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Interleukin‐41 (IL‐41) is a newly discovered cytokine, named Cometin, Subfatin, meteorin‐like transcription (Metrnl), and so forth. It is widely expressed in animals and can exert its biological roles through autocrine and paracrine forms. It has functions such as anti‐inflammatory, improving body metabolism, regulating immunity, regulating fat metabolism and participates in the process of autoimmune disease or inflammatory injury. It plays an important role in psoriasis, diabetes, Crohn's disease (CD), osteoarthritis, Kawasaki disease (KD), Graves' disease, autoimmune hepatitis, infertility, obesity, sepsis, cardiovascular diseases and respiratory diseases. This paper reviews the biological functions of IL‐41, the relationship between IL‐41 and diseases, the effects of IL‐41 in the cytokine network and the possible signalling pathways. In order to explore the same target or the same drug for the treatment of different diseases from the perspective of homotherapy for heteropathy, cytokine strategies based on IL‐41 have been put forward for the precise treatment of immune diseases and inflammatory diseases. It is worth noting that IL‐41 related preparations for lung protection and smoking cessation are interesting research fields. [ABSTRACT FROM AUTHOR]

The article titled "Correction to 'Psychological stress to ovalbumin peptide‐specific T‐cell receptor transgenic mice impairs the suppressive ability of type 1 regulatory T cell'" in the journal Immunology discusses a correction made to the original paper. The authors discovered that Figure 2b was unnecessary as it presented the same data as Figure 2a. Therefore, they removed Figure 2b from the paper. The correction also includes additional information about concurrent exposure to restraint stress and immune response exaggerating endoplasmic reticulum stress in type 1 regulatory T cells. The authors apologize for the error. [Extracted from the article]

Summary: The Immune Epitope Database and Analysis Resource (IEDB) provides the scientific community with open access to epitope data, as well as epitope prediction and analysis tools. The IEDB houses the most extensive collection of experimentally validated B‐cell and T‐cell epitope data, sourced primarily from published literature by expert curation. The data procurement requires systematic identification, categorization, curation and quality‐checking processes. Here, we provide insights into these processes, with particular focus on the dividends they have paid in terms of attaining project milestones, as well as how objective analyses of our processes have identified opportunities for process optimization. These experiences are shared as a case study of the benefits of process implementation and review in biomedical big data, as well as to encourage idea‐sharing among players in this ever‐growing space. [ABSTRACT FROM AUTHOR]

The clonal selection theory (CST) is the centrepiece of the current paradigm used to explain immune recognition and memory. Throughout the past decades, the original CST had been expanded and modified to explain new experimental evidences since its original publication by Burnet. This gave origin to new paradigms that govern experimental immunology nowadays, such as the associative recognition of antigen model and the stranger/danger signal model. However, these new theories also do not fully explain experimental findings such as natural autoimmune immunoglobulins, idiotypic networks, low and high dose tolerance, and dual‐receptor T and B cells. To make sense of these empirical data, some authors have been trying to change the paradigm of immune cognition using a systemic approach, analogies with brain processing and concepts from second‐order cybernetics. In the present paper, we review the CST and some of the theories/hypotheses derived from it, focusing on immune recognition. We point out their main weaknesses and highlight arguments made by their opponents and believers. We conclude that, until now, none of the proposed theories can fully explain the totality of immune phenomena and that a theory of everything is needed in immunology. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS), one of the most prevalent functional gastrointestinal disorders, is characterized by recurrent abdominal pain and abnormal defecation habits, resulting in a severe healthcare burden worldwide. The pathophysiological mechanisms of IBS are multi‐factorially involved, including food antigens, visceral hypersensitivity reactions, and the brain–gut axis. Numerous studies have found that gut microbiota and intestinal mucosal immunity play an important role in the development of IBS in crosstalk with multiple mechanisms. Therefore, based on existing evidence, this paper elaborates that the damage and activation of intestinal mucosal immunity and the disturbance of gut microbiota are closely related to the progression of IBS. Combined with the application prospect, it also provides references for further in‐depth exploration and clinical practice. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis involves various types of immune cells and soluble mediators, including TGF‐β and IL‐35, a recently identified heterodimeric cytokine that belongs to the IL‐12 cytokine family. However, the effect of regulatory IL‐35 may play an important role in fibrotic diseases. The aim of this paper is to explore the immunoregulatory role of IL‐35 in the development of fibrosis in interstitial lung disease (ILD). To gain a better understanding of this issue, the concentrations of IL‐35 and different profibrotic cytokines in fibrotic (F‐ILD) and non‐fibrotic (NF‐ILD) patients by ELISA were compared to that of intracellular IL‐35 and IL‐17 on CD4+ T cells stimulated in the presence of BAL or with different ratios of recombinant IL‐35 (rIL‐35) and TGF‐β (rTGF‐β), which were evaluated by flow cytometry. We observed that BAL concentration of IL‐35 was lower in F patients (p < 0.001) and was negatively correlated with concentrations of TGF‐β (p < 0.001) and IL‐17 (p < 0.001). In supplemented cell cultures, BAL from NF but not F patients enhanced the percentage of IL‐35 + CD4+ T (p < 0.001) cells and decreased the percentage of IL‐17 + CD4+ T cells (p < 0.001). The percentage of IL‐35 + CD4+ T cells correlated positively with BAL concentration of IL‐35 (p = 0.02), but correlated negatively with BAL concentrations of IL‐17 (p = 0.007) and TGF‐β (p = 0.01). After adjusting the concentrations of recombinant cytokines to establish a TGF‐β: IL‐35 ratio of 1:4, an enhanced percentage of IL‐35 + CD4+ T cells (p < 0.001) but a decreased percentage of IL‐17 + CD4+ T cells (p < 0.001) was observed. After adding recombinant IL‐35 to the BAL from F patients until a 1:4 ratio of TGF‐β: IL‐35 was reached, a significantly increased percentage of IL‐35 + CD4+ T cells (p < 0.001) and a decreased percentage of IL‐17 + CD4+ T cells (p = 0.003) was found. These results suggest that IL‐35 may induce an anti‐fibrotic response, regulating the effect of TGF‐β and the inflammatory response on CD4+ T cells. In addition, the TGF‐β: IL‐35 ratio in BAL has been shown to be a potential biomarker to predict the outcome of F patients with ILD. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a frequent gastrointestinal malignancy with high rates of morbidity and mortality; 85% of these tumours are proficient mismatch repair (pMMR)‐microsatellite instability‐low (MSI‐L)/microsatellite stable (MSS) CRC known as ‘cold’ tumours that are resistant to immunosuppressive drugs. Monotherapy with programmed death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) inhibitors is ineffective for treating MSS CRC, making immunotherapy for MSS CRC a bottleneck. Recent studies have found that the multi‐pathway regimens combined with PD‐1/PD‐L1 inhibitors can enhance the efficacy of anti‐PD‐1/PD‐L1 in MSS CRC by increasing the number of CD8+ T cells, upregulating PD‐L1 expression and improving the tumour microenvironment. This paper reviews the research progress of PD‐1/PD‐L1 inhibitors in combination with cytotoxic T‐lymphocyte–associated antigen 4 (CTLA‐4) inhibitors, oncolytic virus, intestinal flora, antiangiogenic agents, chemotherapy, radiotherapy and epigenetic drugs for the treatment of pMMR‐MSI‐L/MSS CRC. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a metabolic inflammatory disease with a high incidence worldwide. Patients with DM are at a high risk for all types of infections. Type 1 DM is characterised with immune destruction of pancreatic β cells, while type 2 diabetes is characterised with insulin resistance and β cell dysfunction, both of which result in disorders of glucose and lipid metabolism. This metabolic disorder causes functional defects of immune cells, aberrant production of inflammatory cytokines, dysregulated immune responses, advanced pathophysiological injury of the body, and increased mortality in populations with DM upon infections. Starting with the change of natural immune system in patients with DM, this paper focused on the enhanced severity of infections in DM and the underlying innate immune alterations in preclinical and clinical studies, aiming to better understand the influence of DM on the susceptibility, pathophysiology, and clinical outcomes in infections. [ABSTRACT FROM AUTHOR]

