Immune System Research Articles

Detection of CRISPR‒Cas and type I R-M systems in Klebsiella pneumoniae of human and animal origins and their relationship to antibiotic resistance and virulence.

The clustered regularly interspaced short palindromic repeats (CRISPR)‒CRISPR-associated protein (Cas) and restriction‒modification (R-M) systems are important immune systems in bacteria. Information about the distributions of these two systems in Klebsiella pneumoniae from different hosts and their mutual effect on antibiotic resistance and virulence is still limited. In this study, the whole genomes of 520 strains of K. pneumoniae from GenBank, including 325 from humans and 195 from animals, were collected for CRISPR‒Cas systems and type I R-M systems, virulence genes, antibiotic resistance genes, and multilocus sequence typing detection. The results showed that host origin had no obvious influence on the distributions of the two systems (CRISPR‒Cas systems in 29.8% and 24.1%, type I R-M systems in 9.8% and 11.8% of human-origin and animal-origin strains, respectively) in K. pneumoniae. Identical spacer sequences from different hosts demonstrated there was a risk of human-animal transmission. All virulence genes (yersiniabactin, colibactin, aerobactin, salmochelin, rmpADC, and rmpA2) detection rates were higher when only the CRISPR‒Cas systems were present but were all reduced when coexisting with type I R-M systems. However, a lower prevalence of most antibiotic-resistance genes was found when the CRISPR‒Cas systems were alone, and when type I R-M systems were coexisting, some of the antibiotic resistance gene incidence rates were even lower (aminoglycosides, clindamycins, rifampicin-associated resistance genes, sulfonamides, methotrexates, beta-lactamases, and ultrabroad-spectrum beta-lactamases), and some of them were higher instead (quinolones, macrolides, tetracyclines, and carbapenems). The synergistic and opposed effects of the two systems on virulence and antibiotic-resistance genes need further study.IMPORTANCEK. pneumoniae is an important opportunistic pathogen responsible for both human and animal infections, and the emergence of hypervirulent and multidrug-resistant K. pneumoniae has made it difficult to control this pathogen worldwide. Here, we find that CRISPR‒Cas and restriction-modification systems, which function as adaptive and innate immune systems in bacteria, have synergistic and opposed effects on virulence and antibiotic resistance genes in K. pneumoniae. Moreover, this study provides insights into the distributions of the two systems in K. pneumoniae from different hosts, and there is no significant difference in the prevalence of the two systems among K. pneumoniae spp. In addition, this study also characterizes the CRISPR arrays of K. pneumoniae from different hosts, suggesting that the strains sharing the same spacer sequences have the potential to spread between humans and animals.

Single-cell RNA sequencing uncovers heterogenous immune cell responses upon exposure to food additive (E171) titanium dioxide

The prospective use of food additive titanium dioxide (E171 TiO2) in a variety of fields (food, pharmaceutics, and cosmetics) prompts proper cellular cytotoxicity and transcriptomic assessment. Interestingly, smaller-sized E171 TiO2 can translocate in bloodstream and induce a diverse immunological response by activating the immune system, which can be either pro-inflammatory or immune-suppressive. Nevertheless, their cellular or immunologic responses in a heterogeneous population of the immune system following exposure of food additive E171 TiO2 is yet to be elucidated. For this purpose, we have used male Sprague-Dawley rats to deliver E171 TiO2 (5 mg/kg bw per day) via non-invasive intratracheal instillation for 13 weeks. After the 4 weeks recovery period, 3 mL of blood samples from both treated and untreated groups were collected for scRNAseq analysis. Firstly, granulocyte G1 activated innate immune response through the upregulation of genes involved in pro-inflammatory cytokine mediated cytotoxicity. Whereas NK cells resulted in heterogeneity role depending on the subsets where NK1 significantly inhibited cytotoxicity, whereas NK2 and NK3 subsets activated pro-B cell population & inhibited T cell mediated cytotoxicity respectively. While NKT_1 activated innate inflammatory responses which was confirmed by cytotoxic CD8+ T killer cell suppression. Similarly, NKT_2 cells promote inflammatory response by releasing lytic granules and MHC-I complex inhibition to arrest cytotoxic T killer cell responses. Conversely, NKT_3 suppressed inflammatory response by release of anti-inflammatory cytokines suggesting the functional heterogeneity of NKT subset. The formation of MHC-I or MHC-II complexes with T-cell subsets resulted in neither B and T cell dysfunction nor cytotoxic T killer cell inhibition suppressing adaptive immune response. Overall, our research offers an innovative high-dimensional approach to reveal immunological and transcriptomic responses of each cell types at the single cell level in a complex heterogeneous cellular environment by reassuring a precise assessment of immunological response of E171 TiO2.Graphical

