immune cells and the release of immune molecules (such as cytokines, antigens, antibodies, etc) in various diseases, as well as the roles of EVs associated with different types of immune cells in various diseases. We aim to provide a comprehensive review of the negative effects that EVs play in the immune system to provide more ideas and strategies for the management of clinical immune diseases. [ABSTRACT FROM AUTHOR]

Lymphoma was diagnosed in two wild tawny frogmouths (Podargus strigoides) presented to the Australian Wildlife Health Centre, Healesville Sanctuary, Victoria. The first case presented with extensive feather loss refractory to treatment. Bacterial and fungal folliculitis and beak and feather disease virus were excluded as primary causes, and the bird was euthanised due to poor response to treatment. Histopathological examination of the skin showed an extensive infiltrate of pleomorphic mononuclear leucocytes, suggestive of cutaneous lymphoma. Immunohistochemistry revealed >95% of these cells were CD3 positive, consistent with T cell lymphoma. The second case presented debilitated and in poor body condition and was euthanised due to poor prognosis. Histopathological examination revealed extensive infiltrates of pleomorphic mononuclear leucocytes in multiple tissues, suggestive of disseminated lymphoma. Immunohistochemistry revealed 70%–80% of these leucocytes were Pax5 positive, consistent with a B cell lymphoma. To the authors' knowledge these cases constitute the first report of malignant neoplasms in members of the Order Caprimulgiformes. Cutaneous lymphoma should be considered as a potential differential diagnosis for severe feather loss in tawny frogmouths and other avian species, when other more common causes have been ruled out. Similarly, disseminated lymphoma is a differential diagnosis worthy of consideration in cases of systemic debilitation in tawny frogmouths. [ABSTRACT FROM AUTHOR]

ABSTRACT Canine cutaneous/subcutaneous soft‐tissue sarcomas (STS) are diversely derived mesenchymal neoplasms with a risk of recurrence and/or metastasis depending on the extent of surgical excision and histologic grade. Lymphoid aggregates (LAs) are often described in these tumours but not characterised. In humans, LA characterised as tertiary lymphoid structures (TLSs) improve the prognosis of many tumours, including sarcomas. We sought to determine if LA meeting a size criterion (> 700 cells) in canine sarcomas met the criteria of TLS and the overall prevalence of LA of any size. RNA expression in large LAs versus aggregate‐adjacent sarcoma tissue (AAS) was measured in laser capture microdissected tissue and compared to curl‐derived RNA from aggregate‐free sarcomas and lymph nodes. CD3, CD20, MUM‐1 and PNAd expressions were measured using immunohistochemistry. CD20 and CD3 mRNA were more highly expressed in LA versus AAS (13.8 fold, p = 0.0003 and 2.3 fold, p = 0.043). This was supported by the IHC findings. The large LAs were also enriched in chemokine RNA expression characteristic of TLS (CXCR5 5.8 fold, p < 00001, CCL19 3.68 fold, p = 0.0209, CCL21 6.87 fold, p = 0.0209 and CXCL13 2.68 fold, p = 0.0924). Plasma cells and high endothelial venules were identified in LA containing tumours but not in control tissue. Large LAs were present in 12% of tumours, and LA of any size in 30%. We conclude that large LAs in canine STS are consistent with TLS. [ABSTRACT FROM AUTHOR]

Background: Recent literature has shown the presence of B cells and autoantibodies in idiopathic pulmonary fibrosis (IPF) which would imply the presence of tertiary lymphoid structures (TLS, sites where the immune response is triggered), yet TLS are not considered features of the histological characteristics of IPF. Aim: This study aims to quantify the presence, size, and degree of activation of TLS in biopsied and explanted lungs from patients with early- and late-IPF, never treated with antifibrotics, and relate their presence and activity to the clinical course, disease progression, and lung inflammation. Methods: Immunohistochestry for B cells and CD4, CD8, and CD45 cells was performed in lung tissue from IPF patients: 18 at diagnosis (early), 39 explanted (end-stage), and 12 smoking controls. TLS activation was assessed by CD40 expression. Spirometry along 31 (12-72) months of follow-up was used to characterize end-stage IPF as slow progressors or rapid progressors. Results: B cells, along with other inflammatory cells, were higher in early- and end-stage IPF than in controls (p < 0.001). In rapid progressors, all inflammatory cells were higher than in slow progressors (p < 0.05). TLS were present in 100% of early- and end-stage IPF and in 50% of controls. In end-stage IPF, the TLS area and activation score were higher than in early IPF (p < 0.0001; p = 0.005) and controls (p < 0.04; p < 0.002). TLS activation score correlated with FVC decline during follow-up in rapid progressors (r = 0.73; p = 0.007) but not in slow progressors. Conclusions: A prominent B-cell infiltration, along with the presence of TLS, the activity of which correlates with FVC decline, is an important component of IPF from the beginning of the disease, likely playing an important role on its mechanism and progression. [ABSTRACT FROM AUTHOR]

The serine/threonine-specific protein kinases (STKs) are important for cell survival, proliferation, differentiation, and apoptosis. In B cells, these kinases play indispensable roles in regulating important cellular functions. Multiple studies on human and other animal cells have shown that multiple STKs are involved in different stages of B cell development and antibody production. However, how STKs affect B cell development and function is still not completely understood. Considering that B cells are clinically important in immunity and diseases, our understanding of STKs' roles in B cells is in great need of investigation with current technologies. Investigating serine/threonine kinases will not only deepen our insight into B cell-related disorders but also facilitate the identification of more effective drug targets for conditions like lymphoma and systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease that currently cannot be completely cured with a great health burden. Since the production of autoantibodies plays a key role in the pathogenesis of SLE, discovering the underlying immunoregulation mechanism of B cells will be helpful for developing promising immunotherapy for SLE. In recent studies, dopamine receptors (DRDs), G protein-coupled receptors that include D1-like and D2-like subtypes, are expressed on B cells and participate in various physiological processes, involving immune responses. However, the regulatory effect of DRDs on B cells has not been determined. Methods: This study explored the expression of DRDs on B-cell subsets from SLE patients and healthy individuals. The effects of D1-like receptor on B-cell activation and differentiation were further explored using D1-like receptor agonists or antagonists. RNA-seq and bioinformatics analyses were used to identify specific molecular mechanisms involved. Results: The D1-like DRDs on B cells of SLE patients were highly expressed compared with those of healthy controls (HCs). D1-like receptor agonist treatment exacerbated lupus-like symptoms in pristane-induced lupus-like mice, while D1-like receptor antagonists alleviated the lupus-like phenotypes. Inhibition of D1-like receptor signals impeded B-cell differentiation, while activation of D1-like receptor signals could promote B cell differentiation. Further RNA-seq confirmed that PTGS2, a gene related to B-cell differentiation, was up-regulated once the D1-like receptor signals were activated, while BMP6 and IL-24 were up-regulated once the D1-like receptor signals were inhibited. Conclusion: D1-like receptors probably promote B-cell differentiation through the PTGS2/PRDM1 pathway. [ABSTRACT FROM AUTHOR]