In the past few years, the evolution of immunotherapy has resulted in a shift in cancer treatment models. However, with immunosuppressive effects of the tumour microenvironment continues to limit advances in tumour immunotherapy. The tumour microenvironment induces metabolic reprogramming in cancer cells, which results in competition for nutrients between tumour cells and host immunocytes. Metabolic and waste products originating in tumour cells can influence the activation and effector properties of immunocytes in numerous ways and ultimately promote the survival and propagation of tumour cells. In this paper, we discuss metabolic reprogramming in tumour cells and the influence of metabolite by‐products on the immune microenvironment, providing novel insights into tumour immunotherapy. [ABSTRACT FROM AUTHOR]

Summary: Some human antibodies may paradoxically inhibit complement activation on bacteria and enhance pathogen survival in humans. This property was also claimed for IgG antibodies reacting with terminal galactose‐α‐1,3‐galactose (Galα3Gal; IgG anti‐αGal), a naturally occurring and abundant antibody in human plasma that targets numerous different pathogens. To reinvestigate these effects, we used IgG anti‐αGal affinity isolated from a pool of normal human IgG and human hypogammaglobulinaemia serum as a complement source. Flow cytometry was performed to examine antibody binding and complement deposition on pig erythrocytes, Escherichia coli O86 and Streptococcus pneumoniae serotype 9V. Specific nanobodies were used to block the effect of single complement factors and to delineate the complement pathways involved. IgG anti‐αGal was capable of activating the classical complement pathway on all the tested target cells. The degree of activation was exponentially related to the density of bound antibody on E. coli O86 and pig erythrocytes, but more linearly on S. pneumoniae 9V. The alternative pathway of complement amplified complement deposition. Deposited C3 fragments covered the activating IgG anti‐αGal, obstructing its detection and highlighting this as a likely general caveat in studies of antibody density and complement deposition. The inherent capacity for complement activation by the purified carbohydrate reactive IgG anti‐αGal was similar to that of normal human IgG. We propose that the previously reported complement inhibition by IgG anti‐αGal relates to suboptimal assay configurations, in contrast to the complement activating property of the antibodies demonstrated in this paper. [ABSTRACT FROM AUTHOR]

Summary: The study of cellular and molecular immunology is almost completely dependent on monoclonal antibody technology. Despite the relatively long history of monoclonal antibodies, there is still huge potential for developing novel and transformative uses for this technology. In this issue of Immunology, we present two such papers, one focussing on anti‐complement (C5) antibodies, the other on anti‐CD6‐specific antibodies. Both manuscripts describe novel ways that monoclonal antibodies may be used for scientific and potentially for therapeutic benefit. [ABSTRACT FROM AUTHOR]