Astragali radix vesicle-like nanoparticles improve energy metabolism disorders by repairing the intestinal mucosal barrier and regulating amino acid metabolism in sleep-deprived mice

BackgroundSleep disorder is widespread and involves a variety of intricate factors in its development. Sleep deprivation is a manifestation of sleep disorder, can lead to energy metabolism disturbances, weakened immune system, and compromised body functions. In extreme situations, sleep deprivation can cause organ failure, presenting significant risks to human health.PurposeThis study aimed to investigate the efficacy and mechanisms of Astragalus Radix vesicles-like nanoparticles (AR-VLNs) in counteracting the deleterious effects of sleep deprivation.MethodsThe ICR mice were divided into control, model, AR-VLNs high dose (equivalent to 20 g/kg crude drug), AR-VLNs low dose (equivalent to 10 g/kg crude drug), AR high dose (equivalent to 20 g/kg crude drug), and AR low dose (equivalent to 10 g/kg crude drug). The REM (rapid eye movement) sleep-deprivation model was established, and evaluations were conducted for motor function, antioxidant capacity, and energy metabolism indices. Moreover, CACO-2 cells damage was induced with lipopolysaccharide to evaluate the repairing ability of AR-VLNs on the intestinal cell mucosa by measuring permeability. Furthermore, metabolomics was employed to elucidate the mechanisms of AR-VLNs action.ResultsAR-VLNs were demonstrated to enhance the motor efficiency and antioxidant capacity in REM sleep-deprived mice, while also minimized pathological damage and restored the integrity of the intestinal mucosal barrier. In vitro experiments indicated the anti-inflammatory effect of AR-VLNs against LPS-induced cell damage. Additionally, metabolomic analysis linked these effects with regulation of the amino acid metabolic pathways. Further confirmation from molecular biology experiments revealed that the protective effects of AR-VLNs against the deleterious effects of REM sleep deprivation were associated with the restoration of the intestinal mucosal barrier and the enhancement of amino acid metabolism.ConclusionAR-VLNs administration effectively improved energy metabolism disorders in REM sleep deprived mice, by facilitating the repair of the intestinal mucosal barrier and regulating the amino acid metabolism.Graphical

Mindfulness-based stress reduction training and supplemented Jinshui Liujun decoction promote recovery in patients with non-small cell lung cancer

BACKGROUND Conventional chemotherapy (CC) administered to patients with non-small cell lung cancer (NSCLC) often causes adverse effects, such as cardiopulmonary dysfunction and immune system imbalance. Patients may experience anxiety and depression during the perioperative period due to various factors, such as treatment costs and cancer recurrence risks, thereby compromising the overall quality of life. Consequently, we hypothesized that integrating mindfulness-based stress reduction training (MSRT) with Jinshui Liujun decoction may mitigate negative emotions and promote recovery in patients with NSCLC. AIM To explore the effects of MSRT and Jinshui Liujun decoction on the immune function and emotional state of NSCLC patients. METHODS A retrospective clinical study was conducted involving 92 patients with stage IIIb-IV NSCLC; 35 patients in the control group (CG) received CC therapy (combination of pemetrexed and carboplatin), and 57 patients in the treatment group (TG) received MSRT-assisted flavored Jinshui Liujun decoction (FJLD) in addition to CC. We evaluated the survival time, Karnofsky performance status, treatment efficacy, traditional Chinese medicine syndrome score, immune function, negative emotional level, and adverse reactions of the CG and TG. RESULTS Median progression-free survival, Karnofsky performance status, and clinical efficacy of the TG were superior to those of the CG (P < 0.05). Symptoms of cough, weakness, bloody sputum, shortness of breath, and chest pain significantly decreased in the TG compared to that in the CG (P < 0.05). In the TG, MSRT + FJLD treatment increased the numbers of CD3+ and CD4+ immune cells, effectively reduced the number of CD8+ cells, and enhanced the CD4+/CD8+ ratio, thereby restoring the immune function of patients. In the TG, the self-rating anxiety scale and self-rating depression scale scores decreased significantly. There was no statistically significant difference in the incidence of adverse reactions between the CG and TG (P > 0.05). CONCLUSION MSRT + FJLD proved to be an effective treatment for patients with NSCLC.