B cell lymphoma 6 (BCL6) is a conserved multi-domain protein that functions principally as a transcriptional repressor. This protein regulates many pivotal aspects of immune cell development and function. BCL6 is critical for germinal center (GC) formation and the development of high-affinity antibodies, with key roles in the generation and function of GC B cells, follicular helper T (Tfh) cells, follicular regulatory T (Tfr) cells, and various immune memory cells. BCL6 also controls macrophage production and function as well as performing a myriad of additional roles outside of the immune system. Many of these regulatory functions are conserved throughout evolution. The BCL6 gene is also important in human oncology, particularly in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), but also extending to many in other cancers, including a unique role in resistance to a variety of therapies, which collectively make BCL6 inhibitors highly sought-after. [ABSTRACT FROM AUTHOR]

Introduction: Numerous research demonstrated the different distributions of lymphocyte subsets in each population. Most studies were performed in Caucasian population. To date, no studies on normal lymphocyte subsets have been conducted involving the children population in Malaysia. Therefore, we conducted this study to determine normal lymphocyte subsets in healthy Malay children (major ethnic group in Malaysia) and to identify the association between age and each of the lymphocyte subsets (CD3+, CD4+, CD8+, CD19+ and CD16/56+). Materials and methods: An approximately 500 µl of blood was taken from 93 healthy Malay children and was subjected to flow cytometry immunophenotyping technique. The subjects were categorised into three age subgroups, namely 0 to 1, 1 to 6 and more than six years old. The mean comparison was done using descriptive analysis and the association of lymphocyte subsets with different age groups was identified using one-way ANOVA. Results: The results showed that the CD3+, CD4+, CD16/56+ and CD19+ subsets were significantly different in all age groups with p-values <0.05. The highest percentage and absolute count of CD3+ and CD4+ were recorded in the 0 to 1 year age group which the values significantly decreased with age. Conclusion: Our study may provide an overview and preliminary guidance on the pattern of lymphocyte subsets distribution in the Malay children's population in Malaysia. For reference range it is recommended that further research is done involving bigger sample size, dividing the samples into more age groups and by sex as well as involving other ethnic groups in Malaysia. [ABSTRACT FROM AUTHOR]

Aim: This study investigates changes in immune cell subsets in peripheral blood of ankylosing spondylitis (AS) patients with colitis or terminal ileitis. It aims to explore the connection between changes in lymphocyte subsets and gut inflammation, providing insights for early detection. Methods: Overall, 50 AS patients undergoing colonoscopy were enrolled. Flow cytometry was employed to analyze lymphocyte subsets, including T and B cells, in peripheral blood. Disease activity was assessed using CRP, ESR, BASDAI, ASDAS‐CRP, and ASDAS‐ESR. Results: Compared to AS patients without gut inflammation, those with colorectal inflammation showed a significant increase in total T cells (p <.05), an increase in exhausted CD4+ T cells (p <.05), and a decrease in Th2 cells and total Tc cells (p <.05). Notably, in AS patients with terminal ileitis, there was an increase in total B cells and classic switched B cells (p <.05), with a decrease in double‐positive T cells (p <.05). However, no significant differences were observed in the distribution of Tfh‐cell subpopulations (Tfh1, Tfh2, Tfh17) and Tc‐cell subpopulations (Tc1, Tc2, Tc17) between AS patients with either colorectal inflammation or terminal ileitis (p >.05). We explored the relationship between disease activity scores, ESR, CRP, and lymphocyte subsets, but found no statistically significant correlation between them. Conclusion: Distinct immune patterns may exist in AS with different types of intestinal inflammation. Colitis in AS is primarily characterized by a significant increase in exhausted CD4+ T cells, along with a decrease in Th2 cells. In contrast, terminal ileum inflammation in AS is marked by an increase in total B cells and classic switched B cells. These findings offer new insights for early detection and therapeutic intervention. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by the accumulation of α‐synuclein (α‐syn) in the brain and progressive loss of dopaminergic neurons in the substantia nigra (SN) region of the brain. Although the role of neuroinflammation and cellular immunity in PD has been extensively studied, the involvement of humoral immunity mediated by antibodies and B cells has received less attention. This article provides a comprehensive review of the current understanding of humoral immunity in PD. Here, we discuss alterations in B cells in PD, including changes in their number and phenotype. Evidence mostly indicates a decrease in the quantity of B cells in PD, accompanied by a shift in the population from naïve to memory cells. Furthermore, the existence of autoantibodies that target several antigens in PD has been investigated (i.e., anti‐α‐syn autoantibodies, anti‐glial‐derived antigen antibodies, anti‐Tau antibodies, antineuromelanin antibodies, and antibodies against the renin‐angiotensin system). Several autoantibodies are generated in PD, which may either provide protection or have harmful effects on disease progression. Furthermore, we have reviewed studies focusing on the utilization of antibodies as a potential treatment for PD, both in animal and clinical trials. This review sheds light on the intricate interplay between antibodies and the pathological processes in PD, including complement system activation. Significance statement: Considering the well‐established involvement of the humoral immune system in the pathophysiology of Parkinson's disease, it is important to explore alterations in both the quantity and characteristics of B lymphocytes as the main humoral immune system cells in individuals with PD. Generally, B lymphocytes in this condition exhibit a decline in numbers and a tendency to adopt memory phenotype. Furthermore, the investigation of antibodies produced against various antigens, possessing either protective or detrimental effects may aid in enhancing our comprehension of the pathophysiological path of the disease. [ABSTRACT FROM AUTHOR]

Maintaining intracellular redox balance is essential for the survival, antibody secretion, and mucosal immune homeostasis of immunoglobulin A (IgA) antibody‐secreting cells (ASCs). However, the relationship between mitochondrial metabolic enzymes and the redox balance in ASCs has yet to be comprehensively studied. Our study unveils the pivotal role of mitochondrial enzyme PCK2 in regulating ASCs' redox balance and intestinal homeostasis. We discover that PCK2 loss, whether globally or in B cells, exacerbates dextran sodium sulphate (DSS)‐induced colitis due to increased IgA ASC cell death and diminished antibody production. Mechanistically, the absence of PCK2 diverts glutamine into the TCA cycle, leading to heightened TCA flux and excessive mitochondrial reactive oxygen species (mtROS) production. In addition, PCK2 loss reduces glutamine availability for glutathione (GSH) synthesis, resulting in a decrease of total glutathione level. The elevated mtROS and reduced GSH expose ASCs to overwhelming oxidative stress, culminating in cell apoptosis. Crucially, we found that the mitochondria‐targeted antioxidant Mitoquinone (Mito‐Q) can mitigate the detrimental effects of PCK2 deficiency in IgA ASCs, thereby alleviating colitis in mice. Our findings highlight PCK2 as a key player in IgA ASC survival and provide a potential new target for colitis treatment. [ABSTRACT FROM AUTHOR]