Summary: The concept of trained immunity refers to remodelling of the monocyte and macrophage metabolic and epigenetic landscape, conferring an amplified inflammatory response upon secondary stimulation. This effect is typically modelled in vitro by stimulating monocytes with either Bacillus Calmette Guerin (BCG) or β‐Glucan for 24 hr, before subsequent stimulation with LPS or Pam‐3‐Cys (P3C) as a secondary stimulus 6 days later. Here, we focus on a recent paper which interrogated the role of the anti‐inflammatory TLR, TLR10, on trained immunity. Using both an in vitro model of trained immunity, and analysis of BCG vaccinated individuals, the authors interestingly demonstrate that, despite its ability to regulate aspects of innate immunity, TLR10 does not have a significant role in this process. [ABSTRACT FROM AUTHOR]

MHC class I-related gene protein (MR1) is a non-polymorphic MHC class IB antigen-presenting molecule that is the restricting molecule for mucosal-associated invariant T (MAIT) cells, a prominent population of innate-like antibacterial T cells. The MAIT cell-MR1 axis represents a new paradigm in antigen presentation, with the MR1 ligand derived from vitamin B compounds or their metabolic precursors. Many bacteria and some fungi produce the activating ligand for MR1. In evolution, MR1 is highly conserved in most, but not all, mammals. In humans and rodents it is expressed in a broad range of cell types, both haematopoietic and non-haematopoietic, although cell surface expression has been difficult to detect. Although MR1 trafficking shares features with both the MHC class I and MHC class II pathways, it is distinct. Several strands of evidence suggest that the intracellular location where MR1 is loaded differs for soluble ligand and for ligand derived from intact bacteria. The regulation of MR1 surface expression may also vary between different cell types. This paper will review what is currently known about the expression and trafficking of MR1 and propose a model for the loading and trafficking of MR1. [ABSTRACT FROM AUTHOR]

The nuclear factor- κB (NF- κB) family of transcription factors play an essential role for the regulation of inflammatory responses, immune function and malignant transformation. Aberrant activity of this signalling pathway may lead to inflammation, autoimmune diseases and oncogenesis. Over the last two decades great progress has been made in the understanding of NF- κB activation and how the response is counteracted for maintaining tissue homeostasis. Therapeutic targeting of this pathway has largely remained ineffective due to the widespread role of this vital pathway and the lack of specificity of the therapies currently available. Besides regulatory proteins and microRNAs, long non-coding RNA (lncRNA) is emerging as another critical layer of the intricate modulatory architecture for the control of the NF- κB signalling circuit. In this paper we focus on recent progress concerning lncRNA-mediated modulation of the NF- κB pathway, and evaluate the potential therapeutic uses and challenges of using lncRNAs that regulate NF- κB activity. [ABSTRACT FROM AUTHOR]

The antigenic reactivity of constituents of Schistosoma mansoni and peanut ( Arachis hypogaea) was investigated to determine whether identical antigenic epitopes possessed by both organisms provided a possible explanation for the negative correlation between chronic schistosome infection and atopy to allergens. Aqueous extracts of peanuts were probed in Western immunoblots with rabbit IgG antibodies raised against the egg, cercarial and adult worm stages of S. mansoni. Several molecules in the peanut extract were antigenically reactive with antibodies from the various rabbit anti-schistosome sera. A pair of cross-reactive peanut molecules at ~30 000-33 000 molecular weight was purified and both proteins were identified by mass spectrometric analysis as the peanut allergen Ara h 1. Anti- S. mansoni soluble egg antigen antibodies that were eluted off the peanut molecules reacted with two S. mansoni egg antigens identified by mass spectrometry as IPSE/ α-1 and κ-5. Alignments of the amino acid sequences of Ara h 1 and either IPSE/ α-1 or κ-5 revealed a low level of peptide sequence identity. Incubation of nitrocellulose paper carrying electrophoresed peanut molecules, six constituents of other allergic plants and S. mansoni egg antigens in a mild solution of sodium metaperiodate before probing with antibodies, inhibited most of the cross-reactivities. The results are consistent with the antigenic cross-reactive epitopes of S. mansoni egg antigens, peanut and other allergic plants being cross-reactive carbohydrate determinants (CCDs). These findings are novel and an explanation based on 'blocking antibodies' could provide an insight for the inverse relationship observed between schistosome infection and allergies. [ABSTRACT FROM AUTHOR]

B cells have an important pathogenic role in the development of type 1 diabetes in the non-obese diabetic ( NOD) mouse. We have previously reported that NOD mice display an increased percentage of TACIhigh-expressing B cells compared with C57 BL/6 mice and this trait is linked to chromosomes 1 and 8. In this paper the genetic association of the transmembrane activator, calcium modulator and cyclophilin ligand interactor ( TACI) trait was confirmed using double congenic NOD. B6C1/Idd22 mice. TACI ligation by a proliferation-inducing ligand ( APRIL) has been shown to influence plasma cell differentiation, immunoglobulin production and isotype switch. Hence, the functional consequence of the up-regulation of TACI on NOD B cells was analysed both in vitro and in vivo. NOD B cells stimulated with APRIL showed an enhanced plasma cell differentiation and class switch to IgG and IgA compared with B cells from C57 BL/6 mice. Moreover, flow cytometry analyses revealed that germinal centre B cells in NOD failed to down-regulate TACI. Availability of the TACI ligand B-cell activating factor ( BAFF) has been shown to be a limiting factor in the germinal centre reaction. In line with this, upon immunization with 4-hydroxy-3-nitrophenylacetyl hapten-conjugated hen egg lysozyme, NOD mice produced higher titres of low-affinity antibodies compared with C57 BL/6 mice. This observation was supported by the detection of increased levels of BAFF in NOD germinal centres after immunization compared with C57 BL/6 by immunofluorescence. Our results support the hypothesis that increased TACI expression on NOD B cells contributes to the pathogenesis of type 1 diabetes in the NOD mouse. [ABSTRACT FROM AUTHOR]