Silver nanoparticle toxicity in rainbow trout: insights into physiological and molecular responses.

Metallic nanoparticles, with their large surface area to volume ratio, are increasingly important in various life fields, but they can cause varying toxic effects on fish. This study investigates the toxicological effects of silver nanoparticles (AgNPs) on rainbow trout (Oncorhynchus mykiss), focusing on hematological, biochemical, antioxidant, and histopathological changes. Fish were exposed to varying concentrations of AgNPs (0.2, 0.8, and 1.4 mg/L) for 21days. Hematological analysis revealed significant reductions in red blood cell (RBC) counts, hemoglobin (Hb), and hematocrit (HCT) at higher AgNPs concentrations, while white blood cell (WBC) counts increased, indicating immune system activation. Biochemical assays demonstrated dose-dependent decreases in total protein and albumin, alongside increased cholesterol and triglyceride levels, suggesting impaired liver function and disrupted lipid metabolism. Antioxidant enzyme activity (SOD, CAT, GST) initially increased at lower AgNPs concentrations but declined at higher exposures, indicating oxidative stress. Molecular analysis further supported these findings, with upregulation of oxidative stress-related genes (SOD1, CAT) and inflammatory markers (HSP70, IL-1β). Histopathological examinations revealed necrosis, hyperplasia, and lamellar fusion in the gills, along with significant liver damage, including vacuolation and Kupffer cell proliferation, particularly at the highest exposure. Behavioral assays showed erratic swimming and reduced feeding in fish exposed to higher AgNPs concentrations. This study highlights the dose-dependent toxic effects of AgNPs on rainbow trout and underscores the potential for long-term, possibly irreversible damage at higher exposure levels. These findings emphasize the need for stricter environmental regulations on nanoparticle use to mitigate their ecological impact.

Lung ultrasound on first postoperative day predicts out-of-hospital pulmonary complications following video-assisted thoracic surgery: A prospective cohort study.

The integration of enhanced recovery after surgery (ERAS) protocols into the peri-operative management of video-assisted thoracic surgery (VATS) has facilitated rapid patient recovery, enabling discharge within 48 h. However, postoperative pulmonary complications (PPCs) postdischarge pose significant concerns for patient welfare. Despite the established utility of lung ultrasound (LUS) in diagnosing the causes of dyspnoea, the effectiveness of quantitative LUS in predicting PPCs after VATS remains uncertain. To determine whether quantitative LUS performed 24 h after surgery can identify patients with a higher risk of developing PPCs within 30 days after discharge from hospital. Single-centre prospective cohort study. Academic tertiary care medical centre. Adults scheduled for elective VATS under general anaesthesia from November 2022 to January 2023. This primary aim was to verify the association between lung ultrasound score (LUSS) on postoperative day 1 (POD1) and PPCs. The secondary aim was to identify other relevant peri-operative factors closely related to PPCs and establish a model capable of predicting the risk of PPCs in patients undergoing fast-track VATS. Of the 200 recruited patients, 182 completed the LUS examination and 30-day follow-up. Of these, 66 (36.2%) developed various types of PPCs. These patients had a higher LUSS on POD 1 (P < 0.001), and more subpleural consolidation areas compared to those without PPCs (P < 0.001). Receiver-operating characteristics (ROC) analysis identified the optimal LUSS cut-off value at 6 points for predicting the occurrence of PPCs, with an area under the curve (AUC) of 0.838 (95% CI, 0.768 to 0.909). Patients with PPCs had higher rates of immune system diseases and ARISCAT score, longer hospital stay and procalcitonin levels, increased frequency of lobar resection, longer durations of surgical and mechanical ventilation, and greater incidence of unplanned hospital readmissions within 30 days postdischarge, compared with those without PPCs (all P < 0.001). Multivariable logistic regression analysis indicated that the comorbidity of immune system disease, along with postoperative 24 h LUSS, were independent risk factor for PPCs within 30 days after VATS. LUSS on POD 1 emerged as an independent risk factor for PPCs in fast-track VATS patients and reliably predicted the occurrence of PPCs within 30 days of hospital discharge. ClinicalTrials. gov No. ChiCTR2200065865.