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with a tripled incidence in the US and Europe over the past decade. Around 80% of MCC is linked to Merkel cell polyomavirus, but the cell of origin remains unknown. We stably introduced Merkel cell polyomavirus (MCPyV)‐sT) and LT antigens to MCC13 and REH cell lines, analyzing DNA methylation and gene transcriptional regulation. Gene ontology analysis assessed MCPyV effects, and integrative analysis correlated gene expression and methylation. Expression patterns were compared with 15 previously sequenced primary MCCs. We found that MCPyV‐LT induces DNA methylation changes in both cell lines, while MCPyV‐sT only affected REH cells. Greater gene expression changes are observed in MCC13 cells, with upregulated genes associated with cellular components and downregulated genes related to biological processes. Integrative analysis of differentially expressed genes (DEG) and differentially methylated regions (DMR) of REH cell lines revealed that no genes were commonly methylated and differentially expressed. The study compared DEGs and DMG in MCC13 and REH cells to overlapping genes in MCPyV‐positive cell lines (MKL1, MKL2, and WaGa), identifying hypomethylated genes in the gene body and hypermethylated genes at TSS1500. GO analysis of the two cell lines showed that MCPyV‐TAs can downregulate genes in MHC‐I pathways; this downregulation offers a target that can be used to create novel and efficient MCC immunotherapy approaches. Finally, it was confirmed that MCPyV‐LT controls gene expression in MCC tissues using an integrative investigation of DNA methylation and gene expression. [ABSTRACT FROM AUTHOR]

The "multi‐hit theory/4‐hit theory" pathogenesis hypothesis is widely accepted and IgA nephropathy (IgAN) is understood to be a disease originating from Hit 1, galactose deficient IgA1 (GdIgA1). The chronic repetitive activation of the complement pathway (alternative and lectin pathways) and the subsequent inflammation results in progressive glomerular damage that spills over into increased intraglomerular pressure and other hemodynamic changes, increased urinary protein, glomerulosclerosis, and tubulointerstitial fibrosis. The basic pathophysiology of this disease is the progression of a mixture of such acute and chronic pathologies. Currently, a number of new drugs has emerged as promising agents, such as complement regulators, endothelin receptor antagonists, and SGLT2 inhibitors, which are associated with each pathological step after glomerular deposition of GdIgA1/immune complexes. On the other hand, the molecular mechanisms of GdIgA1 production are gradually being elucidated, and the development of several novel therapeutic agents targeting the responsible B cells and their international clinical trials are progressing. These agents that inhibit or control the production of the Hit1, GdIgA1, are highly expected as essential therapies for this disease. The large body of clinical and basic research findings to date strongly suggest that nephritogenic GdIgA1 is a polymeric IgA1 of mucosal origin. In addition, the B cells involved in its nephritogenic GdIgA1 production are mainly differentiated mature B cells such as plasma cells, which may migrate to the bone marrow as well as the mucosa. The innate immune system in the mucosa, especially Toll‐like receptors (TLRs), is thought to be involved in their production. Among TLRs, TLT9 and TLR7, which recognize bacterial and viral unmethylated DNA and RNA, have been reported to be involved. The mucosal activation of these TLRs is associated with the production of APRIL (A Proliferation Inducing Ligand) and BAFF (B cell activating factor), which are TNF superfamily cytokines involved in B cell maturation, survival, and IgA class switching, and may also be involved in the production of nephritogenic GdIgA1. It is still inconclusive whether APRIL or BAFF is more closely involved in the production of nephritogenic GdIgA1. Phenotypes in transgenic animal models suggest BAFF involvement, however, a genome wide association study (GWAS) analysis of human IgAN has identified APRIL, not BAFF, as a candidate gene. Based on the above background, several international clinical trials are underway for drugs such as TLR regulators (hydroxychloroquine), anti‐APRIL drugs, anti‐BAFF drugs, APRIL/BAFF receptor (TACI) binding inhibitors, and cytoreductive drugs (proteasome inhibitors, anti‐CD38 antibodies) to inhibit nephritogenic GdIgA1 production in responsible B cells. This session will provide an overview of the responsible B cells, their GdIgA1 production mechanism, and ongoing drugs. [ABSTRACT FROM AUTHOR]

Introduction: Thyroid-associated ophthalmopathy (TAO) is considered to be an organ-specific autoimmune disease. Polymorphonuclear neutrophils (PMN) have been implicated in the pathogenesis of TAO. However, little is known about the role of PMN in the development of TAO, much less the relationship between PMN with B cells and CD4+T cells in TAO. Objective: This study aims to investigate the phenotypic characteristics of PMN and the relationship between PMN with CD4+T cell and B cell subsets in the pathogenesis of TAO. Methods: Blood routine information was collected from 135 TAO patients, 95 Grave's disease without TAO (GD) patients, and 116 normal controls (NC), while surface marker expression of PMN and the level of CD4+T cell and B cell subsets in peripheral blood from 40 TAO patients, 17 GD patients, and 45 NC was assessed by flow cytometry. Result: The level of PMN, CD62L+PMN, CD54+PMN, CD4+T cells, and Th17 cells displayed an increase in TAO patients than NC, while Treg cells were lower in the TAO group compared to NC. There was no statistical difference in Th1 and plasma cells among the groups. PMN were positively correlated with Th17 cells, but not the Th1, Treg, and plasma cells. Conclusion: In the present study, we found that the percentage of PMN and PMN subset cells was significantly higher in TAO than in NC, and PMN were positively correlated with Th17 cells. It suggests that PMN may be involved in the immunopathogenesis of TAO and modulate the Th17 cell response during this process. [ABSTRACT FROM AUTHOR]

In Sjögren's disease (SjD), the salivary glandular epithelial cells can induce the chemotaxis of B cells by secreting B-cell chemokines such as C-X-C motif chemokine ligand 13 (CXCL13). Syndecan-1 (SDC-1) is a major transmembrane heparan sulfate proteoglycan (HSPG) predominantly expressed on epithelial cells that binds to and regulates heparan sulfate (HS)-binding molecules, including chemokines. We aimed to determine whether SDC-1 plays a role in the pathogenesis of SjD by acting on the binding of HS to B-cell chemokines. To assess changes in glandular inflammation and SDC-1 concentrations in the submandibular gland (SMG) and blood, female NOD/ShiLtJ and sex- and age-matched C57BL/10 mice were used. In the SMG of NOD/ShiLtJ mice, inflammatory responses were identified at 8 weeks of age, but increased SDC-1 concentrations in the SMG and blood were observed at 6 weeks of age, when inflammation had not yet started. As the inflammation of the SMG worsened, the SDC-1 concentrations in the SMG and blood increased. The expression of the CXCL13 and its receptor C-X-C chemokine receptor type 5 (CXCR5) began to increase in the SMG at 6 weeks of age and continued until 12 weeks of age. Immunofluorescence staining in SMG tissue and normal murine mammary gland cells confirmed the co-localization of SDC-1 and CXCL13, and SDC-1 formed a complex with CXCL13 in an immunoprecipitation assay. Furthermore, NOD/ShiLtJ mice were treated with 5 mg/kg HS intraperitoneally thrice per week for 6–10 weeks of age, and the therapeutic effects in the SMG were assessed at the end of 10 weeks of age. NOD/ShiLtJ mice treated with HS showed attenuated salivary gland inflammation with reduced B-cell infiltration, germinal center formation and CXCR5 expression. These findings suggest that SDC-1 plays a pivotal role in the pathogenesis of SjD by binding to CXCL13 through the HS chain. [ABSTRACT FROM AUTHOR]

