Abatacept, a biological disease-modifying antirheumatic drug(bDMARD), has demonstrated unique and effective therapeutic properties for rheumatoid arthritis (RA).

This review offers an in-depth examination of the mechanism by which abatacept exerts its effects in RA treatment and assesses its efficacy and safety based on a range of studies. We conducted a comprehensive search of PubMed, Embase databases, Web of Science, the Cochrane Library, MEDLINE, Wanfang Data, and CNKI from the time the databases were created until 30 July 2024.

By modulating the CD28 and CD80/CD86 costimulatory signaling pathways, abatacept is instrumental in regulating immune cells and cytokines implicated in the pathogenesis RA. Longitudinal studies have highlighted its capacity to mitigate disease advancement and maintain joint functionality. The most frequently reported adverse effects associated with abatacept are headache, nausea, and upper respiratory tract infections, which are typically self-resolving. The incidence of serious infections was not high, mainly various types of bacterial pneumonia. Comparative safety analyses of abatacept with other DMARDs yield encouraging results. As our understanding of the mechanism of action of abatacept improves, we may be able to better identify appropriate biologic therapies and advanced combination therapies for RA patients and ultimately improve patient outcomes.

Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin's lymphoma. The applicability of circulating tumor DNA (ctDNA) for predicting treatment response and prognosis in MCL remains underexplored.

This study included 34 MCL patients receiving first-line chemoimmunotherapy. We assessed the ability of plasma ctDNA to detect tumor-specific genetic alterations and explored its potential as a noninvasive biomarker for treatment response and prognosis in MCL.

Commonly mutated genes in MCL included CCND1 (93.5%), ATM (48.4%), KMT2D (25.8%), and TP53 (25.8%). Subgroup analysis of tissue samples showed that CDKN2A mutations (P = 0.028), along with alterations in BCR and TCR signaling (P = 0.004) and the PI3K pathway (P = 0.008), were enriched in the blastoid subtype. ATM mutations (P = 0.041) were more prevalent in MIPI-low patients, while epigenetic chromatin remodeling pathway alterations (P = 0.028) were more common in MIPI-high patients. Plasma ctDNA demonstrated high sensitivity for detecting structural variants (96.6%), followed by mutations (71.3%) and copy number variants (30.0%). 75% of patients exhibited moderate-to-high concordance in detecting genomic variants between plasma and tissue samples. Pretreatment ctDNA levels exhibited high specificity in predicting clinical efficacy but had a suboptimal sensitivity of 68.2%. Higher ctDNA levels were significantly associated with shorter progression-free survival (PFS; P = 0.002) and overall survival (OS; P = 0.009). Additional ctDNA-based genetic features associated with shorter PFS included TP53 (P = 0.002), TRAF2 (P = 0.023), and SMARCA4 (P = 0.023) mutations, while TP53 (P = 0.006) and TERT (P = 0.031) mutations predicted shorter OS. Persistent positive ctDNA in post-treatment plasma samples indicated molecular relapse and poor prognosis, whereas undetectable ctDNA defined a subset of patients with favorable survival outcomes.

This study identified plasma ctDNA as a promising biomarker that noninvasively captures tumor-derived genetic variants associated with treatment response and survival outcomes in MCL, highlighting the clinical value of ctDNA for diagnosis, recurrence prediction, and surveillance monitoring.

Systemic sclerosis (SSc) is an autoimmune disease characterized by specific autoantibodies, vasculopathy and fibrosis of the skin and internal organs. In SSc, chronic activation of the immune system is largely sustained by endogenous inflammatory mediators that act as damage-associated molecular patterns (DAMPs), which activate Toll-like receptors (TLRs). Major autoantigens are nucleic acids or molecules that are able to bind nucleic acids. It is important to identify solid and predictive biomarkers of both disease activity and disease subtype. CXCL4 has been regarded as a new biomarker for early SSc in recent years, and here, we discuss its modulation over the course of a disease and after pharmacological interventions. Moreover, we provide evidence that CXCL4, in addition to being a biomarker of SSc subtypes and a prognostic marker of disease severity, has a dual pathogenic role in SSc: on the one hand, in complex with self-nucleic acids, CXCL4 acts as a DAMP for IFN-I and pro-inflammatory cytokines' release by innate immune cells (such as dendritic cells); on the other hand, CXCL4 is a target of both antibodies and T cells, functioning as an autoantigen. CXCL4 is certainly an interesting molecule in inflammation and autoimmunity, not only in SSc, and it may also be considered as a therapy target.

The immune system relies on carefully calibrated cellular machineries to enable distinction between endogenous and foreign molecules, with autoimmunity arising when this balance is disrupted. As potent autoantibody factories, B cells are major drivers of many autoimmune diseases. A significant fraction of patients affected by chronic autoimmune diseases such as systemic lupus erythematosus (SLE) exhibit pathogenic accumulation of B-cell subsets that are believed to be derived from the extrafollicular (EF) differentiation pathway. These B-cell subsets, although variously named and exhibiting intrinsic heterogeneity, are all poised producers of autoantibodies that correlate with patient pathophysiology. In addition, they are often characterized by biomarkers known to drive the innate immune response, including toll-like receptors and complement receptors. Although many innate receptors have well-established functions in myeloid cells and other immune cell types, their B cell-specific functions are still under active investigation and are crucial for understanding the molecular pathways that drive B-cell breaks of tolerance. In this review, we summarize studies on innate immune receptors that serve prominent roles in regulating EF B-cell activation in health and autoimmunity. By discussing independent and collaborative functions of these receptors, we hope to provide new perspectives in autoimmune disease signature research.

As a heterogeneous B cell subset, age-associated B cells (ABCs) exhibit distinct transcription profiles, extrafollicular differentiation processes, and multiple functions in autoimmunity. TLR7 and TLR9 signals, along with IFN-γ and IL-21 stimulation, are both essential for ABC differentiation, which is also regulated by chemokine receptors including CXCR3 and CCR2 and integrins including CD11b and CD11c. Given their functions in antigen uptake and presentation, autoantibody and proinflammatory cytokine secretion, and T helper cell activation, ABCs display potential in the prognosis, diagnosis, and therapy for autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, multiple sclerosis, neuromyelitis optica spectrum disorders, and ankylosing spondylitis. Specifically targeting ABCs by inhibiting T-bet and CD11c and activating CD11b and ARA2 represents potential therapeutic strategies for SLE and RA. Although single-cell sequencing technologies have recently revealed the heterogeneous characteristics of ABCs, further investigations to explore and validate ABC-target therapies are still warranted.

