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Abstract To date, numerable reviews are found in the literature prominent to the effect of caffeine on the immune system, with the latest review published in 2006. Database screening reveals around three thousand articles that have been published during the last decade. Interestingly, less than hundred articles involved humans and rodents as tested models, out of which 20% is of interest to this paper excluding studies done on the nervous and cardiac systems, and in pregnant and cancer cases. In this review, information pertaining to the experimental setup of various studies, namely, the tested model, the study type (in vivo or in vitro), and caffeine dose is covered to discern the behaviour of major cellular and molecular immune components in light of caffeine exposure. Although it is hard to extrapolate results done in rodents to humans and to relay conclusions from in vitro to in vivo studies, most of the collected data favor the suppressive effects of caffeine on the proliferation of stimulated lymphocytes. Macrophages and natural killer cells also exhibited a reduced activity in the presence of high caffeine doses compared to increased activity at low doses. Immunosuppression is also supported by reduced levels of major anti-inflammatory cytokines, IL-2, IL-6, TNF-α. Moreover, certain innate and adaptive immune receptors, such as TLR1, TLR2, TLR4, and MHC class I-related chain B (MICB) molecules, exhibited decreased expression levels. Thus, we support the use of caffeine to alleviate various inflammatory conditions and autoimmune diseases. [ABSTRACT FROM AUTHOR]

Abstract Mesenchymal stem cells (MSCs) are a population of multipotent cells with the ability of expansion and plastic-adherence in vitro. MSCs can differentiate into chondrocytes, osteocytes and adipocytes; they lack co-stimulatory molecules and have small amount of MHC-I that makes no immunogenicity. These characteristics are empowering MSCs' huge in vivo applications. In addition, MSCs possess the ability of regulating the immune responses in many diseases. Many studies have shown that MSCs have immunosuppressive as well as immunoenhancing properties such as inhibition of T-lymphocytes proliferation and cytokines production which lead to the balance of Th1 and Th2. Some other immunomodulatory features of MSCs are increasing suppressive capacity of T reg , reducing activity of B-lymphocytes and immunoglobulins secretion, inhibition of dendritic cells maturation and antigen presenting capacity, and inhibition of NK-cells activity. MSCs also exert inhibitory effects on neutrophil apoptosis and reduce reactive oxygen species production. The purpose of this paper is to focus on the MSCsʹ effects on immune cells, especially neutrophils. [ABSTRACT FROM AUTHOR]

Abstract The skin is the first anatomical region that dengue virus (DENV) encounters during the natural infection. Although the role of some skin resident cells like dendritic cells and fibroblasts has been demonstrated to be crucial to elucidate the role of resident cells and molecules participating during the early events of the innate immune response, the participation of keratinocytes during DENV infection has not been fully elucidated. In this paper we aimed to evaluate the use of the HaCaT cell line as a model to study the immune responses of skin keratinocytes to DENV infection. We demonstrated productive DENV-2 infection of HaCaT cells and their capability to establish an antiviral response through production of type I and type III interferons (IFN-β and IFN-λ). The production of these cytokines by HaCaT cells correlated with upregulation of IFN-inducible transmembrane protein-3 (IFITM3) and viperin in bystander, uninfected cells. We also observed an increase in secretion of IL-6 and IL-8. Skin keratinocytes are known to secrete antimicrobial peptides (AMPs) during viral infections. In our model, DENV-2 infected HaCaT cells upregulate the production of cytoplasmic LL-37. We evaluated the dual role of LL-37, HBD2, and HBD3 antiviral activity and immunoregulation during DENV-2 infection of HaCaT cells and found that LL-37 significantly reduced DENV-2 replication. This indicates that the HaCaT cell line can be used as a model for studying the innate response of keratinocytes to DENV infection. Our results also suggest that skin keratinocytes play an important role in the skin microenvironment after DENV infection by secreting molecules like type I and type III IFNs, pro-inflammatory molecules, and LL-37, which may contribute to the protection against arboviral infections. [ABSTRACT FROM AUTHOR]

[Display omitted] • TLR-2 agonist Pam3CSK4 had no therapeutic effect on VL in BALB/c mice. • Pam3CSK4 may enhance the pathogenesis of the L. donovani infection in BALB/c mice. • Circadian rhythm may have important regulatory effect on host- Leishmania interaction. Most of the existing Leishmania -related research about TLR-2 agonists was focusing on their role as adjuvants in the vaccine, few studied its therapeutic effect. This paper aims to explore the therapeutic effect of TLR-2 agonist Pam3CSK4 on Leishmania -infected mice and the underlying immune molecular mechanisms. In L. donovani- infected BALB/c mice, one group was treated with Pam3CSK4 after infection and the other group was not treated. Normal uninfected mice treated with Pam3CSK4 or untreated were used as controls. Parasite load, hepatic pathology and serum antibodies were detected to assess the severity of the infection. The expression of immune-related genes, spleen lymphocyte subsets and liver RNA-seq were employed to reveal possible molecular mechanisms. The results showed that the liver and spleen parasite load of infected mice in Pam3CSK4 treated and untreated groups had no statistical difference, indicating Pam3CSK4 might have no therapeutic effect on visceral leishmaniasis. Infected mice treated with Pam3CSK4 possessed more hepatic inflammation focus, lower IgG and IgG2a antibody titers, and a lower proportion of spleen CD3+CD4+ T cells. Transcriptome analysis revealed that Th1/Th2 differentiation, NK cells, Th17 cell, complement system and calcium signaling pathways were down-regulated post-treatment of Pam3CSK4. In this study, TLR-2 agonist Pam3CSK4 showed no therapeutic effect on visceral leishmaniasis in BALB/c mice and might enhance the pathogenesis of the disease possibly due to the down-regulation of several immune-related pathways, which can improve our understanding of the role of TLR-2 in both treatment and vaccine development. [ABSTRACT FROM AUTHOR]

[Display omitted] • Overexpression of Nik in bulge region of hair follicles induced hair follicle loss and tumorigenesis • ChAT-positive cells were localized in the bulge region of hair follicles. • Multiple tumor-related pathways were activated in the Nik-coe mice. The bulge region, a reservoir of multipotent stem cells, is possibly responsible for tumorigenesis. NF-κB-inducing kinase (NIK) is a kinase involved in the activation of the noncanonical NF-κB pathway and exhibits positive staining in tumor cells. However, whether high expression of NIK can result in tumorigenesis has not been reported in published papers. By establishing Nik-coe (Nik-stopF/F crossed with Chat-cre) and Nik-soe (Nik-stopF/F crossed with Sox9-cre) mice, we found that overexpression of Nik in the bulge region of hair follicles induced hair follicle loss and tumorigenesis. Furthermore, RNA sequencing, proteomic and phosphopeptide analyses revealed that multiple cancer pathways are involved in tumor formation. Taken together, these findings indicate that constitutive activation of Nik in the bulge region induces tumorigenesis. [ABSTRACT FROM AUTHOR]

The alternative pathway of complement originated from the Properdin pathway originally described by the Pillemer laboratory in the 1950s. This work generated great controversy and it took several decades for a consensus on its components, its reaction sequence and its functions to emerge. This paper reviews this history and attempts to clarify some of the ambiguities that remain. [ABSTRACT FROM AUTHOR]