Objective To investigate the antigen presentation characteristics of dendritic cells (DC) and B cells in cardiac grafts. Methods The heart of BALB/c mice was transplanted into the abdominal cavity of C57BL/6J mice. CD45+ cells in the heart graft were extracted and sorted by flow cytometry at postoperative 5 d, and single cell RNA sequencing was performed. Taking DC and B cell subsets in cardiac grafts as the main study cells, the changing trend, antigen presenting ability and intercellular communication with T cells after heart transplantation were analyzed by bioinformatics analysis and flow cytometry. Gene ontology (GO) function enrichment difference analysis was adopted to prove the specific function and the reliability annotation of cell subsets. Results Germinal center-like B cell (GC-L B) was the B cell subset with the largest increase in quantity during the acute rejection phase, accounting for 87%. Classical DC (cDC) 2 was the only DC subset with a significant increase in quantity during acute rejection of heart transplantation, accounting for 44% of DC subset, and it occupied the highest communication intensity with T cells after heart transplantation. Mononucleated DC (moDC) and memory B cell (MBC) were the main transmitters of T cell input signals in nontransplanted hearts, whereas transformed into cDC2 and GC-L B during the acute rejection phase. Among them, MBC and GC-L B were the main sources of T cell input signals in non-transplanted hearts and heart grafts. Conclusions Compared with DC, B cells occupy a higher number and weight in the intercellular communication with T cells in non-transplanted hearts and heart grafts, prompting that the antigen presenting activity of B cells is more active and stronger than DC in the early stage of acute rejection of heart transplantation. [ABSTRACT FROM AUTHOR]

In individuals highly exposed to HCV, reinfection is common, suggesting that natural development of sterilising immunity is difficult. In those that are reinfected, some will develop a persistent infection, while a small proportion repeatedly clear the virus, suggesting natural protection is possible. The aim of this study was to characterise immune responses associated with rapid natural clearance of HCV reinfection. Broad neutralising antibodies (nAbs) and Envelope 2 (E2)-specific memory B cell (MBC) responses were examined longitudinally in 15 individuals with varied reinfection outcomes. Broad nAb responses were associated with MBC recall, but not with clearance of reinfection. Strong evidence of antigen imprinting was found, and the B-cell receptor repertoire showed a high level of clonality with ongoing somatic hypermutation of many clones over subsequent reinfection events. Single-cell transcriptomic analyses showed that cleared reinfections featured an activated transcriptomic profile in HCV-specific B cells that rapidly expanded upon reinfection. MBC quality, but not necessarily breadth of nAb responses, is important for protection against antigenically diverse variants, which is encouraging for HCV vaccine development. HCV continues to have a major health burden globally. Limitations in the health infrastructure for diagnosis and treatment, as well as high rates of reinfection, indicate that a vaccine that can protect against chronic HCV infection will greatly complement current efforts to eliminate HCV-related disease. With alternative approaches to testing vaccines, such as controlled human inoculation trials under consideration, we desperately need to identify the correlates of immune protection. In this study, in a small but rare cohort of high-risk injecting drug users who were reinfected multiple times, breadth of neutralisation was not associated with ultimate clearance of the reinfection event. Alternatively, characteristics of the HCV-specific B-cell response associated with B-cell proliferation were. This study indicates that humoral responses are important for protection and suggests that for genetically very diverse viruses, such as HCV, it may be beneficial to look beyond just antibodies as correlates of protection. [Display omitted] • Protection from persistent reinfection was associated with expansion of E2-specific B cells upon reinfection. • E2-specific B cells have a transcriptomic profile associated with activation and proliferation prior to clearance of reinfection. • We observed evidence of antigen imprinting in HCV reinfection. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a typical highly heterogeneous solid tumor with high morbidity and mortality worldwide, especially in China; however, the immune microenvironment of HCC has not been clarified so far. Here, we employed single‐cell RNA sequencing (scRNA‐seq) on diethylnitrosamine (DEN)‐induced mouse HCC model to dissect the immune cell dynamics during tumorigenesis. Our findings reveal distinct immune profiles in both precancerous and cancerous lesions, indicating early tumor‐associated immunological alterations. Notably, specific T and B cell subpopulations are preferentially enriched in the HCC tumor microenvironment (TME). Furthermore, we identified a subpopulation of naïve B cells with high CD83 expression, correlating with improved prognosis in human HCC. These signature genes were validated in The Cancer Genome Atlas HCC RNA‐seq dataset. Moreover, cell interaction analysis revealed that subpopulations of B cells in both mouse and human samples are activated and may potentially contribute to oncogenic processes. In summary, our study provides insights into the dynamic immune microenvironment and cellular networks in HCC pathogenesis, with a specific emphasis on naïve B cells. These findings emphasize the significance of targeting TME in HCC patients to prevent HCC pathological progression, which may give a new perspective on the therapeutics for HCC. [ABSTRACT FROM AUTHOR]

Abstract Background Systemic lupus erythematosus (SLE) is an autoimmune disease that currently cannot be completely cured with a great health burden. Since the production of autoantibodies plays a key role in the pathogenesis of SLE, discovering the underlying immunoregulation mechanism of B cells will be helpful for developing promising immunotherapy for SLE. In recent studies, dopamine receptors (DRDs), G protein-coupled receptors that include D1-like and D2-like subtypes, are expressed on B cells and participate in various physiological processes, involving immune responses. However, the regulatory effect of DRDs on B cells has not been determined. Methods This study explored the expression of DRDs on B-cell subsets from SLE patients and healthy individuals. The effects of D1-like receptor on B-cell activation and differentiation were further explored using D1-like receptor agonists or antagonists. RNA-seq and bioinformatics analyses were used to identify specific molecular mechanisms involved. Results The D1-like DRDs on B cells of SLE patients were highly expressed compared with those of healthy controls (HCs). D1-like receptor agonist treatment exacerbated lupus-like symptoms in pristane-induced lupus-like mice, while D1-like receptor antagonists alleviated the lupus-like phenotypes. Inhibition of D1-like receptor signals impeded B-cell differentiation, while activation of D1-like receptor signals could promote B cell differentiation. Further RNA-seq confirmed that PTGS2, a gene related to B-cell differentiation, was up-regulated once the D1-like receptor signals were activated, while BMP6 and IL-24 were up-regulated once the D1-like receptor signals were inhibited. Conclusion D1-like receptors probably promote B-cell differentiation through the PTGS2/PRDM1 pathway.

Background: Nephrotic syndrome is a special type of chronic kidney disease, the specific pathogenesis of which remains unclear. An increasing number of studies have suggested that B cells play an important role in the pathogenesis of nephrotic syndrome. Summary: Idiopathic nephrotic syndrome is a common kidney disease in children. While previously believed to be primarily caused by T-cell disorders, recent research has shifted its focus to B cells. Studies have shown that B cells play a significant role in the pathogenesis of NS, potentially even more so than T cells. This article provides a comprehensive review of the involvement of B cells in the development of idiopathic nephrotic syndrome. Key Messages: B cells are involved in the pathogenesis of nephrotic syndrome by producing autoantibodies and various cytokines.