Humans are perhaps evolutionarily engineered to get deeply addicted to sugar, as it not only provides energy but also helps in storing fats, which helps in survival during starvation. Additionally, sugars (glucose and fructose) stimulate the feel-good factor, as they trigger the secretion of serotonin and dopamine in the brain, associated with the reward sensation, uplifting the mood in general. However, when consumed in excess, it contributes to energy imbalance, weight gain, and obesity, leading to the onset of a complex metabolic disorder, generally referred to as diabetes. Type 2 diabetes mellitus (T2DM) is one of the most prevalent forms of diabetes, nearly affecting all age groups. T2DM is clinically diagnosed with a cardinal sign of chronic hyperglycemia (excessive sugar in the blood). Chronic hyperglycemia, coupled with dysfunctions of pancreatic β-cells, insulin resistance, and immune inflammation, further exacerbate the pathology of T2DM. Uncontrolled T2DM, a major public health concern, also contributes significantly toward the onset and progression of several micro- and macrovascular diseases, such as diabetic retinopathy, nephropathy, neuropathy, atherosclerosis, and cardiovascular diseases, including cancer. The current review discusses the epidemiology, causative factors, pathophysiology, and associated comorbidities, including the existing and emerging therapies related to T2DM. It also provides a future roadmap for alternative drug discovery for the management of T2DM.

B lymphocytes have emerged as an important immune-regulating target. Inoculation with tumor cell membrane-derived vaccines is a promising strategy to activate B cells, yet their efficiency is limited due to lack of costimulatory molecules. To amplify B cell responses against tumor, herein, a spatiotemporally-synchronized antigen-adjuvant integrated nanovaccine, termed as CM-CpG-aCD40, is constructed by conjugating the immune stimulative CpG oligonucleotide and the anti-CD40 antibody (aCD40) onto the membrane vesicles derived from triple negative breast cancer cells. CM-CpG-aCD40 actively accumulates in lymph nodes and is effectively captured by antigen-presenting cells via the recognition of CD40 by aCD40. Tumor antigens on CM-CpG-aCD40 bind to B cell receptors, providing the first stimulation signal for B cells. Meanwhile, the interaction between CpG/Toll like receptor and aCD40/CD40 provides superposed co-stimulation signals, improving the antibody-secreting and antigen-presenting abilities of B cells. The nanovaccine also stimulates dendritic cells to activate CD8+ T cells, and reprograms tumor associated macrophages. CM-CpG-aCD40 activating humoral, cellular, and innate antitumor immunity achieves a tumor inhibition rate of 89.3%, which is further improved to 95.4% when combined with the anti-programmed death ligand 1 (PD-L1) antibody. CM-CpG-aCD40, as a personalized multi-epitope nanovaccine, paves the way for ushering the era of B cell-based immunotherapy.

TASL is an immune adaptor that binds to the solute carrier SLC15A4 and facilitates activation of the transcription factor IRF5 during Toll-like receptor (TLR) signaling. Similar to IRF5 and SLC15A4, single nucleotide polymorphisms (SNPs) within TASL have been implicated in increased susceptibility to systemic lupus erythematosus (SLE) in patients. However, the biological function of TASL in vivo and how SLE-associated SNPs increase disease risk is unknown. Here we report that mice deficient in Tasl lack responses to TLR7/9 stimulation and are protected from autoimmune symptoms induced by Aldara or pristane. Loss of Tasl reduces IRF5 phosphorylation and cytokine production in multiple immune cell types but has no effect on other aspects of TLR signaling. Conversely, an SLE-associated TASL risk variant increases TASL protein expression via codon usage, resulting in augmented cytokine production in human cells. Altogether, our study validates the essential function of TASL in TLR signaling and autoimmune pathogenesis.

The development of a protective vaccine is critical for conclusively ending the human immunodeficiency virus (HIV) epidemic.

We constructed nucleotide-modified mRNA vaccines expressing HIV-1 Env and Gag proteins. Env-gag virus-like particles (VLPs) were generated through co-transfection with env and gag mRNA vaccines. BALB/c mice were immunized with env mRNA, env-gag VLP mRNA, env plasmid DNA vaccine, or lipid nanoparticle (LNP) controls. HIV Env-specific binding and neutralizing antibodies in mouse sera were assessed via enzyme-linked immunosorbent assay (ELISA) and pseudovirus-based neutralization assays, respectively. Env-specific cellular immune responses in mouse splenocytes were evaluated using an Enzyme-linked immunosorbent assay (ELISpot) and in vivo cytotoxic T cell-killing assays.

The Env-specific humoral and cellular immune responses elicited by HIV-1 env mRNA and env-gag VLP mRNA vaccine were stronger than those induced by the DNA vaccine. Specific immune responses induced by the env mRNA vaccine were significantly stronger in the high-dose group than in the low-dose group. Immunization with co-formulated env and gag mRNAs elicited superior cellular immune responses compared to env mRNA alone.

These findings suggest that the env-gag VLP mRNA platform holds significant promise for HIV-1 vaccine development.

During antigen-driven responses, B cells can differentiate at extra-follicular (EF) sites or initiate germinal centers (GCs) in processes that involve interactions with T cells. Here, we examined the roles of interleukin (IL)-2 secreted by T helper (Th) cells during cognate interactions with activated B cells. IL-2 boosted the expansion of EF plasma cells and the secretion of low-mutated immunoglobulin G (IgG). Conversely, genetically disrupting IL-2 expression by CD4+ T cells, or IL-2 receptor (CD25) expression by B cells, promoted B cell entry into the GC and high-affinity antibody secretion. Mechanistically, IL-2 induced early mTOR activity, expression of the transcriptional regulator IRF4, and metabolic changes in B cells required to form Blimp-1-expressing plasma cells. Thus, T cell help via IL-2 regulates an mTOR-AKT-Blimp-1 axis in activated B cells, providing insight into the mechanisms that determine EF versus GC fates and positioning IL-2 as an early switch controlling plasma cell versus GC B cell commitment.