The selective modulation of immunity is an emerging concept driven by the vast advances in our understanding of this crucial host defense system. Invertebrates have raised researchers’ interest as potential sources of new bioactive molecules owing to their antibacterial, anticancer and immunomodulatory activities. A LipoPolySaccharide (LPS) challenge in the ascidian Ciona intestinalis generates the transcript, Ci 8 short, with cis -regulatory elements in the 3′ UTR region that are essential for shaping innate immune responses. The derived amino acidic sequence in silico analysis showed specific binding to human Major Histocompatibility Complex (MHC) Class I and Class II alleles. The role of Ci 8 short peptide was investigated in a more evolved immune system using human Peripheral Blood Mononuclear Cells (PBMCs) as in vitro model. The biological activities of this molecule include the activation of 70 kDa TCR ζ chain Associated Protein kinase (ZAP-70) and T Cell Receptor (TCR) Vβ oligo clonal selection on CD4 + T lymphocytes as well as increased proliferation and IFN-γ secretion. Furthermore Ci 8 short affects CD4 + /CD25 high induced regulatory T cells (iTreg) subset selection which co-expressed the functional markers TGF-β1/Latency Associated Protein (LAP) and CD39/CD73. This paper describes a new molecule that modulates important responses of the human adaptive immune system. [ABSTRACT FROM AUTHOR]

Introduction Fexofenadine (FXF) is a third-generation antihistamine drug and osthole is assumed as a natural antihistamine alternative. This paper compares results of histamine, FXF and osthole impact on HRH-1, COX-2, NF-κB-p50, CCR1 mRNA expression. We also measured mRNA expression of IL-1β and CCL5/RANTES in incubated peripheral blood mononuclear cells (PBMC) to compared how histamine, FXF and osthole had influence on expression level and interacts on product secretion. Objective The purpose was to investigate expression pattern in asthma PBMC. Methods The cultures were treated 72 h with FXF and osthole. We measured mRNA expression of histamine HRH-1, COX-2, NF-κB-p50, CCR1, IL-1β and CCL5/RANTES with Real-Time PCR (RT-PCR). Results The present study suggest that osthole may be a potential inhibitor of histamine H 1 receptor activity. We also demonstrated that cells cultured with histamine increase COX-2 mRNA expression and osthole reduce it. Conclusion Allergy remains one of the most common chronic diseases in Europe and it is rapidly approaching epidemic proportions; with current predictions estimating that the number of allergy-afflicted will equal the healthy population by 2020. It is therefore paramount to find new pharmaceuticals which successfully combat allergic disease. [ABSTRACT FROM AUTHOR]

Previous works with autumnalamide reported that Store Operated Calcium (SOC) channels were blocked through mitochondrial modulation. In the present paper we studied the effect of autumnalamide on ionomycin Ca 2+ fluxes. Thus, autumnalamide did not modify ionomycin-sensitive intracellular pools while the ionomycin-induced Ca 2+ influx was blocked with similar potency whether the incubation was done before or after ionomycin-sensitive pools depletion. Nevertheless, autumnalamide was not able to inhibit ionomycin-induced Ca 2+ influx once the membrane channels were activated. Moreover, the compound efficiently inhibited flufenamic acid (FFA) Ca 2+ release induced in this organelle but no the next influx. Since in previous work the effect of autumnalamide was inhibited by cyclosporine A (CsA), structures that target this drug were studied. Therefore, the affinity of autumnalamide for cyclophilin D (Cyp D) was examined. The K D obtained for Cyp D- autumnalamide was 1.51 ± 1.399. Moreover, the K D for Cyp A- autumnalamide was calculated. The peptide had a similar order of Cyp A binding affinity than CsA (8.08 ± 1.23 and 6.85 ± 1.1 μM respectively). After testing autumnalamide-binding capacity for Cyp A, the activity of this compound on Cyp A pathway was tested. Thus, the effect on interleukin (IL)-2 release on activated T-lymphocytes was checked. Autumnalamide was able to reduce IL-2 levels near to T cells in resting conditions. Next, the effect over calcineurin and NFATc1 was also evaluated. While CsA inhibits both calcineurin and NFATc1, autumnalamide did not produce any effect. From these results we can conclude that, autumnalamide targeted mitochondrion and prevent T-cells from IL-2 production through the modulation of SOC Ca 2+ channels. [ABSTRACT FROM AUTHOR]

While a number of endogenous risk factors including age and genetics are established for Alzheimer’s disease (AD), identification of acquired, potentially preventable or treatable causes, remains limited. In this paper, we review three epidemiologic case studies and present extensive biologic, immunologic and anatomic evidence to support a novel hypothesis that Bordetella pertussis (BP), the bacterium better known to cause whooping cough, is an important potential cause of AD. Cross-cultural documentation of nasopharyngeal subclinical BP colonization reflecting BP-specific mucosal immunodeficiency, proximate anatomy of intranasal mucosal surfaces to central nervous system (CNS) olfactory pathways, and mechanisms by which BP and BP toxin account for all hallmark pathology of AD are reviewed, substantiating biologic plausibility. Notably, respiratory BP infection and BP toxin secreted from subclinical BP colonization can account for the initiation and accumulation of amyloid β plaques and tau tangles. Additional mechanisms consistent with the immunobiologic effects of subclinical BP colonization include microglial activation and inflammation, atrophy and neurodegeneration, excitotoxicity, distinctive anatomic distribution and sequential spread of disease, impaired glucose utilization, and other characteristic CNS pathology of AD. We conclude by assessing the evidence for causation against the Bradford Hill criteria, and advocate for further investigation into the potential role of BP in the etiology of AD. [ABSTRACT FROM AUTHOR]

Several papers have demonstrated the importance of substances from natural sources which can exert powerful anti-inflammatory effects. In this respect, hydroxytyrosol, one of the major elements of the phenolic components of olive oil, has been extensively studied for its anti-inflammatory activities and safety profile. In this report, we demonstrate that the co-stimulation of human PBMCs from healthy subjects with the Par j 1 allergen and hydroxytyrosol induced a statistically significant increase in the amount of Par j 1-induced IL-10, demonstrating that hydroxytyrosol can modulate an allergen-specific immune response potentiating a suppressive immune response towards an allergen. Our work opens the way to further studies to elaborate the possibility of using hydroxytyrosol as a nutrient for allergy prevention. [ABSTRACT FROM AUTHOR]

Protein citrullination is one of the processes of post-translational modification of proteins and peptides, playing a crucial role in the homeostasis of important processes, however also leading to pathological processes in autoimmune and neoplastic disorders. Citrullination regulates epidermal function, reproduction being also involved in NET formation. Nowadays, the knowledge about citrullination spreads and opens up a new field for investigation of compounds that potentially be used as a treatment. Inhibitors of PADI are currently being tested in various diseases. As these enzymes play an essential role in the disease progression, one should also look for the basics of regulation of their expression in the cell as well as focus on environmental factors like air pollution or smoking, which can augment the process of citrullination. Despite its pathological properties, citrullination can be a prognostic marker of diseases and a good target for therapies. In this revision, we used PubMed, PubMed Central (PMC), and Google Scholar to collect data which presents information from several articles, reviews, case reports, case studies, cohort studies, and clinical trials. Studies conducted in vitro, in vivo on mouse models, postmortem tissue models of animal and human origin were included and non-english articles were excluded. We mainly used keywords like "PAD", Peptidylarginine deiminases", "citrullination" or "deimination" in the search. This revision contains description using both original and review papers can be useful for doctors, scientists, and patients. [ABSTRACT FROM AUTHOR]

GVHD is a crucial mortality factor in allogeneic bone marrow transplantation (ABMT). In this paper, we show that dehydroxymethylepoxyquinomicin (DHMEQ), a novel inhibitor of nuclear factor-κB, suppresses GVHD, resulting in an improved mortality rate in a mouse ABMT model. Bone marrow cells from C57BL/6 mice (B6 mice) were transplanted into lethally irradiated BALB/c mice. Two weeks later, spleen cells from B6 mice were transplanted into the irradiated BALB/c mice. From one week after the injection of spleen cells, when the mice started to show GVHD, the mice were also injected intraperitoneally daily with DHMEQ or vehicle only (DMSO) for 4 weeks. By 80 days after the ABMT, 6/14 of the vehicle-injected mice (43%) had died because of GVHD, whereas all DHMEQ-injected mice survived this observation period and developed milder GVHD than the vehicle-injected mice. When regulatory T cells were reduced by the injection of anti-folate receptor 4 (FR4) antibody, the effects of DHMEQ were reduced. These findings suggest that administration of DHMEQ could become a new strategy for preventing fatalities from GVHD. [ABSTRACT FROM AUTHOR]