Abstract Background Human umbilical cord mesenchymal stem cells-derived extracellular vesicles (hUCMSC-EVs) have potent immunomodulatory properties similar to parent cells. This study investigated the therapeutic effects and immunomodulatory mechanisms of hUCMSC-EVs in an experimental lupus nephritis model. Methods The hUCMSC-EVs were isolated by using differential ultracentrifugation. In vivo, the therapeutic effects of hUCMSC-EVs in lupus-prone MRL/lpr mice were investigated, and the mechanisms of treatment were explored according to the abnormal T and B cell responses among both the spleen and kidney. Results MRL/lpr mice treated with hUCMSC-EVs reduced proteinuria extent, serum creatinine and renal pathological damage; decreased splenic index and serum anti-dsDNA IgG level; and improved survival rate. hUCMSC-EVs lowered the percentage of T helper (Th)1 cells, double-negative T (DNT) cells, and plasma cells among splenocytes; inhibited the infiltration of Th17 cells but promoted regulatory T (Treg) cells in the kidney, followed by a reduction in pro-inflammatory cytokine levels(IFN-γ, IL-2, IL-6, IL-21, and IL-17 A). In addition, hUCMSC-EVs inhibited the activation of STAT3 and down-regulated IL-17 A protein levels in the kidney. Conclusion The results of this study demonstrated that hUCMSC-EVs had therapeutic effects on experimental lupus nephritis (LN) by regulating Th1/Th17/Treg imbalance and inhibiting DNT and plasma cells. Additionally, hUCMSC-EVs inhibited Th17 cell differentiation in kidney by regulating the IL-6/STAT3/IL-17 signal pathway, which might be an important mechanism for alleviating renal injury. Taken together, we demonstrated that hUCMSC-EVs regulating T and B cell immune responses might represent a novel mechanism of hUCMSCs in treating LN, thus providing a new strategy for treating LN.

Abstract Early‐stage lung cancer is now more commonly identified in the form of ground‐glass nodules (GGNs). Presently, the treatment of lung cancer with GGNs mainly depends on surgery; however, issues still exist such as overtreatment and delayed treatment due to the nonuniform standard of follow‐up. Therefore, the discovery of a noninvasive treatment could expand the treatment repertoire of ground‐glass nodular lung cancer and benefit the prognosis of patients. Immunotherapy has recently emerged as a new promising approach in the field of lung cancer treatment. Thus, this study presents a comprehensive review of the immune microenvironment of lung cancer with GGNs and describes the functions and characteristics of various immune cells involved, aiming to provide guidance for the clinical identification of novel immunotherapeutic targets.

Background/purpose: Primary Sjögren's syndrome is a prototypical autoimmune disease, with B cell dysfunction as a dominant feature. Further insights into distribution of B cell subsets in primary Sjögren's syndrome are urgently required to identify the most appropriate target subpopulation. We aimed to evaluate the profiles of B lymphocyte subpopulations in primary Sjögren's syndrome patients and to investigate their clinical significance. Materials and methods: Thirty primary Sjögren's syndrome patients and 15 age-and sex-matched healthy controls were recruited. Peripheral B cell subsets were analyzed by flow cytometry. Results: Compared to healthy controls, circulating CD19+ B cells, CD19+CD20− B cells, CD19+CD27−IgD+ naïve B cells, CD19+IgD+CD38high plasmablasts, CD19+CD24highCD38high transitional B cells and CD19+CD20−CD27+CD38+ plasma cells were elevated in patients with primary Sjögren's syndrome, whereas CD19+CD27+ memory B cells, CD19+CD27−IgD- double negative B cells and CD19+CD24hiCD27+ Bregs were decreased. Furthermore, the percentage of circulating CD19+CD20−CD27+CD38+ plasma cells was positively correlated with serum IgG levels and the proportional area of lymphocytic infiltration of labial gland. Conclusion: We identified a comprehensive B lymphocyte subset distribution profile in primary Sjögren's syndrome. Moreover, we detected a clinical significance of CD19+CD20−CD27+CD38+ plasma cells, suggesting that these cells might play a key role in disease pathology and represent potential therapeutic targets.

B cells play a crucial role in recognizing external antigens through their surface B cell receptor (BCR), essential for generating protective antibodies and immune memory. Regulation of B cell immune activation is closely linked to various upper respiratory tract diseases. Adenoid hypertrophy (ATH), a common childhood condition, is characterized by lymphoid follicular hyperplasia, yet its exact mechanisms remain elusive. This review consolidates research on BCR trophic signaling that sustains B cell viability in resting state. It clarifies the regulatory mechanisms governing B cell immune activation and the establishment of rapid, effective immune memory, with a specific focus on early molecular activation events and the pivotal role of mIgG-tail in memory antibody responses. Dysregulation of B cell activation processes can disrupt immune balance, potentially precipitating disease. This synthesis explores the connection between regulation of B cell activation and ATH pathogenesis, examining the potential impacts of signaling pathway dysregulation or mutations on ATH. The review aims to enhance understanding of the disease mechanisms underlying ATH, with the goal of identifying new diagnostic and therapeutic targets for this condition.

Objective To investigate the effect of Shewanella algae （S.algae） on the occurrence and development of colorectal adenoma and its regulatory effect on the immune microenvironment in mice. Methods Twenty-four mice were divided into three groups： control group， azoxymethane （AOM）/ dextran sodium sulfate （DSS） group， AOM/DSS+S.algae group. The survival status and colorectal adenoma of mice were compared among three groups. Colorectal tissues in the AOM/DSS group and AOM/DSS+S.algae group were collected for high-throughput RNA-seq. Gene set enrichment analysis （GSEA）and cell-type identification by estimating relative subsets of RNA transcripts （CIBERSORT） were used to analyze the changes of immune-related pathways， immune cells and immune factors. Results Compared with the AOM/DSS group， the body weight （P < 0.05） and survival rate were decreased， the hematochezia was aggravated， the survival status was worsened，the colorectal length was shortened （all P < 0.05）， and the average number and size of adenomas were significantly increased （both P < 0.05） in the AOM/DSS+S.algae group. Compared with the AOM/DSS group， the inflammatory responses were significantly enhanced in AOM/DSS+S.algae group （P < 0.05）. The production of pro-inflammatory cytokines including interleukin （IL）-2， IL-6， IL-12， IL-17， interferon （IFN）， tumor necrosis factor （TNF） （all P < 0.05） and IL-1β showed an upward trend in the AOM/DSS+S.algae group， while the production of anti-inflammatory cytokines including IL-4， IL-10， IL-13 （all P < 0.05） and transforming growth factor β showed an inhibitory trend. Both naive B cells and plasma cells （both P < 0.05） were increased in AOM/DSS+S.algae group， and the nuclear factor -κB （NF-κB） signaling pathway was activated. Conclusion S.algae may form a tumor-promoting immune microenvironment by activating immune signals， such as activation of B cells and activation of the NF-κB pathway， and then promote the development of colorectal adenoma.

Syndrome of Congenital Sideroblastic Anemia, B-cell Immunodeficiency, Periodic Fevers, and Developmental Delay (SIFD) is caused by mutations in the tRNA nucleotidyltransferase 1 (TRNT1) gene. We present the case of a 13-month-old boy with developmental delay, microcytic anemia, and recurrent febrile illnesses. Immunological workup revealed B cell lymphopenia. Whole exome sequencing identified two novel heterozygous mutations in the TRNT1 gene (Thr49Fs and Ile122Thr). Our patient had a milder phenotype than previously reported cases of sideroblastic anemia. However, he developed left ventricular dilated cardiomyopathy at the age of 2 years. At the age of 5 years, COVID-19 infection resulted in mitochondrial encephalomyopathy and respiratory failure. Subsequent immunology evaluation revealed low IgG levels, prompting the initiation of immunoglobulin replacement therapy. This case highlights the importance of genetic testing in multisystem disorders and the variable clinical course in SIFD patients. Additionally, it emphasizes the unique susceptibility to COVID-19 due to immunodeficiency and mitochondrial defects.