Experimental models of liver injury have been established utilizing thioacetamide (TAA), a classic liver toxic chemical that causes organ damage via oxidative stress and inflammatory induction. This study examined the impact of Febuxostat (a xanthine oxidase inhibitor; Febu, 10-15 mg/kg, orally) against TAA (500 mg/kg, i.p.) -induced liver injury in rats. Febu significantly attenuated TAA-induced alterations in liver function parameters, in addition to promoting hepatic antioxidant effects through a significant elevation of Heme-oxygenase-1(HO-1), nuclear factor erythroid 2-related factor2 (Nrf2), reduced glutathione (GSH) and superoxide dismutase (SOD) levels and reduction in hepatic malondialdehyde (MDA) content. Moreover, Febu improved the hepatic anti-inflammatory status by increasing the anti-inflammatory cytokine Interleukin (IL-10) level and reducing the levels of the pro-inflammatory cytokines (Nuclear factor kappa B (NF-κB), IL-1β, high-mobility group box1 (HMGB1), receptor for advanced glycation end products (RAGE), and toll-like receptor4 (TLR4) levels, in addition to suppressing the increased protein and mRNA expression levels of tumor necrosis factor alpha (TNF-α) and IL-6, hepatic expression of TNF-α and activated mitogen-activated protein kinases (p-JNK/p-p38 MAPK). Histopathologically, Febu markedly normalized TAA-induced alteration in liver sections. In conclusion, Febu, in a dose-dependent fashion, refines TAA-induced hepatotoxicity by enhancing antioxidant capabilities and decreasing inflammatory signals.

Duck reovirus (DRV) is a universal waterfowl virus that causes significant economic losses in the duck industry. However, the role of the host innate immune response of the Bursa of Fabricius to DRV infection is largely unknown. In the present study, we constructed a single-cell resolution transcriptomic atlas of the Bursa of Fabricius of Cairna moschata after infection with HN10 (a novel DRV). Ten cell-type marker genes were used to annotate the cell type, indicating a high degree of cell heterogeneity in the Bursa of Fabricius. Most of the innate and adaptive immune system-related genes were highly expressed in T cells, B cells, neutrophils, macrophages, and DCs. In the Bursa of Fabricius, the proportions of DCs and macrophages were largely increased by HN10 infection at 14 d, suggesting that DCs and macrophages play important roles in the long-term viral response. Notably, a number of innate and adaptive immune system-related genes were highly expressed at 24 h after HN10 infection, indicating that the Bursa of Fabricius has a very strong immune function even in the early developmental stage. In the immune system, the NOD-like receptor signaling pathway and RIG-I-like receptor signaling pathway were significantly activated at the early stage of HN10 infection, while the Toll-like receptor signaling pathway was significantly activated at the late stage. Enrichment analysis suggested that different immune signaling pathways play roles in specific developmental stages. Our data provide an opportunity to reveal the immune response to DRV infection at the single-cell level.

Botulinum Neurotoxin A (BoNT/A) is a bacterial protein that has proven to be a valuable pharmaceutical in therapeutic indications and aesthetic medicine. One major concern is the formation of neutralizing antibodies (nAbs) to the core BoNT/A protein. These can interfere with the therapy, resulting in partial or complete antibody (Ab)-mediated secondary non-response (SNR) or immunoresistance. If titers of nAbs reach a level high enough that all injected BoNT/A molecules are neutralized, immunoresistance occurs. Studies have shown that continuation of treatment of neurology patients who had developed Ab-mediated partial SNR against complexing protein-containing (CPC-) BoNT/A was in some cases successful if patients were switched to complexing protein-free (CPF-) incobotulinumtoxinA (INCO). This seems to contradict the layperson's basic immunological understanding that repeated injection with the same antigen BoNT/A should lead to an increase in antigen-specific antibody titers. As such, we strive to explain how immunological memory works in general, and based on this, we propose a working hypothesis for this paradoxical phenomenon observed in some, but not all, neurology patients with immunoresistance. A critical factor is the presence of potentially immune-stimulatory components in CPC-BoNT/A products that can act as immunologic adjuvants and activate not only naïve, but also memory B lymphocyte responses. Furthermore, we propose that continuous injection of a BoN/TA formulation with low immunogenicity, e.g., INCO, may be a viable option for aesthetic patients with existing nAbs. These concepts are supported by a real-world case example of a patient with immunoresistance whose nAb levels declined with corresponding resumption of clinical response despite regular INCO injections.

(1) Background: We describe a model of primary mild-Clostridioides difficile infection (CDI) in a naïve host, including gut microbiota analysis, weight loss, mortality, length of colonization. This model was used in order to describe the kinetics of humoral (IgG, IgM) and mucosal (IgA) immune responses against toxins (TcdA/TcdB) and surface proteins (SlpA/FliC). (2) Methods: A total of 105 CFU vegetative forms of C. difficile 630Δerm were used for challenge by oral administration after dysbiosis, induced by a cocktail of antibiotics. Gut microbiota dysbiosis was confirmed and described by 16S rDNA sequencing. We sacrificed C57Bl/6 mice after different stages of infection (day 6, 2, 7, 14, 21, 28, and 56) to evaluate IgM, IgG against TcdA, TcdB, SlpA, FliC in blood samples, and IgA in the cecal contents collected. (3) Results: In our model, we observed a reproducible gut microbiota dysbiosis, allowing for C. difficile digestive colonization. CDI was objectivized by a mean weight loss of 13.1% and associated with a low mortality rate of 15.7% of mice. We observed an increase in IgM anti-toxins as early as D7 after challenge. IgG increased since D21, and IgA anti-toxins were secreted in cecal contents. Unexpectedly, neither anti-SlpA nor anti-FliC IgG or IgA were observed in our model. (4) Conclusions: In our model, we induced a gut microbiota dysbiosis, allowing a mild CDI to spontaneously resolve, with a digestive clearance observed since D14. After this primary CDI, we can study the development of specific immune responses in blood and cecal contents.