Pregnancy is known to induce a transient depression of maternal cell-mediated immunity, to prevent rejection of the fetus, while at the same time it keeps adequate maternal host defense mechanisms to fight infection. Presently, the aim of this paper was to investigate a possible endocrine and immunologic alteration observed during a successful pregnancy. This study consistently showed that plasma corticosterone levels were significantly higher (P < 0.0001) in pregnant Wistar rats than in virgin female. An increased number of peritoneal macrophages was also detected in pregnant females when compared to non-pregnant ones. Macrophages play an important role in the production of bioactive proteins and lipids such as nitric oxide. Then, in support of the latter, the present study showed increased levels of endogenous NO in pregnant rats when compared to non-pregnant ones, thereby mediating the vasodilatation process of normal gestation. Furthermore, our FACS analysis clearly indicated the correlation between reduced CD161 expression on NK cells (P < 0.0001) in pregnant rats when compared to virgin females. It was found that pregnancy appears to be associated with depressed cell immunity, as evidenced by a significant inhibition of lymphocyte proliferation. Understanding the immunological paradox of maternal tolerance, as well as the hormonal modulation of the immune environment during pregnancy is essential for future studies to investigate the potential for these processes to be modulated by diet or effective therapeutics during pregnancy. [ABSTRACT FROM AUTHOR]

• The Omicron variant diminishes the neutralizing capability of the antibodies. • Omicron can easily bypass an individual's humoral immune response. • The Omicron variant has more than 50 mutations. • CD8 + T-cell response may show promise against the Omicron variant. The million-dollar question that has been the talk of the day is how effective the COVID 19 vaccines are against the Omicron variant. Still, there is no clear-cut answer to this question but several studies have concluded that this Variant of Concern (VOC) successfully weakens the neutralizing capability of the antibodies acquired from the COVID 19 vaccines and prior infections, which indicates that Omicron can easily bypass an individual's humoral immune response. However, the most significant confusion revolves around cell-mediated immunity tackling the Omicron variant. This paper aims to provide a clear idea about the status of the body's immune surveillance concerning the infection caused by the Omicron variant by producing the effectivity of the humoral and cell-mediated immunity in handling the same. This work also provides complete detail of the various characteristics of the Omicron variant and how it may be a blessing in disguise. The effectiveness of the current vaccines, the transmissibility rate of the variant compared to the other variants, and the importance of administering a booster dose to prevent the spread of this variant are also discussed. Finally, this work aims to bridge the gap between the past and the current status of the Omicron infection and sheds light on the hypothetical idea that herd immunity developed from the SARS-COV2 infection may help tackle other dangerous variants. [ABSTRACT FROM AUTHOR]

Abstract: The onset of inflammatory response is associated with neutrophil recruitment into infected or injured tissues, whereas the resolution of inflammation, on the contrary, requires blockade of further recruitment and clearance of the recruited cells. Adhesion of circulating neutrophils to the endothelium represents a crucial step in their recruitment into the inflamed tissues. Previous studies have identified a number of proteins which can interfere with neutrophil–endothelial adhesive interactions and act as natural inhibitors of the leukocyte egress from the circulation. Essentially, these proteins are up-regulated in inflammation and, therefore, have potential pro-resolving activity. Knockout animals deficient in the anti-adhesive proteins demonstrated increased magnitude and duration of acute inflammation indicating that the proteins play a non-redundant role in dampening the inflammatory response. This paper is a review of the experimental data supporting the hypothesis that the up-regulation of the anti-adhesive proteins may represent an anti-inflammatory mechanism that contributes to the resolution of inflammation. [Copyright &y& Elsevier]

Abstract: The distinct ability of phagocytes to present antigens, produce cytokines and provide co-stimulatory signals may contribute to the severity of the outcome of Chagas disease. In this paper, we evaluate the phenotypic features of phagocytes along with the cytokine signature of circulating T-cells from Chagas disease patients with indeterminate (IND) and cardiac (CARD) clinical forms of the disease. Our data demonstrated that neutrophils from IND patients displayed an impaired ability to produce cytokines. A lower Trypanosoma cruzi phagocytic index and higher nitric oxide levels were characteristics of monocytes from IND. The impaired phagocytic capacity did not reflect on the levels of anti-T. cruzi IgG, but was detectable in the downregulation of Fc-γR, TLR and CR1 molecules. The monocyte-derived cytokine signature demonstrated that a down-regulated synthesis of IL-12 and a modulatory state were evidenced by a positive correlation between IL-12 and IL-10 with a lower synthesis of TNF-α. The down-regulation of MHC-II and CD86 in monocytes supports the occurrence of particularities in the APC-activation-arm in IND, and may be involved in the T-cell pro-inflammatory pattern counterbalanced by a potent IL-10 response. Our findings support the hypothesis that differential phenotypic features of monocytes from IND may be committed to the induction of a distinct immune response related to low morbidity in chronic Chagas disease. [Copyright &y& Elsevier]

Abstract: The development of the anti-CTLA-4 antibody (ipilimumab; marketed as Yervoy 1 [1] Yervoy is an FDA approved human anti-CTLA-4 monoclonal antibody developed by Bristol-Myers Squibb. ) immune regulatory therapy was based on the premise that “Abrogation of the function of CTLA-4 would permit CD28 to function unopposed and might swing the balance in favor of immune stimulation, tolerance breakdown and tumor eradication…” (). By now, the vast majority of data collected from more than 4000 patients proves that this prediction was entirely correct. Paradoxically, the successful blockade of immune checkpoints raises the question whether an anti-CTLA-4 antibody could ever become an important therapy against cancer. T cells lost their ability to discriminate between self and non-self. Thus, tolerance to self tissues was broken in ∼70% of the patients. In the recent industry-sponsored phase III clinical trial of ipilimumab, 147 (38.7%) of the patients experienced severe adverse events and 6.8% suffered dose-limiting events (8.4%, in the ipilimumab-alone group). There were 14 deaths related to the study drugs and 7 of these were associated with immune-related adverse events. In contrast, the complete response rate was only 0.2%, in one patient out of 403 who received ipilimumab plus a peptide vaccine. Promoters of ipilimumab appear to be unmindful of the clinical trial catastrophe in London. Then, a humanized “superagonist” anti-CD28 monoclonal antibody, TGN1412, which “preferentially” activated regulatory T cells, at a higher dose, also activated all CD28 positive T cells. This precipitated a “cytokine storm” leading to life-threatening multiple organ failure in the six healthy human volunteers. Neither anti-CD28 nor anti-CTLA-4 therapies rely on antigen-specificity. Both release free antibody into the body against common molecular targets that are expressed on the targeted as well as on the non-targeted T cells. At lower antibody doses specific T cells are preferentially activated. With increasing antibody dose, however, the kinetics of the interaction is pushed in favor of widespread non-specific T cell expansion. Using the law of mass action we calculated that the vast majority of the CTLA-4 receptors on all activated T cells (including melanoma specific T cells) in the phase III clinical trial of ipilimumab will have been saturated. This would explain the runaway immune response observed. The conclusions drawn by the authors of the ipilimumab trial paper could bear an independent inspection and reassessment concerning the validation of the blockade of immune checkpoints as an important therapeutic strategy against cancer. [Copyright &y& Elsevier]