Ultrasound nanodroplets loaded with Siglec-G siRNA and Fe3O4 activate macrophages and enhance phagocytosis for immunotherapy of triple-negative breast cancer

BackgroundThe progression of triple-negative breast cancer is shaped by both tumor cells and the surrounding tumor microenvironment (TME). Within the TME, tumor-associated macrophages (TAMs) represent a significant cell population and have emerged as a primary target for cancer therapy. As antigen-presenting cells within the innate immune system, macrophages are pivotal in tumor immunotherapy through their phagocytic functions. Due to the highly dynamic and heterogeneous nature of TAMs, re-polarizing them to the anti-tumor M1 phenotype can amplify anti-tumor effects and help mitigate the immunosuppressive TME.ResultsIn this study, we designed and constructed an ultrasound-responsive targeted nanodrug delivery system to deliver Siglec-G siRNA and Fe3O4, with perfluorohexane (PFH) at the core and mannose modified on the surface (referred to as MPFS@NDs). Siglec-G siRNA blocks the CD24/Siglec-G mediated “don’t eat me” phagocytosis inhibition pathway, activating macrophages, enhancing their phagocytic function, and improving antigen presentation, subsequently triggering anti-tumor immune responses. Fe3O4 repolarizes M2-TAMs to the anti-tumor M1 phenotype. Together, these components synergistically alleviate the immunosuppressive TME, and promote T cell activation, proliferation, and recruitment to tumor tissues, effectively inhibiting the growth of primary tumors and lung metastasis.ConclusionThis work suggests that activating macrophages and enhancing phagocytosis to remodel the TME could be an effective strategy for macrophage-based triple-negative breast cancer immunotherapy.

CAR T-cells in autoimmunity: game changer or stepping stone?

The advent of chimeric antigen receptor (CAR) T-cells has revolutionized the treatment landscape for hematologic malignancies, and emerging evidence suggests their potential in autoimmune diseases (AIDs). This article examines the early successes and future implications of B-cell-targeting CAR T-cell therapy in AIDs. Initial applications, particularly in refractory systemic lupus erythematosus (SLE), have demonstrated significant and durable clinical remissions, with accompanying evaluation of the immune system suggesting a so-called "reset" of innate inflammation and adaptive autoimmunity. This has generated widespread interest in expanding this therapeutic approach. CAR T-cells offer unique advantages over other treatment modalities, including very deep B-cell depletion and unique therapeutic activity within inflamed tissues and associated lymph structures. However, the field must address key concerns, including long-term toxicity, particularly the risk of secondary malignancies, and future accessibility given the higher prevalence of AIDs compared to malignancies. Technological advances in cell therapy, such as next-generation CAR T-cells, allogeneic off-the-shelf products and alternative cell types such as regulatory CAR T-cells, are being explored in AIDs to improve efficacy and safety. In addition, bispecific antibodies are emerging as potential alternatives or complements to CAR T-cells, potentially offering comparable efficacy without the need for complex logistics, lymphodepletion and the risk of insertional mutagenesis. As the field evolves, cellular therapists will play a critical role in the multidisciplinary teams managing these complex cases. The transformative potential of CAR T-cells in AIDs is undeniable, but careful consideration of safety, efficacy, and implementation is essential as this novel therapeutic approach moves forward.

The cow GUTBIOME CY study: investigating the composition of the cattle gut microbiome in health and infectious disease transmission in cyprus

BackgroundRecent evidence suggests that the lower gut microbiome of ruminants presents roles in their health and environment, including the development of the mucosal immune system, milk production efficiency and quality and subsequent methane emissions. However, there are proportionately fewer studies on this complex microbial community in cattle and region-focus studies are non- existent.MethodsHerein, we present the research protocol of the GUTBIOME CY project pertaining to determine the composition of the lower gut microbiome in dairy cows situated in 37 farms across five districts of the island of Cyprus. Detailed questionnaires on animal husbandry and farming practices will be gathered from each farm. Faecal, milk (individual and bulk) and water samples will also be collected from cows and their offspring. Samples will be analysed using a combination of molecular biology and bioinformatics pipelines to define microbiome profiles and antimicrobial resistance (AMR). Information collected from the questionnaires will be used to test for associations between animal husbandry or farming practices and microbiome components and AMR.DiscussionCollected samples will establish the first dairy cattle biobank in the country for contributing substantially towards scientific advancements in microbiome research and providing insights to all stakeholders, tailored to the unique agricultural context of Cyprus.