Under the dual pressure of emerging zoonoses and the difficulty in eliminating conventional zoonoses, the strategic management of bird diseases through vaccination represents a highly efficacious approach to disrupting the transmission of zoonotic pathogens to humans. Immunization with a DNA vaccine yielded limited protection against avian pathogen infection. To improve its immunogenicity, the extracellular domain of duck-derived CD40L (designated as dusCD40L) was employed as a bio-adjuvant. Our findings unequivocally established the evolutionary conservation of dusCD40L across avian species. Notably, dusCD40L exhibited a compelling capacity to elicit robust immune responses from both B and T lymphocytes. Furthermore, when employed as an adjuvant, dusCD40L demonstrated a remarkable capacity to significantly augment the titers of neutralizing antibodies and the production of IFNγ elicited by a DNA vaccine encoding the prM-E region of an avian flavivirus, namely, the Tembusu virus (TMUV). Moreover, dusCD40L could strengthen virus clearance of the prM-E DNA vaccine in ducks post-TMUV challenge. This research study presents a highly effective adjuvant for advancing the development of DNA vaccines targeting TMUV in avian hosts. Additionally, it underscores the pivotal role of duCD40L as a potent adjuvant in the context of vaccines designed to combat zoonotic infections in avian species.

Carboxyamidotriazole (CAI) was previously recognized as a well-tolerated anticancer drug. It has also demonstrated significant anti-inflammatory effects in various cell and animal model experiments, prompting its investigation as a potential treatment for rheumatoid arthritis. In this study, the potential biotransformation metabolites of CAI were identified both in vitro and in vivo. A sensitive, specific, and accurate LC-MS method was developed for the quantitative analysis of CAI and its major metabolite, CAI-OH, in rat plasma. CAI, CAI-OH, and telmisartan (used as an internal standard) were separated using a Zorbax SB C18 column. The mobile phase consisted of water (phase A, containing 0.1% formic acid) and acetonitrile (phase B, containing 0.1% formic acid) at a flow rate of 0.2 mL/min. The analytes were examined using a high-resolution mass spectrometer, with detected mass-to-charge ratios of m/z 424.01293 for CAI, m/z 440.00785 for CAI-OH, and m/z 515.24415 for telmisartan. Good linearity was observed within the range of 10-5000 ng/mL. Both inter- and intra-batch precision (relative standard deviation, %) were below 6%, and the accuracy ranged from 94.9% to 106.1%. The analytes remained stable throughout the entire experimental period. This method was successfully applied in a pharmacokinetic study of CAI following oral administration in rats.

Ascorbic acid can regulate the function of the immune system. This study aimed to investigate the underlying mechanisms of ascorbic acid in plasma cell differentiation and rheumatoid arthritis (RA).

Mice were intraperitoneally injected with either ascorbic acid or an equivalent volume of phosphate-buffered saline (PBS). To elucidate the effects of ascorbic acid on arthritis, we utilized a collagen induced arthritis mouse model (CIA). To investigate the effects of ascorbic acid on antibody response, mice were immunized with (4-Hydroxy-3-nitrophenylacetyl)-Ficoll (NP-Ficoll) or (4-hydroxy-3-nitrophenyl) acetyl-keyhole limpet hemocyanin (NP-KLH) to elicit a T-cell independent (TI) or T-cell dependent (TD) antibody response. To clarify the ability of ascorbic acid on plasma cell production, we tracked the B cell differentiation fate on the NP-specific B1-8hi BCR transgenic background.

Ascorbic acid-injected mice demonstrated significantly delayed disease incidence and decreased disease severity compared to PBS-injected mice. Ascorbic acid can reduce the titers of autoantibodies in both arthritis and lupus mice models. Ascorbic acid can significantly reduce the number of plasma cells and the production of antigen-specific antibodies in TI and TD antibody response. In addition, ascorbic acid can disrupt the antibody affinity maturation. Through B1-8hi adoptive transfer experiments, it has been demonstrated that ascorbic acid restrains B cell differentiation into plasma cells in a cell-intrinsic manner. After in-depth exploration, we found that ascorbic acid can block the cell cycle of B cells and promote cell apoptosis. Mechanistically, ascorbic acid inhibited the production of autoreactive plasma cells by inhibiting the Stat3 signaling pathway.

Our study demonstrates that ascorbic acid has the ability to suppress the generation of autoreactive plasma cells, diminish the production of autoantibodies, and consequently delay the onset of rheumatoid arthritis.

The Jinhua pig is well known in China due to its delicious meat. However, because of large litter size, low birth weight always happens. This experiment used this breed as a model to research bacterial evidence leading to growth restriction and provide a possible solution linked to probiotics. In this experiment, the differences in organs indexes, colonic morphology, short chain fatty acid (SCFA) concentrations, microbiome, and transcriptome were detected between piglets in the standard-birth-weight group (SG) and low-birth-weight group (LG) to find potential evidence leading to low birth weight. We found that LG piglets had a lower liver index (p < 0.05), deeper colonic crypt depth (p < 0.05), fewer goblet cells (p < 0.05), and more inflammatory factor infiltration. In addition, differentially expressed genes (DEGs) were mainly enriched in B-cell immunity and glucose metabolism, and LG piglets had lower concentrations of SCFAs, especially butyrate and isobutyrate (p < 0.05). Finally, most of the significantly differentially abundant microbes were fewer in LG piglets, which affected DEG expressions and SCFA concentrations further resulting in worse energy metabolism and immunity. In conclusion, colonic disrupted microbiota may cause worse glucose metabolism, immunity, and SCFA production in LG piglets, and beneficial microbes colonized in SG piglets may benefit these harmful changes.

Vitamin D deficiency (VDD) is prevalent in the population, with inadequate intake, impaired absorption and metabolism as the main causative factors. VDD increases the risk of developing chronic diseases such as type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN), but the molecular mechanisms underlying this phenomenon are not known. The aim of this study was to investigate the association and potential mechanisms of vitamin D levels with the progression of DN by analyzing general clinical data and using bioinformatics methods.