Abstract: The evolution of man has been characterised by recurrent episodes of migration and settlement with infectious disease a constant threat. This long history of demographic change, together with the action of evolutionary forces such as natural selection and genetic drift, has shaped human genetic diversity. In particular, the interaction between humans, pathogens and the environment has played a crucial role in generating patterns of human genetic variation. The complement system plays a crucial role in the early protective immune response after exposure to a pathogen. Pathogens, over time, have developed mechanisms to circumvent the effects of complement which in turn has led to development of a more complex complement system. During the evolution of the complement system genes coding complement proteins have evolved polymorphisms, some of which have a functional effect, and this may reflect human–pathogen interaction and geographical origin. An example is the polymorphism Ile62Val (rs800292 (A>G)) in the complement regulator Factor H gene which alters the susceptibility to age-related macular degeneration (AMD), with the Ile62 polymorphism protecting against AMD. When sub-Saharan African and European populations are compared, the frequency of this polymorphism shows a very marked geographical distribution. Polymorphisms in other complement genes such as complement factor B show similar trends. This paper describes the geographical variation present in complement genes and discusses the implications of these observations. The analysis of genetic variation in complement genes is a promising tool to unravel mechanisms of host–pathogen interaction and can provide new insights into the evolution of the human immune system. [Copyright &y& Elsevier]

Abstract: The present paper describes the immune role played by a recently identified () member of the rhamnose-binding lectin (RBL) family from the colonial ascidian Botryllus schlosseri. B. schlosseri RBL (BsRBL) can activate phagocytes through: (i) induction of their directional movement towards the source of the molecule; (ii) modification of cytoskeleton, required for shape changes; (iii) stimulation of the respiratory burst, and consequent production of reactive oxygen species (ROS) with microbicidal activity, including superoxide anions and peroxides; and (iv) increase in the ability to phagocytose foreign particles. RBL also induces the synthesis and release, by cytotoxic morula cells (MCs), of cytokines recognised by anti-IL1α and anti-TNFα antibodies. At high concentrations, BsRBL induces degranulation of MCs and the consequent release of the cytotoxic enzyme phenoloxidase into the medium. Results are consistent with the existence of cross-talk between B. schlosseri immunocytes (phagocytes and MCs). In addition, a three-dimensional model for BsRBL is presented. [Copyright &y& Elsevier]

Abstract: Surfactant protein D (SP-D) plays an important role in lung host defence. SP-D levels have been shown to be depleted in cystic fibrosis (CF) patients. A recombinant fragment of the human SP-D (rfhSP-D) which consist of a hydrophobic neck and a CRD has been shown to be active in vivo and partially reverses the symptoms of the SP-D deficiency in the lungs when administered to SP-D knock-out mice. In this paper we studied the in vitro effect of different proteolytic enzymes commonly found in CF patients lungs, such as neutrophil elastase, cathepsin G and protease 3 as well as Pseudomonas elastase, on rfhSP-D. It was also shown that cleavage was inhibited by physiological concentration of calcium. When Western blot was compared with ELISA, we show that an anti-SP-D ELISA is a not a reliable assay of functional SP-D levels since non-functional fragments of SP-D are also detected. Thus, ELISA cannot be used as a reliable “diagnostic” tool for SP-D deficiency. Finally, we observe that SP-D is not cleaved in control patients but is degraded in about half the samples from cystic fibrosis patients, indicating that degradation of endogenous SP-D, by enzymes present in CF bronchioalveolar lavage fluid (BALF), may lead to deficiency of the protein as seen in CF and therefore rfhSP-D may be a useful future therapy. [ABSTRACT FROM AUTHOR]

Abstract: Chagas’ disease is considered the sixth most important neglected tropical disease worldwide. Considerable knowledge has been accumulated concerning the role of zinc on cellular immunity. The steroid hormone dehydroepiandrosterone (DHEA) is also known to modulate the immune system. The aims of this paper were to investigate a possible synchronization of their effects on cytokines and NO production and the resistance to Trypanosoma cruzi during the acute phase of infection. It was found that zinc, DHEA or zinc and DHEA supplementation enhanced the immune response, as evidenced by a significant reduction in parasitemia levels. Zinc and DHEA supplementation exerted additive effects on the immune response by elevation of macrophage counts, and by increasing concentrations of IFN-γ and NO. [Copyright &y& Elsevier]

Abstract: Asthma occurs in more than 5% of the population in industrialized countries and is now characterized as a chronic inflammatory disease. The chronic aspiration of gastric fluid is considered by many investigators to be a primary inflammatory factor exacerbating or predisposing patients to asthma, with more than 50 medical papers per year linking asthma with gastroesophageal reflux disease (GERD), which can lead to aspiration events. However, the mechanisms involved in the inflammatory effects caused by gastric-fluid aspiration are not clear at the present time. The role of macrophages in the pathogenesis of disease seems likely given the involvement of those cells in a variety of chronic inflammatory diseases. To investigate the potential role of gastric fluid and the mechanisms potentially underlying chronic aspiration-associated pathogenesis, we examined the activation of murine macrophages (Raw 264.7 cell line) with gastric fluid. Inflammatory cytokine production and activation of the NF-κB signaling pathway were observed. Toll-like receptor (TLR)-4-dependent activation was observed under some conditions, indicating that bacterial components within the gastric fluid are involved in macrophage activation. Matrix metalloproteinase-9 (MMP-9) expression by macrophages was enhanced by gastric fluid, suggesting a potential mechanism by which remodeling of airways might be induced by gastric-fluid aspiration. [Copyright &y& Elsevier]

Abstract: According to some authors, membrane compartmentalization is a key regulator of CD45 function. Indeed, it has been described that CD45 repositioning from raft microdomains to phospholipid-rich plasma membrane areas leads to the activation of extracellular signal-regulated kinases (ERKs). We have previously shown that interleukin-12 (IL-12) increases the expression of CD26, promoting the interaction of CD26 with CD45R0 (a CD45 isoform) and removing CD45R0 from lipid rafts. Thus, this IL-12-dependent removal of CD45RO from rafts could, hypothetically, fulfill functions like the activation of the ERK1/2 pathway. IL-12 is an important interleukin for T cells. Upon interaction with its receptor (interleukin-12 receptor; IL-12R), this cytokine triggers a signalling cascade, where the classical Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway and other additional routes participate. Due to the promitogenic effect of IL-12 and the influence of this cytokine on CD45RO compartmentalization, ERK kinases were likely candidates to be downstream of IL-12R. However, several research groups have rejected a role for these kinases. Now, results in this paper show that the IL-12R binding, similar to the stimulation via T cell receptor (TCR), promotes the activation of the Raf/MEK-1/ERK1/2 pathway. In addition, the IL-12R-associated Janus kinase JAK2, but not TYK2, seems upstream of this important pathway for the proliferation of human T cells. However, even though c-Myc is slightly up-regulated by IL-12 and partially mediates the proliferative effect of IL-12, this transcription factor was not found downstream of ERK1/2. [Copyright &y& Elsevier]