Summary: There have been substantial strides forward in our understanding of the contribution of regulatory T (Treg) cells to cancer immunosuppression. In this issue, we present a series of papers highlighting emerging themes on this topic relevant not only to our understanding of the fundamental biology of tumour immunosuppression but also to the design of new immunotherapeutic approaches. The substantially shared biology of CD4+ conventional T (Tconv) and Treg cells necessitates a detailed understanding of the potentially opposing functional consequences that immunotherapies will have on Treg and Tconv cells, a prominent example being the potential for Treg‐mediated hyperprogressive disease following anti‐PD‐1 therapy. Such understanding will aid patient stratification and the rational design of combination therapies. It is also becoming clear, however, that Treg cells within tumours exhibit distinct biological features to both Tconv cells and Treg cells in other tissues. These distinct features provide the opportunity for development of targeted immunotherapies with greater efficacy and reduced potential for inducing systemic toxicity. [ABSTRACT FROM AUTHOR]

Nik is a classically trained immunologist in the field of T-cell activation and memory, and has also become something of an engineer in preclinical mouse models. This month, I'll be kicking off a series of editorials written based on more or less casual conversations I've had with some emerging leaders in the field of immunology. I I think the excitement over the immunology of cancer and its microenvironment has helped catalyse the transition to understanding immunity in at least that transformed tissue. [Extracted from the article]

Summary: Mass vaccination of the global population against SARS‐CoV‐2 will, we hope, turn the tide against this devastating pandemic. To complement vaccinations, better tools are needed to enable viral infections and immunological protection to be monitored. Accurate tools provide sound data for informed decision‐making at many levels, from personal to governmental. The measurement of viral RNA is currently routinely used to detect active infections, but only gives a positive result during infection and is unable to reveal historic infections. Tests involving a detection of SARS‐CoV‐2‐specific antibodies can reveal prior exposures to virus and can measure anti‐viral immune responses induced after natural infection or after vaccination. They may eventually also be used to predict an individual's likelihood of becoming re‐infected. Here, we report on the development of a sensitive ELISA technique to detect multiple isotypes of antibodies against the spike glycoprotein, in samples of both serum and saliva. This paper provides an important step towards understanding the immune response to SARS‐CoV‐2 and may therefore eventually help us to effectively control it. [ABSTRACT FROM AUTHOR]

Summary: Hepatitis B virus (HBV) infection causes a self‐limiting disease in most individuals. However, < 10% of infected subjects develop a chronic disease. Genetic host variability of polymorphic genes at the interface of innate and acquired immunity, such as killer immunoglobulin‐like receptors (KIR), their human leucocyte antigen (HLA) and IgG allotypes (GM), could explain this different clinical picture. We previously showed a protective role of the KIR2DL3 gene for the development of chronic hepatitis B (CHB), and a detrimental role of the KIR ligand groups, HLA‐A‐Bw4 and HLA‐C2. We have expanded the previous analysis genotyping patients for GM23 and GM3/17 allotypes. The comparison of the patients with CHB with those who resolved HBV infection showed that the presence of GM17 allele virtually eliminated the risk of developing CHB (OR, 0·03; 95% CI, 0·004–0·16; P < 0·0001). In addition, the combination of GM17, KIR2DL3, HLA‐A‐Bw4 and HLA‐C2 was highly sensitive to predict the outcome of HBV infection. [ABSTRACT FROM AUTHOR]

We had several manuscripts out for review, grants submitted and a looming move of our lab to an updated new facility down the street. It could be a junior faculty member submitting grant after grant only to get a dreaded "ND" weeks later, time and time again. I have also thought about if "science burnout" is distinct from that experienced in other life paths. [Extracted from the article]

Summary: The cre‐loxP system has been revolutionary in the field of immunology. The technology enables genetic deletion in mice with unprecedented precision. It is therefore now widely used to investigate gene functions in animal models of disease, and in fundamental studies of the immune response. This widespread adoption of cre‐loxP technology has allowed a thorough investigation of its strengths and weaknesses. Here we highlight an important paper which not only describes potential problems with the commonly‐used screening procedures used when identifying offspring of the correct genotype, but also describes how this screening can be improved to ensure that the right animals are produced. [ABSTRACT FROM AUTHOR]

Dachshund family transcription factor 1 (DACH1) has been shown to exhibit a tumour‐suppressive role in a number of human cancers. However, the role of DACH1 in hypopharyngeal squamous cell carcinoma (HPSCC) and its function in the tumour microenvironment (TME) are still not clear. Crosstalk between cancer cells and tumour‐associated macrophages (TAMs) mediates tumour progression in HPSCC. The expression of DACH1, CD86 and CD163 was detected in 71 matched HPSCC–non‐cancerous tissue pairs using quantitative real‐time polymerase chain reaction and IHC analysis. Cell proliferation, migration and invasion were monitored by colony formation, Transwell and EdU incorporation assays. ChIP‐qPCR and dual‐luciferase reporter assays were applied to verify the targeting relationships between DACH1 and IGF‐1. Stably transfected HPSCC cells were co‐cultured with MΦ macrophages to assess macrophage polarization and secretory signals. DACH1 was decreased in HPSCC tissues and was indicative of a poor prognosis for HPSCC patients. Decreased DACH1 expression in HPSCC was associated with fewer CD86+ TAMs and more CD163+ TAMs. Knockdown of DACH1 inhibited the proliferation, migration and invasion of FaDu cells via Akt/NF‐κB/MMP2/9 signalling. Additionally, DACH1 was found to directly bind to the promoter region of IGF‐1 to downregulate the secretion of IGF‐1, which inhibited TAMs polarization through the IGF‐1R/JAK1/STAT3 axis. Furthermore, in nude mice, the effects of DACH1 inhibition on tumour progression and M2‐like TAMs polarization were confirmed. These findings suggest that IGF‐1 is a critical downstream effector of DACH1 that suppresses cell migration and invasion and inhibits TAMs polarization. DACH1 could be a therapeutic target and prognostic marker for HPSCC. [ABSTRACT FROM AUTHOR]