The study included 567 diabetes mellitus type 2 (T2DM) patients from the Rocket Force Characteristic Medical Center as the case group and 221 healthy examinees as the normal control group. T2DM patients were categorized into T2DM, early diabetic nephropathy (EDN), and advanced diabetic nephropathy (ADN) based on the progression of diabetic nephropathy. The renal RNA-seq and scRNA-seq data of patients with DN were mined from public databases, and the differential expression of vitamin D-related genes in normal-EDN-ADN was analyzed by bioinformatics method, protein interaction network was constructed, immune infiltration was evaluated, single cell map was drawn, and potential mechanisms of VD and DN interaction were explored.

Chi-square test showed that vitamin D level was significantly negatively correlated with DN progression (p < 0.001). Bioinformatics showed that the expression of vitamin D-related cytochrome P450 family genes was down-regulated, and TLR4 and other related inflammatory genes were abnormally up-regulated with the progression of DN. Vitamin D metabolism disturbance up-regulate "Nf-Kappa B signaling pathway," B cell receptor signaling pathway and other immune regulation and insulin resistance related pathways, and inhibit a variety of metabolic pathways. In addition, vitamin D metabolism disturbance are strongly associated with the development of diabetic cardiomyopathy and several neurological disease complications.

VDD or vitamin D metabolism disturbance is positively associated with the severity of renal injury. The mechanisms may involve abnormal regulation of the immune system by vitamin D metabolism disturbance, metabolic suppression, upregulation of insulin resistance and inflammatory signalling pathways.

Using an Ig H chain conferring specificity for N-acetyl-d-glucosamine (GlcNAc), we developed transgenic (VHHGAC39 TG) mice to study the role of self-antigens in GlcNAc-reactive B-1 B cell development. In VHHGAC39 TG mice, GlcNAc-reactive B-1 B cell development during ontogeny and in adult bone marrow was normal. However, adult TG mice exhibited a block at transitional-2 immature B cell stages, resulting in impaired allelic exclusion and accumulation of a B cell subset coexpressing endogenous Ig gene rearrangements. Similarly, VHHGAC39 B cell fitness was impeded compared with non-self-reactive VHJ558 B TG cells in competitive mixed bone marrow chimeras. Nonetheless, adult VHHGAC39 mice immunized with Streptococcus pyogenes produce anti-GlcNAc Abs. Peritoneal cavity B cells transferred from VHHGAC39 TG mice into RAG-/- mice also exhibited robust expansion and anti-GlcNAc Ab production. However, chronic treatment of young VHHGAC39 mice with GlcNAc-specific mAbs leads to lower GlcNAc-binding B cell frequencies while increasing the proportion of GlcNAc-binding B1-a cells, suggesting that Ag masking or clearance of GlcNAc Ags impedes maturation of newly formed GlcNAc-reactive B cells. Finally, BCR H chain editing promotes expression of endogenous nontransgenic BCR alleles, allowing potentially self-reactive TG B cells to escape anergy or deletion at the transitional stage of precursor B cell development. Collectively, these observations indicate that GlcNAc-reactive B cell development is sensitive to the access of autologous Ags.

Grass Carp Reovirus (GCRV) and Aeromonas hydrophila (Ah) are the causative agents of haemorrhagic disease in grass carp. This study aimed to investigate the molecular mechanisms and immune responses at the miRNA, mRNA, and protein levels in grass carp kidney cells (CIK) infected by Grass Carp Reovirus (GCRV, NV) and Aeromonas hydrophilus (Bacteria, NB) to gain insight into their pathogenesis. Within 48 h of infection with Grass Carp Reovirus (GCRV), 99 differentially expressed microRNA (DEMs), 2132 differentially expressed genes (DEGs), and 627 differentially expressed proteins (DEPs) were identified by sequencing; a total of 92 DEMs, 3162 DEGs, and 712 DEPs were identified within 48 h of infection with Aeromonas hydrophila. It is worth noting that most of the DEGs in the NV group were primarily involved in cellular processes, while most of the DEGs in the NB group were associated with metabolic pathways based on KEGG enrichment analysis. This study revealed that the mechanism of a grass carp haemorrhage caused by GCRV infection differs from that caused by the Aeromonas hydrophila infection. An important miRNA-mRNA-protein regulatory network was established based on comprehensive transcriptome and proteome analysis. Furthermore, 14 DEGs and 6 DEMs were randomly selected for the verification of RNA/small RNA-seq data by RT-qPCR. Our study not only contributes to the understanding of the pathogenesis of grass carp CIK cells infected with GCRV and Aeromonas hydrophila, but also serves as a significant reference value for other aquatic animal haemorrhagic diseases.

Recently, we reported that preexposure of B cells to IL-4 induced an alternate, signalosome-independent BCR signaling pathway leading to protein kinase C (PKC)δ phosphorylation (pTyr311), which occurs in the membrane compartment. This is considered to represent a form of receptor crosstalk and signal integration. Unlike the classical BCR signaling pathway, Lyn kinase is indispensable for BCR-induced downstream events in the alternate pathway. Our previous report that alternate BCR signaling leading to ERK phosphorylation is triggered by LPS and PAM3CSK4 (much like IL-4) raises the possibility that other signaling outcomes such as PKCδ phosphorylation might be similarly affected. To explore the range of mediators capable of producing an alternate pathway for BCR signaling, we examined PKCδ translocation and phosphorylation in LPS- and PAM3CSK4-treated B cells stimulated by anti-Ig. We found that LPS and PAM3CSK4 alter the signaling pathway used by the BCR to produce PKCδ phosphorylation. As with IL-4, elements of the signalosome are not needed for PKCδ phosphorylation when BCR triggering occurs after LPS and PAM3CSK4. However, with LPS and PAM3CSK4, anti-Ig-induced phosphorylation of PKCδ takes place in the cytosol, in contrast to the IL-4-induced alternate pathway, wherein PKCδ phosphorylation occurs in the membrane. Furthermore, the BCR signaling pathway induced by LPS and PAM3CSK4 differs from that induced by IL-4 by not requiring Lyn. Thus, an alternate, signalosome-independent BCR signaling pathway for PKCδ phosphorylation is induced by TLR agonists but differs in important ways from the alternate pathway induced by IL-4.