Abstract: We have recently established a novel method for bone marrow transplantation: intra-bone marrow–bone marrow transplantation (IBM–BMT), by which the rapid recovery of donor-derived hematopoiesis can be expected even when reduced radiation doses are used. In this paper, we examine, using mice, whether the combination of pretreatment of recipients with granulocyte-colony-stimulating factor (G-CSF) and IBM–BMT can induce a more rapid recovery of donor-derived hematopoiesis than IBM–BMT alone. We first pretreated recipients with recombinant human (rh) G-CSF (250μg/kg/day) for 5 consecutive days (days −6 to −2). On day −1, the recipients were irradiated, and IBM–BMT was carried out on day 0. On day 12, we performed colony-forming units of spleen (CFU-S) assays. The combination of G-CSF pretreatment and IBM–BMT augmented the CFU-S counts, the weight of spleens, and the numbers of donor-derived hematopoietic cells. We next analyzed the mechanisms underlying these effects of G-CSF and found that (i) G-CSF induces Th2 polarization, which can prevent graft rejection, and (ii) G-CSF augments natural suppressor activity, which suppresses graft rejection. The combination of G-CSF pretreatment and IBM–BMT can produce the rapid recovery of donor-derived hematopoiesis and suppress graft rejection. This method would lighten the burden on patients in allogeneic BMT. [Copyright &y& Elsevier]

Abstract: Diet selection is a complex problem that animals in wildlife have to deal with daily. In their natural environment, these animals meet a great variety of foods some of which they are able and prepared to eat, yet, not all of it is eaten. In addition to the biological factors, some of which we shall discuss deeper in this paper, an important factor in food preference is social contact. Alterations in the physiology of mammals can have profound effects on the choice or preference for certain foods. On the other hand the decline of taste and smell perception in the elderly, the degree of food restriction, the sensorial properties of foods (such as presentation, taste, and smell) can be considered factors that influence feeding behavior leading to aversion. Many species, including man, learn to associate nausea with taste, and as a consequence avoid its specific intake, which has been shown to be persistent. Conditioned taste aversion is a form of associative learning in which animals display an aversion to the taste of a food that has previously been paired with illness. Our group has investigated the pattern of ingestion of foods that are frequently eaten by mice in wildlife and are potentially allergenic to humans in order to study the immunological consequences to these foods such as oral tolerance and inflammatory processes of the gut. We have chosen two seeds, peanuts (Arachis hypogea) and cashew nuts (Anacardium occidentale), as our source of antigens as the first is considered to be one of the most potent food allergens and for the second there seems to be very little allergy in the human setting. We used male and female, normal, adult CBA/J, A/J, C57BL/6 and Balb/c mice 2–3 months old and hybrid (C57Bl/6×Balb/c) F1, (Balb/c×C57Bl/6) F1), (C57Bl/6×DBA2) F1 mice. Food preference appeared to be strain-specific. Animals tolerized to a determined seed, then immunized with its protein extract and re-exposed to the seed in natura alter their feeding pattern. We suggest that diet selection, a multi-factorial event, is influenced by genetic factors such as the MHC and the immunological status of the animal. [Copyright &y& Elsevier]

Abstract: Laboratory and epidemiological studies have provided indirect but compelling evidence that toll-like receptor (TLR) signaling pathways play an important role in host responsiveness to ambient immunostimulatory factors. Nonetheless, direct evidence is limited. This paper will present our experience investigating the innate immunostimulatory activities of sterile house dust extracts (HDEs). In initial studies, bone marrow derived dendritic cells (BMDDCs) were cultured with HDEs, and cytokine production and co-stimulatory molecule expression were evaluated. In additional experiments, the TLR dependence of these responses was determined. HDEs induced concentration-dependent BMDDC activation. Moreover, the relative bioactivities of HDEs correlated with their endotoxin content. Finally, HDE-mediated responses were found to be partially dependent on TLR2, TLR4, and TLR9 and almost completely dependent on MyD88. These investigations provide the first direct evidence that TLR signaling pathways play a key role in innate responsiveness to non-infectious factors ubiquitous in living environments. [Copyright &y& Elsevier]

Abstract: A review of 250 patients with the catastrophic antiphospholipid (Asherson''s) syndrome (CAPS) taken from the web site organized by the Europhospholipid Group (http://www.med.ub.es/MIMMUN/FORUM/CAPS.HTM) is presented in this paper. A short historical overview of the antiphospholipid syndrome (APS) is followed by a description of the “triggering” factors, associated autoimmune diseases, clinical presentation, presumed pathogenesis, prognosis, mode of death and suggested therapies. Triggering factors are present in approximately 50% of patients and consist predominantly of infections, trauma, including minor surgical procedures such as biopsies, obstetric-related multiorgan failure and malignancy-associated CAPS. The patients present mainly with multiorgan failure resulting from predominantly small vessel occlusions affecting mainly intra-abdominal organs such as bowel, liver, pancreas, and adrenals, although large vessel occlusions do occur and comprise mainly deep vein thromboses (DVT) of the veins of the lower limbs and arterial occlusions causing strokes and peripheral gangrene. They do not however dominate the clinical picture. The condition differs considerably from the simple/classic APS in several respects, viz. the rapid development of multiorgan failure following the above-mentioned identifiable precipitating factors, the involvement of unusual organs such as bowel, reproductive organs, and bone marrow, complicating features of disseminated intravascular coagulation in 20% of cases, the acute (adult) respiratory distress syndrome (ARDS) in one third of patients, and severe thrombocytopenia; these not being encountered in the simple/classic APS. Treatment consisting of regular and repeated plasma exchanges using fresh frozen plasma, and IV immunoglobulins in addition to parenteral steroids and anticoagulation are necessary to improve the survival in a condition where the mortality is still of the order of 50%. Treatment may have to be continued for several weeks. Parenteral antibiotics may be indicated where an underlying infection is suspected. Antifungal therapy may also be indicated with prolonged treatment and the use of the monoclonal anti-CD20 molecule, Rituximab, has proven useful in those patients where thrombocytopenia poses a major risk of hemorrhage. [Copyright &y& Elsevier]

Abstract: The immunostimulatory effects of cytosine-phosphate-guanosine (CpG)-containing oligodeoxynucleotides (ODNs) have been extensively documented. In this paper, we describe the inhibitory effects of ODNs that contain natural phosphodiester backbones (O-ODNs) on the immunostimulation caused by CpG-containing phosphorothioated ODNs (CpG-S). CpG-S stimulation of mouse splenocyte proliferation was reduced by the addition of O-ODNs that contained or lacked the CpG-motif (CpG-containing phosphodiester oligodeoxynucleotide, CpG-O or GpC-O). The total number of cultured splenocytes was up-regulated by CpG-S, whereas repetitive addition of O-ODNs to the cell cultures inhibited this effect. The frequency of T2-like B cells was found to be increased by CpG-S. The culture supernatants of CpG-S-treated splenocytes contained elevated levels of IL-10 and IL-6. However, IL-10 and IL-6 production was down-regulated significantly by the combination of CpG-S and either CpG-O or GpC-O. The O-ODN mediated inhibition of proliferation was less pronounced in IL-10−/− mice. Thus, the O-ODNs, irrespective of CpG content, exerted inhibitory activities on the proliferation of B cells. These anti-proliferative effects appear to be mediated both by the down-regulation of IL-10 production and increased apoptosis. [Copyright &y& Elsevier]

Summary: Th2 cells play a central role in type I allergies. However, the source of interleukin-4 which may lead to a Th1/Th2 imbalance is unknown. Vα24+CD161+ Natural killer T (NKT) cells secrete high amounts of interleukin-4 and/or interferon-γ and are assumed to participate in the initiation of Th1/Th2 immune responses. Their contribution to the development of Th2-dependent type I allergies is controversial.Our objective in this paper was to determine whether Vα24+CD161+ NKT cells differ in atopic and non-atopic adults.Venous blood was obtained from thirteen atopic and sixteen healthy adult probands. Vα24+CD161+ NKT cells were determined in CD4+, CD8bright/dim and CD4−CD8− lymphocytes by flow cytometry. At the molecular level, the amounts of T cell receptor (TCR) AV24-AJ18 transcripts were quantified with respect to TCRAV24 chain transcripts alone or to all TCR alpha chain transcripts. To detect potential inserted nucleotides in the N-region, a novel real-time PCR-based technology was applied.Both CD4+ and CD4−CD8− NKT cells were present at higher frequencies than CD8+ NKT cells in all probands. CD8dim NKT cell levels were lower in healthy individuals, although not statistically significantly different to the patients. Amounts of AV24-AJ18 transcripts in relation to total TCR alpha-chains and to TCRAV24 alone were equal in both proband groups. N-region diversity was detected in four clones from four different individuals, but altered the amino acid sequence in only one clone of an atopic donor.Analysis of Vα24+CD161+ NKT cell frequencies at both the cellular and molecular levels failed to reveal significant differences in peripheral blood of atopic and non-atopic probands. If NKT cells contribute to development of type I allergies they must do so at earlier times or in other locations. [Copyright &y& Elsevier]