Novel approaches are required to improve the efficacy of immunotherapies and increase the proportion of patients who experience a benefit. Antibody‐dependent cell‐mediated cytotoxicity (ADCC) contributes to the efficacy of many monoclonal antibodies therapies. Natural killer (NK) cells mediate ADCC, though responses are highly variable and depend on prior treatment as well as other factors. Thus, strategies to increase NK cell activity are expected to improve multiple therapies. Both cytokine treatment and NK cell receptor engineering are being explored to increase ADCC. Post‐translational modifications, including glycosylation, are widely recognized as mediators of cellular processes but minimally explored as an alternative strategy to increase ADCC. We evaluated the impact of treatment with kifunensine, an inhibitor of asparagine‐linked (N‐)glycan processing, on ADCC using primary and cultured human NK cells. We also probed affinity using binding assays and CD16a structure with nuclear magnetic resonance spectroscopy. Treating primary human NK cells and cultured YTS‐CD16a cells with kifunensine doubled ADCC in a CD16a‐dependent manner. Kifunensine treatment also increased the antibody‐binding affinity of CD16a on the NK cell surface. Structural interrogation identified a single CD16a region, proximal to the N162 glycan and the antibody‐binding interface, perturbed by the N‐glycan composition. The observed increase in NK cell activity following kifunensine treatment synergized with afucosylated antibodies, further increasing ADCC by an additional 33%. These results demonstrate native N‐glycan processing is an important factor that limits NK cell ADCC. Furthermore, optimal antibody and CD16a glycoforms are defined that provide the greatest ADCC activity. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis (CRS) represents chronic inflammation of the sinus mucosa characterised by dysfunction of the sinuses' natural defence mechanisms and induction of different inflammatory pathways ranging from a Th1 to a Th2 predominant polarisation. Recalcitrant CRS is associated with Staphylococcus aureus dominant mucosal biofilms; however, S. aureus colonisation of the sinonasal mucosa has also been observed in healthy individuals challenging the significance of S. aureus in CRS pathogenesis. We aimed to investigate the relationship between CRS key inflammatory markers, S. aureus biofilm properties/virulence genes and the severity of the disease. Tissue samples were collected during endoscopic sinus surgery from the ethmoid sinuses of CRS patients with (CRSwNP) and without (CRSsNP) nasal polyps and controls (n = 59). CD3+ T‐cell subset frequencies and key inflammatory markers of CD4+ helper T cells were determined using FACS analysis. Sinonasal S. aureus clinical isolates were isolated (n = 26), sequenced and grown into biofilm in vitro, followed by determining their properties, including metabolic activity, biomass, colony‐forming units and exoprotein production. Disease severity was assessed using Lund–Mackay radiologic scores, Lund–Kennedy endoscopic scores and SNOT22 quality of life scores. Our results showed that S. aureus biofilm properties and CRS severity scores correlated positively with total CD4+ T‐cell frequencies but looking into CD4+ T‐cell subsets showed an inverse correlation with Th1 and Th17 cell frequencies. CD4+ T‐cell frequencies were higher in patients harbouring lukF.PV‐positive S. aureus while its regulatory and Th17 cell subset frequencies were lower in patients carrying sea− and sarT/U‐positive S. aureus. Recalcitrant CRS is characterised by increased S. aureus biofilm properties in relation to increased total CD4+ helper T‐cell frequencies and reduced frequencies of its Th1, Th17 and regulatory T‐cell subsets. These findings offer insights into the pathophysiology of CRS and could lead to the development of more targeted therapies. [ABSTRACT FROM AUTHOR]

Glioblastoma is a common and fatal malignant tumour of the central nervous system, with high invasiveness. Conventional treatments for this disease, including comprehensive treatment of surgical resection combined with chemoradiotherapy, are ineffective, with low survival rate and extremely poor prognosis. Targeted therapy is promising in overcoming the difficulties in brain tumour treatment and IL‐13Rα2 is a widely watched target. The development of new therapies for glioma, however, is challenged by factors, such as the unique location and immune microenvironment of gliomas. The unique advantages of single‐domain antibodies (sdAbs) may provide a novel potential treatment for brain tumours. In this study, Chiloscyllium plagiosum was immunized with recombinant IL‐13Rα2 protein to produce sdAb and sdAb sequences were screened by multi‐omics. The targeted sdAb genes obtained were efficiently expressed in the Escherichia coli prokaryotic expression system, showing a significant binding capacity to IL‐13Rα2 in vitro. The cell proliferation and migration inhibitory effects of recombinant variable domain of the new antigen receptor (VNAR) on glioma cells were detected by CCK‐8 and cell scratch assays. The sdAb obtained in this study showed high in vitro activity and favourable cell proliferation inhibitory effect on glioma cells, with potential clinical application value. The present study also provides a new direction and experimental basis for the development of targeted therapies for glioma. [ABSTRACT FROM AUTHOR]