Advancements in Immunity and Dementia Research: Highlights from the 2023 AAIC Advancements: Immunity Conference.

The immune system is a key player in the onset and progression of neurodegenerative disorders. While brain resident immune cell-mediated neuroinflammation and peripheral immune cell (eg, T cell) infiltration into the brain have been shown to significantly contribute to Alzheimer's disease (AD) pathology, the nature and extent of immune responses in the brain in the context of AD and related dementias (ADRD) remain unclear. Furthermore, the roles of the peripheral immune system in driving ADRD pathology remain incompletely elucidated. In March of 2023, the Alzheimer's Association convened the Alzheimer's Association International Conference (AAIC), Advancements: Immunity, to discuss the roles of the immune system in ADRD. A wide range of topics were discussed, such as animal models that replicate human pathology, immune-related biomarkers and clinical trials, and lessons from other fields describing immune responses in neurodegeneration. This manuscript presents highlights from the conference and outlines avenues for future research on the roles of immunity in neurodegenerative disorders. HIGHLIGHTS: The immune system plays a central role in the pathogenesis of Alzheimer's disease. The immune system exerts numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The 2023 AAIC, Advancements: Immunity, encouraged discussions and collaborations on understanding the role of the immune system.

The AxBioTick study – immune gene expression signatures in human skin bitten by Borrelia-infected versus non-infected ticks

BackgroundBorrelia infection is caused by Borrelia burgdorferi sensu lato and transmitted by Ixodes ricinus ticks, a common tick-borne infection in Northern Europe. The establishment of Borrelia infection depends on transmission of the spirochetes, as well as the immune response generated in the skin after a bite. Here we aim to investigate the local immune response in the skin after a tick bite and assess the possible direct effects of Borrelia, by applying gene expression analysis of the immune response in skin exposed to Borrelia-infected and non-infected ticks, respectively.MethodsSkin biopsies from the study participants were taken 7–10 days after the tick-bite. The ticks and skin biopsies were analysed by real-time PCR for Borrelia spp. and other tick-borne pathogens. Dermal transcriptome profiles derived from RNA sequencing with focus on immune system regulation were created. In addition, we performed enrichment analysis of dermal transcriptome profiles with focus on immune system regulation.ResultsSkin biopsies exposed to a Borrelia-positive tick induced an overall higher expression of immune-related genes. Cytokines involved in the regulation of T-cell and macrophage activation, pro-inflammatory regulators and Toll-like receptor 2, 3 and 7 involved in pathogen recognition were upregulated in skin exposed to Borrelia, although Borrelia DNA was not detected in the biopsies.ConclusionThe evidence of upregulation of genes in Borrelia exposed skin suggests an influence on the immune system of ticks and spirochetes. Characterization of Borrelia-associated gene expression signatures in the skin could contribute to future diagnostics and increase our understanding of the development of various manifestations of Borrelia infection.

Quantitative real-time PCR analysis of gut microbiota in rheumatoid arthritis patients compared to healthy controls

Rheumatoid arthritis (RA) is an autoimmune disorder with synovial inflammation of joints and extra articular manifestations. The results of recent researches consider the relationship between microbiota and the immune system as a double-edged sword. Considering that the relationship between the composition of intestinal microbiota and the immunological and clinical status of the body has been confirmed, it is very important to investigate the effect of each genus and species of bacteria on the state of the immune system. The current study was determined using 16S rRNA gene sequencing to explore the 4 selected gut microbiota from 25 people suffering from rheumatism (RA group) with a time interval of at least 3 years from the onset of the disease and 25 Healthy people by real time PCR. Gut dysbiosis in patients with rheumatoid arthritis (RA) is identified alongside key serological and clinical markers such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), immunofluorescence (IF), anti-cyclic citrullinated peptide (Anti-CCP), white blood cell count (WBC), mean corpuscular volume (MCV), aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), Platelet count (PLT), thyroid-stimulating hormone (TSH), creatinine (Cr), and hemoglobin (Hb). Additionally, data from individuals with incomplete or unverified records were excluded from the study to ensure accuracy and reliability. Bacteroides fragilis, Roseburia faecis and Fusobacterium nucleatum genera showed a much lower median in Rheumatoid arthritis patients in comparison with healthy people (P > 0.001, p = 0.002, P < 0.001 respectively). While the difference in the median of E. coli genera was not significant in the two studied groups (p = 0.31). In such a way that the change in the Gut normal flora homeostasis and the reduction of beneficial bacteria such as Bacteroides fragilis, Roseburia faecis, Fusobacterium nucleatum genera, may stimulate the immune system to initiate autoimmunity.