There is increasing evidence that histamine affects dendritic cell (DC) activation, maturation, and preference for Th1/Th2 differentiation. In this paper we report that histamine affects interleukin (IL)-12 and IL-6 production in an immature DC (iDC) line derived from murine spleen. Histamine treatment of iDC significantly increased the IL-12 p40 mRNA and protein levels compared to histamine untreated iDC. In the presence of tumor necrosis factor (TNF)-α histamine also increased IL-12 p40 and IL-6 production. However, histamine significantly decreased IL-12 p40 production by lipopolysaccharide (LPS)-stimulated DC in a concentration dependent manner. When expressions of histamine H1 (H1R) and H2 (H2R) receptors in DC were analyzed by RT-PCR, both receptors were down-regulated after LPS or TNF-α stimulation compared to unstimulated iDC. Histamine treatment significantly increased the expression of H2R mRNA in iDC and H1R mRNA in LPS-activated DC. However, histamine treatment decreased the expression of both histamine receptors in TNF-α-stimulated DC. Similar results were obtained by flow cytometry with FITC-conjugated histamine. These results demonstrate that histamine can regulate the expression of its own receptors and activate iDC, which may influence subsequent functional states of mature DC in a maturation signal-dependent manner. Consequently, histamine may contribute to an immune response outcome. [ABSTRACT FROM AUTHOR]

• Rapamycine treated monocyte-derived dendritic cells (moDCs) exhibit an incomplete tolerogenic profile. • Rapamycine reduces indoleamine 2,3 dioxygenase in moDCs. • Il-10 and IL-12 are both reduced in rapamycine-treated moDCs. • Tacrolimus does not change moDCs' phenotype and function. Immunosuppressive-drugs are needed after solid organ transplantation to prevent allograft rejection but induce severe side effects. Understanding the alloimmune response is critical to modulate it and to achieve graft operational tolerance. The role of regulatory T cells and tolerogenic dendritic cells (Tol-DCs) is undoubtedly essential in tolerance induction. Tacrolimus is considered as the cornerstone of immunosuppression in solid organ transplantation. mTOR inhibitor such as rapamycin are thought to induce tolerance and are used as anticancer drugs in several cancers. The aim of this study was to better understand the effect of these immunosuppressive drugs on the differentiation, maturation and function of human monocyte derived dendritic cells (DCs). DCs were differentiated from monocytes of healthy donors with either rapamycin (Rapa-DCs) or tacrolimus (Tac-DCs). The phenotype was evaluated by flow cytometry analysis. The production of pro- and anti-inflammatory cytokines was assessed by ELISA. The mRNA expression level of IDO and PD-L1 was assessed by RTqPCR. Mixed leukocytes reactions were performed to analyse suppressive activity of DCs. Rapa-DC were characterised by a lower expression of the co-stimulatory molecules and CD83 than control-DCs (CTR-DC) (p < 0.05). In contrast, tacrolimus had no effect on the expression of surface markers compared to CTR-DCs. Rapamycin reduced both IL-12 and IL-10 secretions (p < 0.05). Rapa-DCs had a suppressive effect on CD4+ allogenic T cells compared to CTR-DCs (p < 0.05). However, neither Rapa-DCs nor Tac-DCs favoured the emergence of a CD4+CD25highFoxp3+ population compared to CTR-DCs. Surprisingly, Rapa-DCs had a reduced expression of IDO and PD-L1 compared to Tac-DCs and CTR-DCs. Rapa-DCs exhibit an incomplete phenotypic tolerogenic profile. To our knowledge this is the first paper showing a reduction of expression of pro-tolerogenic enzyme IDO in DCs. Tacrolimus does not change the phenotypical or functional characteristics of moDCs. [ABSTRACT FROM AUTHOR]

Background/aim: To investigate the distribution of subpopulations of peripheral blood B lymphocytes in individuals with hepatocellular carcinoma (HCC), and to evaluate the effect of dexmedetomidine (DEX) on B lymphocyte differentiation in patients with HCC in vitro., Methods: Peripheral blood mononuclear cells (PBMCs) were collected from the HCC group and the healthy group, and the distribution of peripheral blood B-lymphocyte subpopulations in the two groups was examined by Flow Cytometry (FCM). B lymphocytes extracted from the peripheral blood of the HCC group were divided into D0, D1, D2 and D4 groups according to the different dose of DEX in the culture medium (0 μM, 1 μM, 2 μM and 4 μM). After 72 h of in vitro culture, FCM was used to detect differences in the percentage of apoptotic B lymphocytes and the percentage of B lymphocytes that can express interleukin 10(IL-10) and transforming growth factor-β (TGF-β) in each group., Results: In contrast to the healthy group, the HCC group exhibited a statistically significant increase in the proportion of CD19 + CD73 + B lymphocyte subpopulation (P<0.05). In the in vitro culture experiment, the differences in apoptosis of B lymphocytes and the percentage of TGF-β expression in each group were not statistically significant; When compared to the control group, there was a significant increase in the percentage of B lymphocytes expressing IL-10 across the D1, D2, and D4 groups (P<0.05)., Conclusion: The peripheral blood of HCC patients is characterized by an elevated presence of CD19 + CD73 + B lymphocyte subpopulations; DEX may have an immunosuppressive effect by promoting IL-10 secretion from peripheral blood B lymphocytes of HCC patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Due to the urgent need to create appropriate treatment techniques, which are currently unavailable, LPS-induced sepsis has become a serious concern on a global scale. The primary active component in the pathophysiology of inflammatory diseases such as sepsis is the Gram-negative bacterial lipopolysaccharide (LPS). LPS interacts with cell surface TLR4 in macrophages, causing the formation of reactive oxygen species (ROS), TNF-α, IL-1β and oxidative stress. It also significantly activates the MAPKs and NF-κB pathway. Excessive production of pro-inflammatory cytokines is one of the primary characteristic features in the onset and progression of inflammation. Cytokines mainly signal through the JAK/STAT pathway. We hypothesize that blocking of TLR4 along with TNFR1 might be beneficial in suppressing the effects of STAT1/STAT3 due to the stimulation of SOCS3 proteins. Prior to the LPS challenge, the macrophages were treated with antibodies against TLR4 and TNFR1 either individually or in combination. On analysis of the macrophage populations by flowcytometry, it was seen that receptor blockade facilitated the phenotypic shift of the M1 macrophages towards M2 resulting in lowered oxidative stress. Blocking of TLR4/TNFR1 upregulated the SOCS3 and mTOR expressions that enabled the transition of inflammatory M1 macrophages towards the anti-inflammatory M2 phenotype, which might be crucial in curbing the inflammatory responses. Also the reduction in the production of inflammatory cytokines such as IL-6, IL-1β due to the reduction in the activation of the STAT1 and STAT3 molecules was observed in our combination treatment group. All these results indicated that neutralization of both TLR4 and TNFR1 might provide new insights in establishing an alternative therapeutic strategy for LPS-sepsis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Hepatocellular carcinoma (HCC) stands as one of the most prevalent malignancies. While PD-1 immune checkpoint inhibitors have demonstrated promising therapeutic efficacy in HCC, not all patients exhibit a favorable response to these treatments. Glutamine is a crucial immune cell regulatory factor, and tumor cells exhibit glutamine dependence. In this study, HCC patients were divided into two subtypes (C1 and C2) based on glutamine metabolism-related genes via consensus clustering. The C1 pattern, in contrast to C2, was associated with a lower survival probability among HCC patients. Additionally, the C1 pattern exhibited higher proportions of patients with advanced tumor stages. The activity of C1 in glutamine metabolism and transport is significantly enhanced, while its oxidative phosphorylation activity is reduced. And, C1 was mainly involved in the progression-related pathway of HCC. Furthermore, C1 exhibited high levels of immunosuppressive cells, cytokine-receptor interactions and immune checkpoint genes, suggesting C1 as an immunosuppressive subtype. After stepwise selection based on integrated four machine learning methods, SLC1A5 was finally identified as the pivotal gene that distinguishes the subtypes. The expression of SLC1A5 was significantly positively correlated with immunosuppressive status. SLC1A5 showed the most significant correlation with macrophage infiltration, and this correlation was confirmed through the RNA-seq data of CLCA project and our cohort. Low-SLC1A5-expression samples had better immunogenicity and responsiveness to immunotherapy. As expected, SubMap and survival analysis indicated that individuals with low SLC1A5 expression were more responsive to anti-PD1 therapy. Collectively, this study categorized HCC patients based on glutamine metabolism-related genes and proposed two subclasses with different clinical traits, biological behavior, and immune status. Machine learning was utilized to identify the hub gene SLC1A5 for HCC classification, which also could predict immunotherapy response., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