Multiple sclerosis (MS) is a frequently disabling neurological disorder characterized by symptoms, clinical signs and imaging abnormalities that typically fluctuate over time, affecting any level of the CNS. Prominent lymphocytic inflammation, many genetic susceptibility variants involving immune pathways, as well as potent responses of the neuroinflammatory component to immunomodulating drugs, have led to the natural conclusion that this disease is driven by a primary autoimmune process. In this Hypothesis and Theory article, we discuss emerging data that cast doubt on this assumption. After three decades of therapeutic experience, what has become clear is that potent immune modulators are highly effective at suppressing inflammatory relapses, yet exhibit very limited effects on the later progressive phase of MS. Moreover, neuropathological examination of MS tissue indicates that degeneration, CNS atrophy, and myelin loss are most prominent in the progressive stage, when lymphocytic inflammation paradoxically wanes. Finally, emerging clinical observations such as "progression independent of relapse activity" and "silent progression," now thought to take hold very early in the course, together argue that an underlying "cytodegenerative" process, likely targeting the myelinating unit, may in fact represent the most proximal step in a complex pathophysiological cascade exacerbated by an autoimmune inflammatory overlay. Parallels are drawn with more traditional neurodegenerative disorders, where a progressive proteopathy with prion-like propagation of toxic misfolded species is now known to play a key role. A potentially pivotal contribution of the Epstein-Barr virus and B cells in this process is also discussed. [ABSTRACT FROM AUTHOR]

In recent years, there has been increasing attention towards understanding the relationship between age‐related alterations in the oral microbiota and age‐associated diseases, with reports emphasizing the significance of maintaining a balanced oral microbiota for host health. However, the precise mechanisms underlying age‐related changes in the oral microbiota remain elusive. We recently reported that cellular senescence of ileal germinal center (GC) B cells, triggered by the persistent presence of commensal bacteria, results in diminished IgA production with aging and subsequent alterations in the gut microbiota. Consequently, we hypothesize that a similar phenomenon may occur in the oral cavity, potentially contributing to age‐related changes in the oral microbiota. Examination of p16‐luc mice, wherein the expression of the senescent cell marker p16INK4a can be visualized, raised under specific pathogen‐free (SPF) or germ‐free (GF) conditions, indicated that, unlike ileal GC B cells, the accumulation of senescent cells in GC B cells of cervical lymph nodes increases with age regardless of the presence of commensal bacteria. Furthermore, longitudinal studies utilizing the same individual mice throughout their lifespan revealed concurrent age‐related alterations in the composition of the oral microbiota and a decline in salivary IgA secretion. Further investigation involving Rag1−/− mice transplanted with B cells from wild‐type or p16INK4a and p21Waf1/Cip1 ‐double knockout mice unveiled that B cell senescence leads to reduced IgA secretion and alteration of the oral microbiota. These findings advance our understanding of the mechanism of age‐associated changes in the oral microbiota and open up possibilities of their control. [ABSTRACT FROM AUTHOR]

In the earliest days, the idea that surviving a single infection often resulted in lifelong immunity to the infecting pathogen was recorded and then led to the discovery of vaccination. We have now confirmed that such protection is primarily based on the generation of immunological memory in antibody response. With the wide implementation of more and more vaccines around the world, it is well documented that different vaccines have different potential regarding to the duration of antibody response. In clinical observations, live-attenuated vaccines often elicit long-term immunity but are also accompanied with risks in safety that are hard to avoid. In order to develop novel vaccines with both excellent potential in eliciting antibody memory and low safety risk, it is critical to further investigate the mechanism of antibody memory in the perspective of immunology. Antibody memory is mediated by certain longlived B cells: long-lived plasma cell can secret antibody to maintain serum antibody titer while memory B cell contributes to the rapid immune response during the secondary encounter of pathogens. Cellular and molecular processes that drive the production of long-lived plasma cells and memory B cells are subjects of intensive research and have important implications for global health. Several factors in the vaccine would indeed affect and regulate these processes, including the antigen valency, vaccine kinetics and the signal integration of both antigen and danger molecules. Many studies have focused on strategies to manipulate these factors to improve or develop new vaccines. Here, we will summarize our current knowledge on how the component in vaccines will affect their potential in generating and sustaining antibody memory, and also point out the challenges we face in the route of developing a "perfect" vaccine. [ABSTRACT FROM AUTHOR]

Objective: To study the risk of lupus nephritis flare (LNF) or severe lupus flare (SLF) as a function of B cell count kinetics in lupus nephritis (LN) patients after they achieve at least a partial renal response (PRR) with induction treatment that includes rituximab (RTX) and/or belimumab (BLM). Methods: We performed a retrospective analysis of a cohort of 19 patients with severe LN that received a B cell agent (BCA), RTX and/or BLM, as part of an initial treatment regimen for an LN flare and had subsequent CD19+ B cell measurements in peripheral blood. We then characterized the follow-up periods, after B cell depressions occurred and PRR were achieved, by the corresponding trajectories of B cell counts (BCC). Time periods with sustained low BCC were type 1 (T1) episodes, while those with repletion of BCC>100 cells/μL were called type 2 (T2) episodes. Time periods with rapid BCC repletion, defined as >50 cells/μL in ≤6 months, were called T2b episodes. Corresponding C3, C4, and anti-dsDNA levels were recorded for each episode. The time from PRR until an event, either a LNF or SLF, or to censoring, either at the end of the study period or the end of available patient follow-up, was assessed for each episode type. Kaplan-Meier survival analysis was used to compare time to flare between T1 and T2 episodes. Results: There were 26 episodes of B cell depression. Seventeen (65%) were T1 and 9 (35%) were T2. Compared to T1 episodes, T2 episodes were 9.0 times more likely to result in flare over the follow-up period (hazard ratio (HR) = 9.0, 95% CI for HR = 2.2-36.7); this risk was even larger for T2b vs T1 episodes. Median BCC was 14 cells/μL in T1 and 160 cells/μL in T2 episodes. Both C3 and C4 levels significantly increased over the duration of the episode in T1 episodes only. Conclusion: Sustained low BCC was associated with prolonged serologic and clinical response, whereas repletion, and particularly rapid repletion, of B cells after treatment with BCA was associated with subsequent disease flare. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells, and it is the most frequent form of leukemia diagnosed in Western countries. It is characterized by the proliferation and accumulation of neoplastic B lymphocytes in the blood, lymph nodes, bone marrow and spleen. We report the synthesis and antiproliferative effects of a series of novel ethanoanthracene compounds in CLL cell lines. Structural modifications were achieved via the Diels–Alder reaction of 9-(2-nitrovinyl)anthracene and 3-(anthracen-9-yl)-1-arylprop-2-en-1-ones (anthracene chalcones) with dienophiles, including maleic anhydride and N-substituted maleimides, to afford a series of 9-(E)-(2-nitrovinyl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-diones, 9-(E)-3-oxo-3-phenylprop-1-en-1-yl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-diones and related compounds. Single-crystal X-ray analysis confirmed the structures of the novel ethanoanthracenes 23f, 23h, 24a, 24g, 25f and 27. The products were evaluated in HG-3 and PGA-1 CLL cell lines (representative of poor and good patient prognosis, respectively). The most potent compounds were identified as 20a, 20f, 23a and 25n with IC50 values in the ranges of 0.17–2.69 µM (HG-3) and 0.35–1.97 µM (PGA-1). The pro-apoptotic effects of the potent compounds 20a, 20f, 23a and 25n were demonstrated in CLL cell lines HG-3 (82–95%) and PGA-1 (87–97%) at 10 µM, with low toxicity (12–16%) observed in healthy-donor peripheral blood mononuclear cells (PBMCs) at concentrations representative of the compounds IC50 values for both the HG-3 and PGA-1 CLL cell lines. The antiproliferative effect of the selected compounds, 20a, 20f, 23a and 25n, was mediated through ROS flux with a marked increase in cell viability upon pretreatment with the antioxidant NAC. 25n also demonstrated sub-micromolar activity in the NCI 60 cancer cell line panel, with a mean GI50 value of 0.245 µM. This ethanoanthracene series of compounds offers potential for the further development of lead structures as novel chemotherapeutics to target CLL. [ABSTRACT FROM AUTHOR]