Nutritional availability during fasting and refeeding affects the temporal redistribution of lymphoid and myeloid immune cells among the circulating and tissue‐resident pools. Conversely, nutritional imbalance and impaired glucose metabolism are associated with chronic inflammation, aberrant immunity and anomalous leukocyte trafficking. Despite being exposed to periodic alterations in blood insulin levels upon fasting and feeding, studies exploring the physiological effects of these hormonal changes on quiescent immune cell function and trafficking are scanty. Here, we report that oral glucose load in mice and healthy men enhances the adherence of circulating peripheral blood mononuclear cells (PBMCs) and lymphocytes to fibronectin. Adherence to fibronectin is also observed upon regular intake of breakfast following overnight fasting in healthy subjects. This glucose load‐induced phenomenon is abrogated in streptozotocin‐injected mice that lack insulin. Intra‐vital microscopy in mice demonstrated that oral glucose feeding enhances the homing of PBMCs to injured blood vessels in vivo. Furthermore, employing flow cytometry, Western blotting and adhesion assays for PBMCs and Jurkat‐T cells, we elucidate that insulin enhances fibronectin adherence of quiescent lymphocytes through non‐canonical signalling involving insulin‐like growth factor‐1 receptor (IGF‐1R) autophosphorylation, phospholipase C gamma‐1 (PLCγ‐1) Tyr783 phosphorylation and inside‐out activation of β‐integrins respectively. Our findings uncover the physiological relevance of post‐prandial insulin spikes in regulating the adherence and trafficking of circulating quiescent T‐cells through fibronectin–integrin interaction. [ABSTRACT FROM AUTHOR]

Vaccines based on tumour‐specific antigens are a promising approach for immunotherapy. However, the clinical efficacy of tumour‐specific antigens is still challenging. Twelve conjugates with self‐assembly properties were designed and synthesized using MAGE‐A1 peptide and TLR2 agonist, combined with different covalent bonds. All the developed conjugates formed spherical nanoparticles with a diameter of approximately 150 nm, and enhanced the efficacy of the peptide vaccines with the better targeting of lymph nodes. All the conjugates could well bind to serum albumin and improve the plasma stability of the individual antigenic peptides. In particular, conjugate 6 (N‐Ac PamCS‐M‐6) had a more significant ability to promote dendritic cell maturation, CD8+ T cell activation, and subsequent killing of tumour cells, with an in vivo tumour inhibition rate of 70 ± 2.9%. The interaction between specific response and the different conjugation modes was further explored, thereby providing a fundamental basis for novel immune anti‐tumour molecular platforms. [ABSTRACT FROM AUTHOR]

Citrullination and homocitrullination are stress induced post‐translational modifications (siPTMs) which can be recognized by T cells. Peripheral blood mononuclear cells isolated from healthy donors and rheumatoid arthritis (RA) patients were stimulated with nine siPTM‐peptides. CD45RA/CD45RO depletion was employed to determine if peptide‐specific responses are naïve or memory. Human leucocyte antigen (HLA)‐DP4 and HLA‐DR4 transgenic mice were immunized with siPTM‐peptides and immune responses were determined with ex vivo ELISpot assays. The majority (24 out of 25) of healthy donors showed CD4 T cell‐specific proliferation to at least 1 siPTM‐peptide, 19 to 2 siPTM‐peptides, 14 to 3 siPTM‐peptides, 9 to 4 siPTM‐peptides, 6 to 5 siPTM‐peptides and 4 to 6 siPTM‐peptides. More donors responded to Vim28‐49cit (68%) and Bip189‐208cit (75%) compared with Vim415‐433cit (33%). In RA patients, the presentation of citrullinated epitopes is associated with HLA‐SE alleles; however, we witnessed responses in healthy donors who did not express the SE allele. The majority of responding T cells were effector memory cells with a Th1/cytotoxic phenotype. Responses to Vim28‐49cit and Eno241‐260cit originated in the memory pool, while the response to Vim415‐433cit was naïve. In the HLA‐DP4 and HLA‐DR4 transgenic models, Vim28cit generated a memory response. Peptide‐specific T cells were capable of Epstein–Barr virus transformed lymphoblastoid cell line recognition suggesting a link with stress due to infection. These results suggest siPTM‐peptides are presented under conditions of cellular stress and inflammation and drive cytotoxic CD4 T cell responses that aid in the removal of stressed cells. The presentation of such siPTM‐peptides is not restricted to HLA‐SE in both humans and animal models. [ABSTRACT FROM AUTHOR]

Keywords: antibodies; mucosal immunology; vaccination; viral EN antibodies mucosal immunology vaccination viral 384 387 4 06/19/23 20230701 NES 230701 Abbreviations 95% CI 95% confidence intervals BAU/mL binding antibody units per mL GMC geometric mean concentrations Vaccination against COVID-19 has mitigated the impact of SARS-CoV-2 infection, decreasing the probability of progression to severe disease and death in vaccinated people. In this study, we observed a high salivary antibody prevalence (81%), detecting antibodies even in children whose last contact with SARS-CoV-2 antigens had been 270 days before sample collection. Antibody concentrations in binding antibody units (BAU) per mL (BAU/mL) were obtained interpolating the OD 450 nm values of samples into a calibration curve constructed with the provided standard (400 BAU/mL). [Extracted from the article]