4-1BB agonists for cancer immunotherapy have shown good preliminary efficacy in clinical trials, but several of the first-generation 4-1BB agonistic antibodies entering the clinic have failed due to safety issues. Selenium nanoparticles (SeNPs) exhibit anti-inflammatory, anti-tumor, antioxidant, and immune-modulating properties. In addition, they have been shown to have detoxifying effects and prevent oxidative liver damage. In this study, we used an anti-4-1BB antibody in combination with SeNPs to evaluate the anti-lung cancer effects in in vitro and in vivo experiments and explore the underlying mechanisms by pathological analyses, quantitative PCR, and enzyme-linked immunoassay. We found that 5 μmol·L -1 anti-4-1BB antibody combined with 1 μmol·L -1 SeNPs increased the expression of IFN-γ and promoted the killing effects of peripheral blood mononuclear cells on Lewis lung carcinoma cells, with a lethality rate up to 56.88 %. Experiments in tumor-bearing mice showed that the tumor inhibition rate was 58.61 % after treatment with 3.5 mg/kg anti-4-1BB antibody combined with 0.25 mg/kg SeNPs, and the liver function index returned to normal. When the combined treatment was compared with the antibody treatment alone, detection of immune relevant factors demonstrated that the expression of FOXP3, IL-2, IL-12, and TNF-α in the spleen was downregulated, whereas the expression of IFN-γ in the spleen, serum, and tumor was upregulated, accompanied by increased Fas ligand expression in the tumor tissues. Based on these findings, we get the conclusion that anti-4-1BB antibody combined with SeNPs may alleviate the immunosuppression of regulatory T cells, promote the immune cell proliferation and metastasis to synergistically kill tumor cells. This combination also reduces the inflammatory damage to normal tissues and slows overstimulation of the splenic immune response., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Bei Huang reports financial support and equipment, drugs, or supplies were provided by Hefei HankeMab Biotechnology co., Ltd,. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Aim: Twenty to thirty percent of non-small cell lung cancers (NSCLC) are caused by lung squamous cell carcinoma (LUSC), especially in smokers and there has been limited study previously evaluating the situation in terms of the genome and gene expression profile, which demonstrates the relationship among DEL-1, leucocyte recruitment, and pro-inflammatory cytokines in LUSC., Material and Methods: In the current study, the m-RNA expression patterns and mutation profiles of our target genes, such as, pro-inflammatory cytokines, chemoattractant molecules, and DEL-1 genes, in 511 LUSC patients. To find the harmful mutations, the PolyPhen-2 and SNAP programs were employed. Not only gene expression was detected, but also survival analysis and correlation between DEL-1 and other target genes' expression levels were explored too., Results: Target genes such as, DEL-1, TNF, IL-18, IL-1, CXCL8, CXCL13, and IL-6 were found to have a total genetic anomaly carrying rate of 16.4%. Seven mutations were found, and two of those mutations have a pathogenic aspect. Deep deletion and gene amplification of the genetic anomalies were also observed. According to gene expression analysis results in the LUSC patient group; DEL-1 and IL-6 levels were significantly lower than those of the control group, whereas the CXCL13 level was found to be higher., Conclusion: Findings of the current study revealed that, there is a significant role of DEL-1 in LUSC pathogenesis. Since present study is an in silico-centered study, this approach can give more insight on experimental studies. These events may support that one of the cancer improvement mechanisms depending on DEL-1 gene at the molecular level., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