Studies in animal models and human subjects have shown that, in addition to their implication in innate immunity, inflammasomes also can play a role in adaptive immunity. However, the contribution of the nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway to adaptive immunity remains incompletely explored. Here, we show that NLRP3 plays an important role in different facets of B cell functions, including proliferation, antibody production, and secretion of inflammatory and anti-inflammatory cytokines. When exposed to B cell receptor engagement, Toll-like receptor activation, stimulation in conditions that mimic T cell-dependent responses, or NLRP3 activation, B cells manifest disparate responses and produce different cytokine patterns critical for modulating innate and adaptive immunity, indicating that the cytokines produced serve a critical link between the early innate immune response and the delayed adaptive immunity. Importantly, genetic ablation of nlrp3 reduced the inflammasome-mediated functions of B cells. We propose that, in the absence of other cell types, the potential of B lymphocytes to respond to NLRP3 engagement enables them to initiate inflammatory cascades through recruitment of other cell subsets, such as macrophages and neutrophils. Since NLRP3 activation of B cells is not followed by pyroptosis, even in the presence of a basal caspase-1 activity, this pathway acts as a bridge that optimizes interactions between the innate and adoptive branches of the immune response. [ABSTRACT FROM AUTHOR]

Genetic variants of the OX40 ligand (OX40L) locus are associated with the risk of systemic lupus erythematosus (SLE), it is unclear how the OX40L blockade delays the lupus phenotype. Therefore, we examined the effects of an anti‐OX40L antibody in MRL/Lpr mice. Next, we investigated the effect of anti‐OX40L on immunosuppression in keyhole limpet hemocyanin‐immunized C57BL/6J mice. In vitro treatment of anti‐OX40L in CD4+ T and B220+ B cells was used to explore the role of OX40L in the pathogenesis of SLE. Anti‐OX40L alleviated murine lupus nephritis, accompanied by decreased production of anti‐dsDNA and proteinuria, as well as lower frequencies of splenic T helper (Th) 1 and T‐follicular helper cells (Tfh). In keyhole limpet hemocyanin‐immunized mice, decreased levels of immunoglobulins and plasmablasts were observed in the anti‐OX40L group. Anti‐OX40L reduced the number and area of germinal centers. Compared with the control IgG group, anti‐OX40L downregulated CD4+ T‐cell differentiation into Th1 and Tfh cells and upregulated CD4+ T‐cell differentiation into regulatory T cells in vitro. Furthermore, anti‐OX40L inhibited toll‐like receptor 7‐mediated differentiation of antibody‐secreting cells and antibody production through the regulation of the SPIB‐BLIMP1‐XBP1 axis in B cells. These results suggest that OX40L is a promising therapeutic target for SLE. [ABSTRACT FROM AUTHOR]

How different classes of the B cell antigen receptor (BCR) sense viral antigens used in vaccination protocols is poorly understood. Here, we study antigen binding and sensing of human Ramos B cells expressing a BCR of either the IgM or IgG1 class with specificity for the CD4-binding-site of the envelope (Env) protein of the HIV-1. Both BCRs carry an identical antigen binding site derived from the broad neutralizing antibody (bnAb) CH31. We find a five times higher expression of the IgG1-BCR in comparison to the IgM-BCR on the surface of transfected Ramos B cells. The two BCR classes also differ from each other in their interaction with cognate HIV Env antigens in that the IgG1-BCR and IgM-BCR bind preferentially to polyvalent and monovalent antigens, respectively. By generating an IgM/IgG1 chimeric BCR, we found that the class-specific BCR expression and antigen-sensing behavior can be transferred with the CH1γ domain from the IgG1-BCR to the IgM-BCR. Thus, the class of CH1 domain has an impact on BCR assembly and expression as well as on antigen sensing. [ABSTRACT FROM AUTHOR]

Background: Human umbilical cord mesenchymal stem cells-derived extracellular vesicles (hUCMSC-EVs) have potent immunomodulatory properties similar to parent cells. This study investigated the therapeutic effects and immunomodulatory mechanisms of hUCMSC-EVs in an experimental lupus nephritis model. Methods: The hUCMSC-EVs were isolated by using differential ultracentrifugation. In vivo, the therapeutic effects of hUCMSC-EVs in lupus-prone MRL/lpr mice were investigated, and the mechanisms of treatment were explored according to the abnormal T and B cell responses among both the spleen and kidney. Results: MRL/lpr mice treated with hUCMSC-EVs reduced proteinuria extent, serum creatinine and renal pathological damage; decreased splenic index and serum anti-dsDNA IgG level; and improved survival rate. hUCMSC-EVs lowered the percentage of T helper (Th)1 cells, double-negative T (DNT) cells, and plasma cells among splenocytes; inhibited the infiltration of Th17 cells but promoted regulatory T (Treg) cells in the kidney, followed by a reduction in pro-inflammatory cytokine levels(IFN-γ, IL-2, IL-6, IL-21, and IL-17 A). In addition, hUCMSC-EVs inhibited the activation of STAT3 and down-regulated IL-17 A protein levels in the kidney. Conclusion: The results of this study demonstrated that hUCMSC-EVs had therapeutic effects on experimental lupus nephritis (LN) by regulating Th1/Th17/Treg imbalance and inhibiting DNT and plasma cells. Additionally, hUCMSC-EVs inhibited Th17 cell differentiation in kidney by regulating the IL-6/STAT3/IL-17 signal pathway, which might be an important mechanism for alleviating renal injury. Taken together, we demonstrated that hUCMSC-EVs regulating T and B cell immune responses might represent a novel mechanism of hUCMSCs in treating LN, thus providing a new strategy for treating LN. [ABSTRACT FROM AUTHOR]