In severe respiratory virus infections, including influenza, an exaggerated host immune response has been linked to the severe disease and death. Control of the overwhelming immune response is thus essential. Efforts with broad‐spectrum immunosuppressive agents such as steroids are disappointing. A better understanding of host immune response using animal experimental system is required to avoid undesired outcome of experimental manipulation. Following severe influenza virus infection in influenza hemagglutinin antigen‐specific transgenic mouse experimental model, step‐wise evolving cells from a pool of naïve hemagglutinin‐specific CD4+ T cells were studied for phenotypic, genomic, and functional characterization in vivo. Naïve CD4+ T cells respond with Th1 commitment in the absolute majority. They first develop into LAG‐3MedIFN‐γ‐secreting Th1 effectors and then evolve into LAG‐3HighIFN‐γ‐not‐secreting regulators with increasing LAG‐3 expression upon continuous activation and cell division. The LAG‐3MedIFN‐γ‐secreting effectors contribute to inflammation, boost inflammatory response of cognate antigen‐specific CD8+ T cells, and aggravate the disease despite facilitated virus clearance. In contrast, LAG‐3High regulators do not contribute to inflammation, suppress CD8+ T cell inflammatory response, alleviate lung pathology, and ameliorate the disease with preserved virus clearance. Moderated CD8+ T cells retain proliferative capacity, and persist beyond virus clearance. Such moderation is distinct from Foxp‐3+ regulator‐mediated suppression, which suppresses proliferative and inflammatory responses of the CD8+ T cells and impairs virus clearance with inflammation alleviation. Origin of regulatory from the effector cells of LAG‐3‐marked Th1 immunity alleviates lung inflammation without impairment of virus eradication. [ABSTRACT FROM AUTHOR]

Taurine (Tau) is a special sulphur‐containing amino acid and has been widely used as a dietary supplement. Although Tau exists in lymphocytes in large quantities, the physiological significance of Tau to modulate human immunity is unknown. In the present study, we first found that Tau regulates the B‐cell receptor (BCR)‐mediated signal transduction and induces the B cells activation. The IgG production of mice after ovalbumin immunization was also increased by Tau administration. Moreover, the isothermal titration calorimetry and surface plasmon resonance analysis have shown that Tau specifically bound to the IgG2a‐BCR. The Tau could bind to IgG F(ab′)2 regions via fluorescence spectroscopy analysis. In the molecular docking analysis, Tau bound to the framework regions (FRs) of variable region of the heavy chains (VH) and in the light chains (VL) of IgG2a‐BCR. Our results suggested that Tau could improve the activation of B cells by interaction with the VH/VL FRs of BCR. [ABSTRACT FROM AUTHOR]

Oncogene SET Domain Bifurcated 1 (SETDB1)/ESET, an H3K9 methyltransferase, was originally discovered over two decades ago; however, its function in the immune response was not first reported until 2011. SETDB1 immune functions include B cell maturation, T cell activity regulation, and immune escape in cancer cells. In B lymphocytes, SETDB1 mediates the transition from pro‐B to pre‐B cells and represses endogenous retroviruses (ERV) to encourage B cell lineage differentiation and maturation. SETDB1 alters T cell function by methylating IL‐2 and IL‐17 promoters and mediating T cell lineage commitment and development. In addition, SETDB1 plays a critical role in ERV silencing within a variety of immune cells, which can indirectly weaken the immune response. Although SETDB1 is critical for normal immune cell function, overexpression in cancer cells negatively impacts immune cell fights against cancer through decreased tumour immunogenicity. Within cancer cells, SETDB1 overexpression represses production and infiltration of antitumour immune cells, mediates immune escape through TE and ERV silencing, represses the type I interferon pathway, and interferes in immune checkpoint blockade (ICB) outcomes by regulation of PD‐L1 expression and IFN signalling. In this review, we further discuss the immunological mechanisms of SETDB1 in normal and cancerous cells and its implications in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Sjӧgren's syndrome (SS) is an autoimmune inflammatory disease characterized by chronic inflammation and dysfunction of exocrine glands and causes dry mouth, dry eyes and various systemic health problems. The objective of this study is to define the in vivo actions of the endogenous NLRP3 inflammasome, a key initiator and mediator of various immune and inflammatory conditions, in newly established SS disease. MCC950, a highly specific small‐molecule inhibitor of NLRP3 inflammasome formation and activation, was intraperitoneally administered to the female non‐obese diabetic (NOD) mice aged 11 weeks, which have newly established SS‐like hyposalivation and pathologies. The injection was conducted three times weekly for three consecutive weeks and mice were analysed for characteristic SS pathologies at the end of the treatments. MCC950 treatment resulted in a marked reduction in salivary secretion and an exacerbation of leukocyte infiltration of submandibular glands. The disease‐worsening effect of MCC950 treatment was accompanied by increased T and B cell numbers, enhanced T helper 1 response and reduced aquaporin 5 expression in submandibular glands. Hence, ablation of endogenous NLRP3 inflammasome activity by MCC950 with established autoimmune exocrinopathy exacerbates salivary gland dysfunction and inflammation, indicating a disease‐alleviating and inflammation‐dampening action of the endogenous NLRP3 inflammasome activity during established SS disease in the non‐obese diabetic mouse model. [ABSTRACT FROM AUTHOR]