Vaccines are used for the control of infectious diseases of animals. Over other types of vaccinations like live attenuated or killed vaccines, mRNA-based vaccines have significant advantages. As only a small portion of the pathogen's genetic material is employed and the dose rate of mRNA-based vaccines is low, there is the least possibility that the pathogen will reverse itself. A carrier or vehicle that shields mRNA-based vaccines from the host's cellular RNases is necessary for their delivery. mRNA vaccines have been shown to be effective and to induce both a cell-mediated immune response and a humoral immune response in clinical trials against various infectious diseases (viral and parasitic) affecting the animals, including rabies, foot and mouth disease, toxoplasmosis, Zikavirus, leishmaniasis, and COVID-19. The current review aims to highlight the use of mRNA-based vaccines both in viral and parasitic diseases of animals.

Astragali radix (AR) and anemarrhenae rhizoma (AAR) are used clinically in Chinese medicine for the treatment of chronic heart failure (CHF), but the exact therapeutic mechanism is unclear. In this study, a total of 60 male C57BL/6 mice were divided into 5 groups, namely sham, model, AR, AAR, and AR-AAR. In the sham group, the chest was opened without ligation. In the other groups, the chest was opened and the transverse aorta was ligated to construct the transverse aortic constriction model. After 8 weeks of feeding, mice were given medicines by gavage for 4 weeks. Left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were detected by echocardiography. Heart weight index (HWI) and wheat germ agglutinin staining were used to evaluate cardiac hypertrophy. Hematoxylin-eosin staining was used to observe the pathological morphology of myocardial tissue. Masson staining was used to evaluate myocardial fibrosis. The content of serum brain natriuretic peptide (BNP) was detected by enzyme-linked immunosorbent assay kit. The content of serum immunoglobulin G (IgG) was detected by immunoturbidimetry. The mechanism of AR-AAR in the treatment of CHF was explored by proteomics. Western blot was used to detect the protein expressions of complement component 1s (C1s), complement component 9 (C9), and terminal complement complex 5b-9 (C5b-9). The results show that AR-AAR inhibits the expression of complement proteins C1s, C9, and C5b-9 by inhibiting the production of IgG antibodies from B cell activation, which further inhibits the complement activation, attenuates myocardial fibrosis, reduces HWI and cardiomyocyte cross-sectional area, improves cardiomyocyte injury, reduces serum BNP release, elevates LVEF and LVFS, improves cardiac function, and exerts myocardial protection.

The functional performance of immune cells relies on a complex transcriptional regulatory network. The three-dimensional structure of chromatin can affect chromatin status and gene expression patterns, and plays an important regulatory role in gene transcription. Currently available techniques for studying chromatin spatial structure include chromatin conformation capture techniques and their derivatives, chromatin accessibility sequencing techniques, and others. Additionally, the recently emerged deep learning technology can be utilized as a tool to enhance the analysis of data. In this review, we elucidate the definition and significance of the three-dimensional chromatin structure, summarize the technologies available for studying it, and describe the research progress on the chromatin spatial structure of dendritic cells, macrophages, T cells, B cells, and neutrophils.

Ischemia/reperfusion injury-mediated (IRI-mediated) primary graft dysfunction (PGD) adversely affects both short- and long-term outcomes after lung transplantation, a procedure that remains the only treatment option for patients suffering from end-stage respiratory failure. While B cells are known to regulate adaptive immune responses, their role in lung IRI is not well understood. Here, we demonstrated by intravital imaging that B cells are rapidly recruited to injured lungs, where they extravasate into the parenchyma. Using hilar clamping and transplant models, we observed that lung-infiltrating B cells produce the monocyte chemokine CCL7 in a TLR4-TRIF-dependent fashion, a critical step contributing to classical monocyte (CM) recruitment and subsequent neutrophil extravasation, resulting in worse lung function. We found that synergistic BCR-TLR4 activation on B cells is required for the recruitment of CMs to the injured lung. Finally, we corroborated our findings in reperfused human lungs, in which we observed a correlation between B cell infiltration and CM recruitment after transplantation. This study describes a role for B cells as critical orchestrators of lung IRI. As B cells can be depleted with currently available agents, our study provides a rationale for clinical trials investigating B cell-targeting therapies.

Increasing evidence confirms that histone modification plays a critical role in preserving long-term immunological memory. Immune priming is a novel form of immunological memory recently verified in invertebrates. Toll-like receptor (TLR) signaling and cytokines have been reported to be involved in the immune priming of the Pacific oyster Crassostrea gigas. In the present study, the expression of Toll-like receptor 3 (CgTLR3), myeloid differentiation factor 88-2 (CgMyd88-2) and interleukin 17-1 (CgIL17-1) was found to be elevated in the hemocytes of C. gigas at 6 h after the secondary stimulation with Vibrio splendidus, which was significantly higher than that at 6 h after the primary stimulation (p < 0.05). A significant increase in histone H3 lysine 4 trimethylation (H3K4me3) enrichment was detected in the promoter region of the CgTLR3 gene at 7 d after the primary stimulation with inactivated V. splendidus (p < 0.05). After the treatment with a histone methyltransferase inhibitor (5'-methylthioadenosine, MTA), the level of H3K4me3 at the promoter of the CgTLR3 gene decreased significantly at 7 d after the primary stimulation with inactivated V. splendidus (p < 0.05), and the expression of CgTLR3, CgMyD88-2 and CgIL17-1 was significantly repressed at 6 h after the secondary stimulation with V. splendidus (p < 0.05). Conversely, the treatment with monomethyl fumarate (MEF, an inhibitor of histone demethylases) resulted in a significant increase in H3K4me3 enrichment levels at the CgTLR3 promoter at 7 d after the primary stimulation (p < 0.05), and the expression of CgTLR3, CgMyD88-2 and CgIL17-1 was observed to increase significantly at 6 h after the secondary stimulation (p < 0.05). These results suggested that H3K4me3 regulated MyD88-dependent TLR signaling in the hemocytes of C. gigas, which defined the role of histone modifications in invertebrate immune priming.