Tertiary lymphoid structures (TLS) represent the ectopic aggregations of immune cells arising during chronic inflammation or tumor progression. In cancer, TLS are often associated with beneficial clinical outcomes in patients undergoing immunotherapy, underscoring their prognostic and predictive significance. Mature TLS, characterized by germinal centers and areas of T-cell and B-cell aggregation, are considered primary locations for activating and maintaining both humoral and cellular anti-tumor immune effects. Despite their recognized importance, the mechanisms driving the formation of mature TLS in cancer and their influence on the immune response within tumors remain insufficiently understood. Therefore, this review aims to comprehensively explore the structural composition, development mechanisms, maturity impact factors, immunological function, and innovative therapeutic strategies of mature TLS within the tumor microenvironment. The research summarized herein offers novel insights and considerations for therapeutic approaches to promote TLS generation and maturation in patients with cancer, representing a promising avenue for future cancer therapies. [ABSTRACT FROM AUTHOR]

The structural patterns of pyloric tonsil in turkey (Meleagris gallopavo) were investigated in this study. Turkeys, less resistant to disease than chickens, are a crucial source of protein with low cholesterol levels and a high protein/calorie ratio. Pyloric tonsil, involved in the chicken defense barrier, is a component of GALT. To evaluate the specific region, adult turkeys were taken from slaughterhouses. Crossman's modified triple staining demonstrated the general histological structure, PAS revealed the density of goblet cells synthesizing mucus, and Safranin O showed the capsule around the follicles. The width of lymphoid follicles in the pyloric tonsil (204.0±22.33) differed significantly from that of the middle part of the duodenum (111.7±4.741). It was noticed that the specific area harbors T cells, B cells, and follicular dendritic cells. Interfollicular regions were infiltrated with CD3+T cells, but the CD268+B cells occupied primarily germinal centers. However, it was noticed that T cells were present in germinal centers and some B cells in the interfollicular region. Anti-Vimentin antibody revealed follicular dendritic cells in the pyloric zone. It was noted that the epithelial layer of the pyloric tonsil is devoid of CK18-positive cells. Findings of the semi-thin section indicated that some columnar epithelial cells were stained differently in the transition zone (lymphoepithelium). To sum up, a pyloric region in turkeys is structurally dissimilar to pyloric tonsils detected in chicken, chukar partridge, and duck. More research is needed to reveal the effect of pyloric tonsil on the alimentary tract in poultry in terms of defense mechanisms. [ABSTRACT FROM AUTHOR]

Simple Summary: The B cell receptor (BCR) is a membrane-bound protein complex that is required for the normal development of B cells. BCR signalling is also involved in the pathogenesis of B cell cancers. While there is substantial literature on genomic analyses of the BCR, there are limited proteomic studies of receptor structure and its interactions with neighbouring proteins. This is partly due to the location of the BCR in the surface-membrane lipid environment that has limited the ability to enrich the complex for proteomic analysis. Here, we report an enrichment technique that can be used for mass spectrometry analyses of the BCR from live B cells. B cells are central to the adaptive immune response and provide long-lasting immunity after infection. B cell activation is mediated by the surface membrane-bound B cell receptor (BCR) following recognition of a specific antigen. The BCR has been challenging to analyse using mass spectrometry (MS) due to the difficulty of isolating and enriching this membrane-bound protein complex. There are approximately 120,000 BCRs on the B cell surface; however, depending on the B cell activation state, there may be hundreds-of-millions to billions of proteins in a B cell. Consequently, advanced proteomic techniques such as MS workflows that use purified proteins to yield structural and protein-interaction information have not been published for the BCR complex. This paper describes a method for enriching the BCR complex that is MS-compatible. The method involves a Protein G pull down on agarose beads using an intermediary antibody to each of the BCR complex subcomponents (CD79a, CD79b, and membrane immunoglobulin). The enrichment process is shown to pull down the entire BCR complex and has the advantage of being readily compatible with further proteomic study including MS analysis. Using intermediary antibodies has the potential to enrich all isotypes of the BCR, unlike previous methods described in the literature that use protein G-coated beads to directly pull down the membrane IgG (mIgG) but cannot be used for other mIg isotypes. [ABSTRACT FROM AUTHOR]

Early‐stage lung cancer is now more commonly identified in the form of ground‐glass nodules (GGNs). Presently, the treatment of lung cancer with GGNs mainly depends on surgery; however, issues still exist such as overtreatment and delayed treatment due to the nonuniform standard of follow‐up. Therefore, the discovery of a noninvasive treatment could expand the treatment repertoire of ground‐glass nodular lung cancer and benefit the prognosis of patients. Immunotherapy has recently emerged as a new promising approach in the field of lung cancer treatment. Thus, this study presents a comprehensive review of the immune microenvironment of lung cancer with GGNs and describes the functions and characteristics of various immune cells involved, aiming to provide guidance for the clinical identification of novel immunotherapeutic targets. [ABSTRACT FROM AUTHOR]

Primary Sjögren's syndrome is a prototypical autoimmune disease, with B cell dysfunction as a dominant feature. Further insights into distribution of B cell subsets in primary Sjögren's syndrome are urgently required to identify the most appropriate target subpopulation. We aimed to evaluate the profiles of B lymphocyte subpopulations in primary Sjögren's syndrome patients and to investigate their clinical significance. Thirty primary Sjögren's syndrome patients and 15 age-and sex-matched healthy controls were recruited. Peripheral B cell subsets were analyzed by flow cytometry. Compared to healthy controls, circulating CD19+ B cells, CD19+CD20− B cells, CD19+CD27−IgD+ naïve B cells, CD19+IgD+CD38high plasmablasts, CD19+CD24highCD38high transitional B cells and CD19+CD20−CD27+CD38+ plasma cells were elevated in patients with primary Sjögren's syndrome, whereas CD19+CD27+ memory B cells, CD19+CD27−IgD- double negative B cells and CD19+CD24hiCD27+ Bregs were decreased. Furthermore, the percentage of circulating CD19+CD20−CD27+CD38+ plasma cells was positively correlated with serum IgG levels and the proportional area of lymphocytic infiltration of labial gland. We identified a comprehensive B lymphocyte subset distribution profile in primary Sjögren's syndrome. Moreover, we detected a clinical significance of CD19+CD20−CD27+CD38+ plasma cells, suggesting that these cells might play a key role in disease pathology and represent potential therapeutic targets. [ABSTRACT FROM AUTHOR]

As a vital mechanism of survival, lymphopoiesis requires the collaboration of different signaling molecules to orchestrate each step of cell development and maturation. The PI3K pathway is considerably involved in the maturation of lymphatic cells and therefore, its dysregulation can immensely affect human well-being and cause some of the most prevalent malignancies. As a result, studies that investigate this pathway could pave the way for a better understanding of the lymphopoiesis mechanisms, the undesired changes that lead to cancer progression, and how to design drugs to solve this issue. The present review addresses the aforementioned aspects of the PI3K pathway and helps pave the way for future therapeutic approaches. In order to access the articles, databases such as Medicine Medline/PubMed, Scopus, Google Scholar, and Science Direct were utilized. The search formula was established by identifying main keywords including PI3K/Akt/mTOR pathway, Lymphopoiesis, Lymphoid malignancies, and inhibitors. The PI3K pathway is crucial for lymphocyte development and differentiation, making it a potential target for therapeutic intervention in lymphoid cancers. Studies are focused on developing PI3K inhibitors to impede the progression of hematologic malignancies, highlighting the pathway's significance in lymphoma and lymphoid leukemia. [ABSTRACT FROM AUTHOR]