Association between sleep duration and lung function among U.S. adults

BackgroundSleep’s impact on the human immune system and inflammatory responses makes it a potential risk factor for lung function impairment. However, the relationship between sleep duration and lung function impairment in middle-aged and young adults has been rarely investigated.MethodsA total of 9,284 aged 20–64 years were categorized into four groups according to sleep duration (≤ 6 h, 7 h, 8 h, and ≥ 9 h), with 7 h as the reference, by using the U.S. NHANES data, 2007–2012. Forced expiratory volume in the 1 s (FEV1), forced vital capacity (FVC), FEV1 to FVC (FEV1/FVC) ratio, peak expiratory flow (PEF), and forced expiratory flow at 25–75% (FEF25 − 75%) were measured by spirometry. Restrictive impairment was defined as baseline FVC < 80% predicted and obstructive impairment as FEV1/FVC < 0.70. Generalized linear regression and logistic regression were performed to estimate the associations between sleep duration and lung function.ResultsCompared with 7 h of sleep duration, shorter and longer sleep duration were associated with decreases in FEV1 (≤ 6 h: β=-0.010, 95% CI=-0.014 to -0.006; 8 h: β=-0.005, 95% CI=-0.009 to -0.001), FVC (≤ 6 h: β=-0.018, 95% CI=-0.014 to -0.007; 8 h: β=-0.005, 95% CI=-0.009 to -0.002), and PEF (≤ 6 h: β=-0.006, 95% CI=-0.010 to -0.002; 8 h: β=-0.007, 95% CI=-0.011 to -0.002; ≥ 9 h: β=-0.012, 95% CI=-0.020 to -0.004). Similarly, shorter (≤ 6 h: OR = 1.346, 95% CI = 1.065 to 1.700) and longer (≥ 9 h: OR = 1.827, 95% CI = 1.236 to 2.700) sleep duration were associated with increased risks of restrictive impairment. Moreover, the aforementioned associations were more pronounced among male participants.ConclusionsCompared with 7 h of sleep duration, shorter and longer sleep duration were associated with impaired lung function among adults aged 20–64 years, and these associations were stronger among males.

Complement C3d enables cell-mediated immunity capable of distinguishing spontaneously transformed from nontransformed cells

Immune surveillance depends in part on the recognition of peptide variants by T cell antigen receptors. Given that both normal B cells and malignant B cells accumulate mutations we chose a murine model of multiple myeloma to test conditions to induce cell-mediated immunity targeting malignant plasma cell (PC) clones but sparing of normal PCs. Revealing a previously unknown function for intracellular C3d, we found that C3d engaged T cell responses against malignant PC in the bone marrow of mice that had developed multiple myeloma spontaneously. Our results show that C3d internalized by cells augments immune surveillance by several mechanisms. In one, C3d induces a master transcription regulator, E2f1, to increase the expression of long noncoding (lnc) RNAs, to generate peptides for MHC-I presentation, and increase MHC-I expression. In another, C3d increases expression of RNAs encoding ribosomal proteins linked to processing of defective ribosomal products that arise from noncanonical translation and known to promote immunosurveillance. Cancer cells are uniquely susceptible to increased expression and presentation of mutant peptides given the extent of protein misfolding and accumulation of somatic mutations. Accordingly, although C3d can be internalized by any cell, C3d preferentially targets malignant clones by evoking specific T cell-mediated immunity and sparing most nontransformed polyclonal B cells and PC with lower mutation loads. Malignant PC deletion was blocked by cyclosporin or by CD8 depletion confirming that endogenous T cells mediated malignant clone clearance. Besides the potential for therapeutic application our results highlight how intracellular C3d modifies cellular metabolism to augment immune surveillance.