While the immunomodulation effects of per- and polyfluoroalkyl substances (PFASs) are described on the level of clinical signs in epidemiological studies (e.g., suppressed antibody response after vaccination), the underlying mechanism has still not been fully elucidated. To reveal mechanisms of PFAS exposure on immunity, we investigated the genome-wide transcriptomic changes of peripheral blood mononuclear cells (PBMCs) responding to PFAS exposure (specifically, exposure to PFPA, PFOA, PFNA, PFDA, PFUnDA, PFHxS, and PFOS). Blood samples and the chemical load in the blood were analyzed under the cross-sectional CELSPAC: Young Adults study. The overall aim of the study was to identify sensitive gene sets and cellular pathways conserved for multiple PFAS chemicals. Transcriptome networks related to adaptive immunity were perturbed by multiple PFAS exposure (i.e., blood levels of at least four PFASs). Specifically, processes tightly connected with late B cell development, such as B cell receptor signaling, germinal center reactions, and plasma cell development, were shown to be affected. Our comprehensive transcriptome analysis identified the disruption of B cell development, specifically the impact on the maturation of antibody-secreting cells, as a potential mechanism underlying PFAS immunotoxicity.

In multicellular organisms, regulatory cell death is a crucial aspect of growth and development. Ferroptosis, which was postulated roughly ten years ago, is a mode of cell death that differs from apoptosis, autophagy, and pyrodeath. This distinct pattern of cell death is triggered by an imbalance between oxidants and antioxidants and strongly associated with the metabolism of iron, lipids, amino acids, and glutathione. A growing body of research has implicated ferroptosis in the incidence and progression of many organ traumas and degenerative diseases. Recently, ferroptosis has gained attention as a crucial regulatory mechanism underlying the initiation and development of a variety of cardiovascular diseases, including myocardial ischemia/reperfusion injury, cardiomyopathy, arrhythmia, chemotherapy, and Corona Virus-2-induced cardiac injury. Pharmacological therapies that inhibit ferroptosis have great potential for the management of cardiovascular disorders. This review discusses the prevalence and regulatory mechanisms of ferroptosis, effect of ferroptosis on the immune system, significance of ferroptosis in cardiovascular diseases, and potential therapeutic value of regulating ferroptosis in a variety of heart diseases.

The maternal balance between B regulatory (Breg) cells and inflammatory B cells is of central importance for protection against preterm birth (PTB). However, the impact of B cell signaling in early maternal and fetal immune responses on inflammatory insults remains underinvestigated. To understand which role B cells and B-cell-specific signaling play in the pathogenesis of PTB, the later was induced by an injection of LPS in B cell-sufficient WT mice, CD19-/-, BMyD88-/- and µMT murine dams at gestational day 16 (gd 16). WT dams developed a strong inflammatory response in their peritoneal cavity (PC), with an increased infiltration of granulocytes and enhanced IL-6, TNF-α, IL-17 and MCP-1 levels. However, they demonstrated a reduced NOS2 expression of PC macrophages 4 h after the LPS injection. Simultaneously, LPS-challenged WT dams upregulated pregnancy-protective factors like IL-10 and TARC. The concentrations of inflammatory mediators in the placental supernatants, amniotic fluids, fetal serums and gestational tissues were lower in LPS-challenged WT dams compared to CD19-/-, BMyD88-/- and µMT dams, thereby protecting WT fetuses from being born preterm. B cell deficiency, or the loss of B-cell-specific CD19 or MyD88 expression, resulted in an early shift from immune regulation towards inflammation at the fetomaternal interface and fetuses, resulting in PTB.

Safe and effective vaccines are crucial for the control and eventual elimination of malaria. Novel approaches to optimize and improve vaccine efficacy are urgently required. Nanoparticle-based delivery platforms are considered potent and powerful tools for vaccine development.

In this study, we developed a transmission-blocking vaccine against malaria by conjugating the ookinete surface antigen PSOP25 to the Acinetobacter phage coat protein AP205, forming virus-like particles (VLPs) using the SpyTag/SpyCatcher adaptor system. The combination of AP205-2*SpyTag with PSOP25-SpyCatcher resulted in the formation of AP205-PSOP25 complexes (VLP-PSOP25). The antibody titers and avidity of serum from each immunization group were assessed by ELISA. Western blot and IFA were performed to confirm the specific reactivity of the elicit antisera to the native PSOP25 in Plasmodium berghei ookinetes. Both in vitro and in vivo assays were conducted to evaluate the transmission-blocking activity of VLP-PSOP25 vaccine.

Immunization of mice with VLP-PSOP25 could induced higher levels of high-affinity antibodies than the recombinant PSOP25 (rPSOP25) alone or mixtures of untagged AP205 and rPSOP25 but was comparable to rPSOP25 formulated with alum. Additionally, the VLP-PSOP25 vaccine enhanced Th1-type immune response with remarkably increased levels of IgG2a subclass. The antiserum generated by VLP-PSOP25 specifically recognizes the native PSOP25 antigen in P. berghei ookinetes. Importantly, antisera generated by inoculation with the VLP-PSOP25 could inhibit ookinete development in vitro and reduce the prevalence of infected mosquitoes or oocyst intensity in direct mosquito feeding assays.

Antisera elicited by immunization with the VLP-PSOP25 vaccine confer moderate transmission-reducing activity and transmission-blocking activity. Our results support the utilization of the AP205-SpyTag/SpyCatcher platform for next-generation TBVs development.