It is known that conventional antigen presentation involves phagocytosis of antigens followed by its internalization in endocytic compartments and presentation of epitopes through MHC class II molecules for CD4 T cells. However, since 1976 a cross-presentation pathway has been studied, in which CD8 T cells are activated via MHC class I with antigens acquired through phagocytosis or endocytosis by dendritic cells (DCs). Among some important molecules involved in the cross-presentation, the C-type lectin receptor of the Dectin-1 cluster (CLECs), particularly the CLEC9A receptor, not only is expressed in dendritic cells but also presents a pivotal role in this context. In special, CLEC12A has been highlighted as a malaria pigment hemozoin (HZ) receptor. During Plasmodium infection, hemozoin crystals defend the parasite against heme toxicity within erythrocytes, as well as the released native HZ elicits pro-inflammatory responses and can induce cross-presentation. Particularly, this crystal can be synthesized from hematin anhydride and mimics the native form, and the gaps generated between the nanocrystal domains during its synthesis allow for substance coupling followed by its coating. Therefore, this study aimed to assess whether synthetic hemozoin (sHz) or hematin anhydride could be a nanocarrier and promote cross-presentation in dendritic cells. Firstly, it was verified that sHz can carry coated and coupled antigens, the compounds can associate to LAMP1-positive vesicles and decrease overall intracellular pH, which can potentially enhance the cross-presentation of ovalbumin and Leishmania infantum antigens. Thus, this study adds important data in the molecular intricacies of antigen presentation by showing not only the sHz immunomodulatory properties but also its potential applications as an antigen carrier., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Background: Dysregulation of RNA guanine-7 methyltransferase (RNMT) plays a crucial role in the tumor progression and immune responses. However, the detailed role of RNMT in pan-cancer is still unknown., Methods: Bulk transcriptomic data of pan-cancer were obtained from the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) databases. Single-cell transcriptomic and proteomics data of lung squamous cell carcinoma (LUSC) were analyzed in the Tumor Immune Single-cell Hub 2 (TISCH2) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases, respectively. The correlation between RNMT expression and cancer prognosis was analyzed by Cox proportional hazards regression and Kaplan-Meier analyses. The correlation of RNMT expression with common immunoregulators, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and DNA methyltransferase (DNMT) was analyzed. Additionally, the correlation between RNMT expression and immune infiltration level was evaluated. A total of 1287 machine learning combinations were used to construct prognostic models for LUSC. qRT-PCR and Western blot were used to validate the bioinformatics findings of RNMT upregulation in LUSC., Results: RNMT was widely expressed across different cancers, with significant correlation to prognosis in cancers such as kidney chromophobe (KICH) (p = 0.0033, HR = 7.12), liver hepatocellular carcinoma (LIHC) (p = 0.01, HR = 1.41), and others. Notably, RNMT participates in the regulation of the tumor microenvironment. RNMT expression positively correlated with immune cell expression (Spearman's rank correlation, p < 0.05). Moreover, RNMT expression was strongly associated with immunoregulators, TMB, MSI, MMR, and DNMT in most cancer types. Notably, RNMT expression displayed excellent prognostic and immunological performance in LUSC. The expression of RNMT was mainly enriched in B cells of LUSC tissues. qRT-PCR and Western blot verified the high expression of RNMT in LUSC., Conclusion: RNMT expression widely correlated with prognosis and immune infiltration in various tumors, especially LUSC. The RNMT detection may provide a new idea for future tumor immune studies and treatment strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Podocytes maintain renal filtration integrity when the glomerular filtration barrier (GFB) is integrated. Impairment or attrition of podocytes, leading to compromised GFB permeability, constitutes the primary etiology of proteinuria and is a hallmark pathological feature of diabetic nephropathy (DN). This study centers on Heterogeneous Nuclear Ribonucleoprotein I (HNRNP I), an RNA-binding protein, delineating its role in facilitating DN-induced renal damage by modulating podocyte health. Comparative analyses in renal biopsy specimens from DN patients and high-glucose-challenged podocyte models in vitro revealed a marked downregulation of HNRNP I expression relative to normal renal tissues and podocytes. In vitro assays demonstrated that high-glucose conditions precipitated a significant reduction in podocyte viability and an escalation in markers indicative of apoptosis. Conversely, HNRNP I overexpression was found to restore podocyte viability and attenuate apoptotic indices. IRAK1, a gene encoding a protein integral to inflammatory signaling, was shown to interact with HNRNP I, which promotes IRAK1 degradation. This interaction culminates in suppressing the PI3K/AKT/mTOR signaling pathway, thereby diminishing podocyte apoptosis and mitigating renal damage in DN. This investigation unveils the mechanistic role of HNRNP I in DN for the first time, potentially informing novel therapeutic strategies for DN renal impairment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Although Bacillus Calmette-Guerin (BCG) has been used in human for centuries, tuberculosis (TB) remains one of the deadliest infectious diseases.There have been remarkable successes in the field of TB vaccine research over the past decade, but the search for a better vaccine candidate is still a challenge. Extracellular vesicles (EVs) possess a multitude of properties that make them attractive candidates for the development of novel, cell-free, non-replicative, and safe vaccine system. These properties include their small size, inherent immunogenicity, ability to be taken up by immune cells, self-adjuvant capability and the comprehensive distribution of concentrated antigens. In this study, we designed a newly chimeric antigen TB vaccine (CA) with three Mycobacterium tuberculosis (M. tb) antigens that identified from extracellular vesicle derived from M. tb-infected macrophage. We confirmed that the CA stimulated a more pronounced immune response and enhanced T-cell activation, thereby providing superior protection against Mycobacterium tuberculosis infection in comparison to the bivalent antigens. Importantly, the EVs carrying CA (EVs-CA) provided enhanced protection against M. tb infection compared to unencapsulated CA antigen. Moreover, we established an EV-carried CA system (EVs-CA) and released from a transformed cell line using endogenous loading of antigen method. This method displayed the CA could efficiently package into EVs and increased concentration of this antigen. The chimeric antigen carried by EVs induced higher levels of cytokines production and specific cytotoxic T lymphocytes, resulted in enhancing antibody response and improving protective efficacy. Our findings suggested that the potential of EVs as delivery system to carry the M. tb-specific chimeric antigen for controlling Mycobacterium tuberculosis infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that represents a significant challenge in cancer research and clinical management. In this study, we reanalyzed a published single-cell RNA sequencing (scRNA-seq) dataset from PDAC and adjacent tissues to investigate the heterogeneity of tumor and normal tissue, specifically focusing on the regulatory T cells (Tregs) and their interactions with other cells in the tumor microenvironment (TME). Treg cells were identified and clustered into natural Tregs (nTreg) and induced Tregs (iTreg) based on the expression of specific genes. It was found that the number of iTregs was higher in the tumor than in healthy tissues, while the number of n Tregs was higher in healthy tissues. Differential gene expression analysis was performed, and biological process analysis revealed that the Tregs in PDAC were mostly involved in protein targeting and translation pathways. In addition, ligand-receptor pairs between Tregs and other cell types were identified, and the critical communication pathways between Tregs and endothelial and ductal cells were revealed, which could potentially contribute to the immunosuppressive TME of PDAC. These findings provide insights into the role of Tregs in PDAC and their interactions with other cell types in the TME, highlighting potential targets for immunotherapy, such as the inhibitory immune checkpoint receptors CTLA4 and TIGIT, which are known to be expressed on Tregs and have been shown to play a role in suppressing anti-tumor immune responses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Acute lung injury caused by severe malaria (SM) is triggered by a dysregulated immune response towards the infection with Plasmodium parasites. Postmortem analysis of human lungs shows diffuse alveolar damage (DAD), the presence of CD8 lymphocytes, neutrophils, and increased expression of Intercellular Adhesion Molecule 1 (ICAM-1). P. berghei ANKA (PbA) infection in C57BL/6 mice reproduces many SM features, including acute lung injury characterized by DAD, CD8 + T lymphocytes and neutrophils in the lung parenchyma, and tissular expression of proinflammatory cytokines and adhesion molecules, such as IFNγ, TNFα, ICAM, and VCAM. Since this is related to a dysregulated immune response, immunomodulatory agents are proposed to reduce the complications of SM. The monocyte locomotion inhibitory factor (MLIF) is an immunomodulatory pentapeptide isolated from axenic cultures of Entamoeba hystolitica. Thus, we evaluated if the MLIF intraperitoneal (i.p.) treatment prevented SM-induced acute lung injury. The peptide prevented SM without a parasiticidal effect, indicating that its protective effect was related to modifications in the immune response. Furthermore, peripheral CD8 + leukocytes and neutrophil proportions were higher in infected treated mice. However, the treatment prevented DAD, CD8 + cell infiltration into the pulmonary tissue and downregulated IFNγ. Moreover, VCAM-1 expression was abrogated. These results indicate that the MLIF treatment downregulated adhesion molecule expression, impeding cell migration and proinflammatory cytokine tissular production, preventing acute lung injury induced by SM. Our findings represent a potential novel strategy to avoid this complication in various events where a dysregulated immune response triggers lung injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Recent evidence has shown that T cell exhaustion is implicated in Allergen-specific Immunotherapy (AIT). However, how T cell exhaustion plays a role in AIT is far from clear. Our study aimed to investigate T cell exhaustion associated with allergen exposure during AIT in mice. Ovalbumin (OVA) - sensitized C57BL/6J asthma mouse and AIT mouse models were constructed. Quantitative real-time PCR (qRTPCR) and flow cytometry were used to monitor the occurrence of local and systemic CD4 + T cells and Th2 + T cells exhaustion in OVA-sensitized mice. The inhibitory surface marker programmed cell death protein 1 (PD-1) on CD4 + T cells and Th2 + T cells was significantly upregulated in AIT mice compared with asthmatic and control mice. The level of PD-1 on the surface of CD4 + T cells of asthma mice was significantly higher than that of control mice. The inhibitory surface marker cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on CD4 + T cells and Th2 + T cells showed no significant difference between the AIT, asthma and control mice. Collectively, our study indicated that the expression of PD-1 on CD4 + T cells and Th2 + T cells was increased in AIT. Allergen exposure promotes the expression of PD-1 on the surface of CD4 + T cells. T cell exhaustion plays an important role in AIT., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)