Unraveling the SARS-CoV-2 spike protein long-term effect on neuro-PASC

The persistence or emergence of long-term symptoms following resolution of primary SARS-CoV-2 infection is referred to as long COVID or post-acute sequelae of COVID-19 (PASC). PASC predominantly affects the cardiovascular, neurological, respiratory, gastrointestinal, reproductive, and immune systems. Among these, the central nervous system (CNS) is significantly impacted, leading to a spectrum of symptoms, including fatigue, headaches, brain fog, cognitive impairment, anosmia, hypogeusia, neuropsychiatric symptoms, and peripheral neuropathy (neuro-PASC). However, the risk factors and pathogenic mechanisms responsible for neuro-PASC remain unclear. This review hypothesis discusses the leading hypotheses regarding the pathophysiological mechanisms involved in long COVID/PASC, focusing on neuro-PASC. We propose vascular dysfunction mediated by activation of astrocytes and pericytes followed by blood–brain barrier (BBB) disruption as underlying pathophysiological mechanisms of neurological manifestations. Additionally, we provide insights into the role of spike protein at the blood–brain interface. Finally, we explore the potential pathogenic mechanisms initiated by the interaction between the spike protein and cellular receptors at the brain endothelial and tissue levels.

Increased Herpes simplex virus 1, Toxoplasma gondii and Cytomegalovirus antibody concentrations in severe mental illness

Infections with Cytomegalovirus (CMV), Herpes simplex virus 1 (HSV1) and Toxoplasma gondii (TG) have been implicated in severe mental illness. All three pathogens have high seroprevalence in the human population, are neurotropic and establish a persistent infection. We hypothesized that exposed (seropositive) patients with severe mental illness would show higher immunoglobulin G (IgG) concentrations than exposed healthy controls (HC). We included 765 patients with severe mental illness (schizophrenia n = 515, bipolar disorder n = 250) and 541 HC. CMV, HSV1 and TG IgG seropositivity and concentrations were measured with immunoassays (seropositivity: CMV, n = 447 patients vs. 296 HC; HSV1, n = 355 vs. 238; and TG, n = 159 vs. 126). Among seropositive participants, patients had higher HSV1 (p < 0.001) and TG (p = 0.003) IgG concentrations than HC. Stratifying by diagnosis, both schizophrenia (p = 0.001) and bipolar disorder (p = 0.001) had higher HSV1 IgG concentrations, while schizophrenia only had higher TG (p = 0.009) and CMV (p = 0.045) IgG concentrations than HC. In SZ, higher HSV1 IgG concentrations were associated with higher psychotic (p = 0.030) and manic (p = 0.008) symptom scores, but only among CMV- or TG-infected patients which suggests synergistic effects. Among all participants, HSV1 IgG concentrations were inversely associated with interleukin-18 (p < 0.001) and positively associated with high-sensitivity C-reactive protein (p = 0.002) and B cell-activating factor (p = 0.004), possibly indicating T cell exhaustion, enhanced inflammation, and increased B-cell response, respectively. Patients with severe mental illness exhibit a heightened immune system response to HSV1, TG, and CMV infections suggesting immune system dysfunction and/or a more severe infection. For HSV1, higher IgG concentrations were linked to a greater clinical burden.

Unraveling the Link between Obesity and Tuberculosis: A Systematic Review of the Underlying Mechanisms

Background: Tuberculosis (TB) and obesity are significant global health concerns with potentially complex interactions. Obesity, through its effects on metabolism, inflammation, and the immune system, may influence TB susceptibility, progression, and treatment outcomes. This systematic review aims to analyze the published literature on the relationship between obesity and TB, focusing on the underlying mechanisms. Methods: A systematic search of PubMed, Science Direct, and Google Scholar was conducted for articles published in the last 10 years. The search strategy included keywords such as "tuberculosis," "TB," "obesity," and "BMI." Articles were selected using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) method. Results: The review identified 11 studies that met the inclusion criteria. The studies revealed a complex relationship between obesity and TB, with nutritional status, immunity, and diabetes mellitus (DM) playing key roles. Obesity can alter the immune response to TB, potentially increasing the risk of disease and affecting treatment efficacy. Conclusion: The relationship between obesity and TB is multifaceted, with obesity potentially influencing both disease susceptibility and outcomes. Further research is needed to fully elucidate the underlying mechanisms and to develop targeted interventions for individuals with both obesity and TB.