The meningeal space is a critical brain structure providing immunosurveillance for the central nervous system (CNS), but the impact of infections on the meningeal immune landscape is far from being fully understood. The extracellular protozoan parasite Trypanosoma brucei, which causes human African trypanosomiasis (HAT) or sleeping sickness, accumulates in the meningeal spaces, ultimately inducing severe meningitis and resulting in death if left untreated. Thus, sleeping sickness represents an attractive model to study immunological dynamics in the meninges during infection. Here, by combining single-cell transcriptomics and mass cytometry by time-of-flight (CyTOF) with in vivo interventions, we found that chronic T. brucei infection triggers the development of ectopic lymphoid aggregates (ELAs) in the murine meninges. These infection-induced ELAs were defined by the presence of ER-TR7+ fibroblastic reticular cells, CD21/35+ follicular dendritic cells (FDCs), CXCR5+ PD1+ T follicular helper-like phenotype, GL7+ CD95+ GC-like B cells, and plasmablasts/plasma cells. Furthermore, the B cells found in the infected meninges produced high-affinity autoantibodies able to recognise mouse brain antigens, in a process dependent on LTβ signalling. A mid-throughput screening identified several host factors recognised by these autoantibodies, including myelin basic protein (MBP), coinciding with cortical demyelination and brain pathology. In humans, we identified the presence of autoreactive IgG antibodies in the cerebrospinal fluid (CSF) of second stage HAT patients that recognised human brain lysates and MBP, consistent with our findings in experimental infections. Lastly, we found that the pathological B cell responses we observed in the meninges required the presence of T. brucei in the CNS, as suramin treatment before the onset of the CNS stage prevented the accumulation of GL7+ CD95+ GC-like B cells and brain-specific autoantibody deposition. Taken together, our data provide evidence that the meningeal immune response during chronic T. brucei infection results in the acquisition of lymphoid tissue-like properties, broadening our understanding of meningeal immunity in the context of chronic infections. These findings have wider implications for understanding the mechanisms underlying the formation ELAs during chronic inflammation resulting in autoimmunity in mice and humans, as observed in other autoimmune neurodegenerative disorders, including neuropsychiatric lupus and multiple sclerosis.

Intelectin is a lectin with the capacity to recognize and bind to carbohydrates. In this study, we successfully cloned cITLN3 from common carp, which consists of a signal peptide domain, a FReD domain, and an intelectin domain. The expression levels of cITLN3 were detected in various organs of common carp, including the liver, head kidney, spleen, foregut, midgut, and hindgut, with the highest expression observed in the liver. Following infection with Staphylococcus aureus (S. aureus) or Aeromonas hydrophila (A. hydrophila), the expression level of cITLN3 was significantly upregulated in all organs of common carp. Subsequently, we expressed and purified the recombinant cITLN3 protein using an E. coli expression system. The cITLN3 could aggregate both gram-positive and gram-negative bacteria in the presence of Ca2+, with a stronger affinity for gram-positive bacteria. Moreover, our study demonstrated that cITLN3 displayed a higher binding affinity towards PGN compared to LPS. Furthermore, we observed that cITLN3 had the potential to inhibit bacterial proliferation in common carp and safeguard intestinal integrity during bacterial stimulation. And the results also indicated that cITLN3 might played a role in the Toll-like receptors (TLRs) signaling pathway activation.

mRNA vaccines can be translated into protein antigens, in vivo, to effectively induce humoral and cellular immunity against these proteins. While current mRNA vaccines have generated potent immune responses, the need for ultracold storage conditions (- 80 °C) and healthcare professionals to administer the vaccine through the parenteral route has somewhat limited their distribution in rural areas and developing countries. Overcoming these challenges stands to transform future deployment of mRNA vaccines. In this study, we developed an mRNA vaccine that can trigger a systemic immune response through administration via the gastrointestinal (GI) tract and is stable at 4 °C. A library of cationic branched poly(β-amino ester) (PBAE) polymers was synthesized and characterized, from which a polymer with high intracellular mRNA delivery efficiency and immune stimulation capacity was down-selected. mRNA vaccines made with the lead polymer-elicited cellular and humoral immunity in mice. Furthermore, lyophilization conditions of the formulation were optimized to enable storage under refrigeration. Our results suggest that PBAE nanoparticles are potent mRNA delivery platforms that can elicit B cell and T cell activation, including antigen-specific cellular and humoral responses. This system can serve as an easily administrable, potent oral mRNA vaccine.

Cysticercosis pisiformis, a highly prevalent parasitic disease worldwide, causes significant economic losses in the rabbit breeding industry. Previous investigations have identified a novel microRNA, designated as novel-miR1, within the serum of rabbit infected with Cysticercus pisiformis. In the present study, we found that C. pisiformis-derived novel-miR1 was released into the rabbit serum via exosomes. Through computational analysis using TargetScan, miRanda, and PITA, a total of 634 target genes of novel-miR1 were predicted. To elucidate the functional role of novel-miR1, a dual-luciferase reporter assay was utilized and demonstrated that novel-miR1 targets rabbit Toll-like receptor 2 (TLR2). Rabbit peripheral blood lymphocytes (PBLCs) were transfected with novel-miR1 mimic and mimic NC, and the in vitro experiments confirmed that novel-miR1 suppressed the expression of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 through the nuclear factor kappa B (NF-κB) pathway. In vivo experiments demonstrated that novel-miR1 was significantly upregulated during the 1-3 months following infection with C. pisiformis in rabbits. Notably, this upregulation coincided with a downregulation of TLR2, P65, pP65, TNF-α, IL-1β, and IL-6 in PBLCs. Collectively, these results indicate that the novel-miR1 derived from C. pisiformis inhibited the rabbits' immune response by suppressing the NF-κB-mediated immune response. This immune modulation facilitates parasite invasion, survival, and establishment of a persistent infection.

Maturation of antibody responses entails somatic hypermutation (SHM), class-switch DNA recombination (CSR), plasma cell differentiation, and generation of memory B cells, and it is thought to require T cell help. We showed that B cell Toll-like receptor 4 (TLR4)-B cell receptor (BCR) (receptor for antigen) coengagement by 4-hydroxy-3-nitrophenyl acetyl (NP)-lipopolysaccharide (LPS) (Escherichia coli lipid A polysaccharide O-antigen) or TLR5-BCR coengagement by Salmonella flagellin induces mature antibody responses to NP and flagellin in Tcrβ-/-Tcrδ-/- and NSG/B mice. TLR-BCR coengagement required linkage of TLR and BCR ligands, "linked coengagement." This induced B cell CSR/SHM, germinal center-like differentiation, clonal expansion, intraconal diversification, plasma cell differentiation, and an anamnestic antibody response. In Tcrβ-/-Tcrδ-/- mice, linked coengagement of TLR4-BCR by LPS or TLR5-BCR by flagellin induced protective antibodies against E. coli or Salmonella Typhimurium. Our findings unveiled a critical role of B cell TLRs in inducing neutralizing antibody responses, including those to microbial pathogens, without T cell help.