Inhibition of fibulin-3 ameliorates periodontal inflammation through reducing M1 macrophage polarization via EGFR/PI3K/AKT pathway.

This study aimed to evaluate the role of fibulin-3 (FBLN3) in macrophage polarization, its mechanism, and its effect on periodontitis. We conducted studies on periodontitis using both clinical samples and ligature-induced mouse periodontitis model. The inflammatory state was assessed using microcomputed tomography, hematoxylin and eosin staining, immunohistochemical staining, and immunofluorescence staining. In vitro, bone marrow-derived macrophages, and RAW 264.7 macrophages were treated with lipopolysaccharide (LPS) and interleukin (IL)-4 to induce polarization. The role of FBLN3 in macrophage polarization was investigated using overexpression plasmids or siRNAs. Furthermore, local injection of adeno-associated virus was employed to suppress FBLN3 expression in periodontal tissues. FBLN3 levels were greater in periodontitis tissues. FBLN3 promoted M1 polarization and suppressed M2 polarization in macrophages. The overexpression of FBLN3 promoted M1 polarization via the EGFR/PI3K/AKT signaling pathway, an effect that the epidermal growth factor receptor (EGFR) inhibitor PD153035 reversed. Suppressing FBLN3 expression improved periodontal inflammation and reduced alveolar bone loss in periodontitis. FBLN3 suppression can mitigate periodontitis by decreasing the M1 macrophage ratio. FBLN3 regulates M1 macrophage polarization through the EGFR/PI3K/AKT signaling pathway. Disruption in the collaboration between extracellular matrix (ECM) and immune system is a significant pathology in periodontitis. Macrophages are a crucial part of the immune system and have unique functions, such as polarization. Fibulin-3, an ECM protein, may play a vital role in this dynamic interplay. Fibulin-3 expression is elevated in periodontitis and is closely related to immune cell function. Inhibiting fibulin-3 can alleviate periodontitis by reducing infiltration of immune cells and M1 macrophage ratio. Furthermore, fibulin-3 promoted macrophage M1 polarization by activating the PI3K/AKT signaling pathway through EGFR binding. Our findings offer a clinically relevant rationale for immune response modulation through fibulin-3.

A systematic review of age-structured malaria transmission models (2019–2024)

Malaria remains a serious and potentially fatal vector-borne disease, consistently ranking among the world’s deadliest infections. This study presents a systematic review of age-structured malaria transmission models. Articles were sourced from PubMed, Google Scholar, and the Research Gate Library, resulting in the identification and inclusion of eleven papers in the review. The findings highlight that children under the age of five are more susceptible to malaria than adults, due to their still-developing immune systems. The highest rates of morbidity and mortality are seen in youngsters, pregnant women, and people with impaired immune systems, making age structure a critical factor in the spread of malaria within populations. Personal protection and vector control are key strategies in reducing the transmission of malaria in communities. The study also suggests that the use of fractional operators in modeling could offer new insights into the dynamics of malaria transmission and potential control strategies.

Pre-immunization of diet-induced obese male mice with inactivated pathogens increases power in a liraglutide intervention study.

Pre-immunization with inactivated antigens has been developed as an alternative to the use of 'dirty' mice, which in contrast to specific pathogen free (SPF) mice, harbour a range of pathogens. Within certain research areas, such mice are considered better models for humans than SPF mice, as they have an immune system that better mirrors human immunity. We inactivated murine adenovirus type 1 (FL), minute virus of mice, mouse hepatitis virus (A59), respirovirus muris (Sendai), Theiler's encephalomyelitis virus (GD7) and Mycoplasma pulmonis by ultraviolet irradiation. We show that pre-immunization with these inactivated pathogens combined with adjuvant prior to the dietary induction of obesity in C57BL/6NTac mice substantially reduced the group sizes needed for showing an effect of the GLP-1 receptor analogue, liraglutide. Nesting, open field and novel object behaviours of the mice were unaffected. We conclude that pre-immunization with inactivated pathogens may be a simple tool to increase power in this type of intervention study on the DIO mouse model.