Autoimmune and autoinflammatory diseases (AIIDs) involve a deficit in an individual's immune system function, whereby the immune reaction is directed against self‐antigens. Many AIIDs have a strong genetic component, but they can also be triggered by environmental factors. AIIDs often have a highly negative impact on the individual's physical and mental wellbeing. Understanding the genetic underpinning of AIIDs is thus crucial both for diagnosis and for identifying individuals at high risk of an AIID and mental illness as a result thereof. The aim of the present study was to perform systematic statistical and genetic analyses to assess the role of human leukocyte antigen (HLA) alleles in 30 AIIDs and to study the links between AIIDs and psychiatric disorders. We leveraged the Danish iPSYCH Consortium sample comprising 65 534 individuals diagnosed with psychiatric disorders or selected as part of a random population sample, for whom we also had genetic data and diagnoses of AIIDs. We employed regression analysis to examine comorbidities between AIIDs and psychiatric disorders and associations between AIIDs and HLA alleles across seven HLA genes. Our comorbidity analyses showed that overall AIID and five specific AIIDs were associated with having a psychiatric diagnosis. Our genetic analyses found 81 significant associations between HLA alleles and AIIDs. Lastly, we show connections across AIIDs, psychiatric disorders and infection susceptibility through network analysis of significant HLA associations in these disease classes. Combined, our results include both novel associations as well as replications of previously reported associations in a large sample, and highlight the genetic and epidemiological links between AIIDs and psychiatric disorders. [ABSTRACT FROM AUTHOR]

Arthralgia is a hallmark of chikungunya virus (CHIKV) infection and can be very debilitating and associated with a robust local inflammatory response. Many pathophysiological aspects associated with the disease remain to be elucidated. Here, we describe a novel model of CHIKV infection in immunocompetent mice and evaluate the role of tumour necrosis factor in the pathogenesis of the disease. C57BL/6 wild type (WT) or TNF receptor 1 deficient (TNFR1−/−) mice were inoculated with 1 × 106 PFU of CHIKV in the paw. Alternatively, etanercept was used to inhibit TNF in infected WT mice. Hypernociception, inflammatory and virological analysis were performed. Inoculation of CHIKV into WT mice induced persistent hypernociception. There was significant viral replication in target organs and local production of inflammatory mediators in early time‐points after infection. CHIKV infection was associated with specific humoral IgM and IgG responses. In TNFR1−/− mice, there was a decrease in the hypernociception threshold, which was associated with a milder local inflammatory response in the paw but delayed viral clearance. Local or systemic treatment with etanercept reduced CHIKV‐induced hypernociception. This is the first study to describe hypernociception, a clinical correlation of arthralgia, in immunocompetent mice infected with CHIKV. It also demonstrates the dual role of TNF in contributing to viral clearance but driving tissue damage and hypernociception. Inhibition of TNF may have therapeutic benefits but its role in viral clearance suggests that viral levels must be monitored in CHIKV‐infected patients and that TNF inhibitors should ideally be used in combination with anti‐viral drugs. [ABSTRACT FROM AUTHOR]

The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway is an essential component of the innate immune system and is central to the identification of abnormal DNA leakage caused by ionising radiation (IR) damage. Cell‐intrinsic cGAS–STING initiation has been revealed to have tremendous potential for facilitating interferon synthesis and T‐cell priming. Targeting the cGAS–STING axis has been proposed as a strategy to improve radiosensitivity or enhance immunosurveillance. However, due to the complex biology of the irradiated tumour microenvironment and the extensive involvement of the cGAS–STING pathway in various physiological and pathological processes, many defects in this strategy limit the therapeutic effect. Here, we outline the molecular mechanisms by which IR activates the cGAS–STING pathway and analyse the dichotomous roles of the cGAS–STING pathway in modulating cancer immunity after radiotherapy (RT). Then, based on the crosstalk between the cGAS–STING pathway and other signalling events induced by IR, such as necroptosis, autophagy and other cellular effects, we discuss the immunomodulatory actions of the broad cGAS–STING signalling network in RT and their potential therapeutic applications. Finally, recent advances in combination therapeutic strategies targeting cGAS–STING in RT are explored. [ABSTRACT FROM AUTHOR]

Oesophageal adenocarcinoma (OAC) has a relatively poor long‐term survival and limited treatment options. Promising targets for immunotherapy are short peptide neoantigens containing tumour mutations, presented to cytotoxic T‐cells by human leucocyte antigen (HLA) molecules. Despite an association between putative neoantigen abundance and therapeutic response across cancers, immunogenic neoantigens are challenging to identify. Here we characterized the mutational and immunopeptidomic landscapes of tumours from a cohort of seven patients with OAC. We directly identified one HLA‐I presented neoantigen from one patient, and report functional T‐cell responses from a predicted HLA‐II neoantigen in a second patient. The predicted class II neoantigen contains both HLA I and II binding motifs. Our exploratory observations are consistent with previous neoantigen studies in finding that neoantigens are rarely directly observed, and an identification success rate following prediction in the order of 10%. However, our identified putative neoantigen is capable of eliciting strong T‐cell responses, emphasizing the need for improved strategies for neoantigen identification. [ABSTRACT FROM AUTHOR]

Tumour‐associated macrophages (TAMs) are one of the primary sources of PD‐L1 expression in the tumour microenvironment (TME). Ionizing radiation (IR) promotes PD‐L1 expression in tumour cells. However, the effect of IR on macrophage PD‐L1 expression and the underlying mechanisms remain unclear. ATM kinase, as the key kinase for initiating DNA damage repair (DDR) process, is associated with innate immune STING axis activation. Here, we explored the molecular mechanism implicated in macrophage PD‐L1 expression regulated by IR as well as the role of ATM kinase in this process. IR‐regulated PD‐L1 expression in macrophages and associated signalling pathways were explored by in vitro studies using murine and human macrophage cell lines. A colorectal xenograft murine model was employed to demonstrate the impact of targeting ATM and PD‐L1 expression in TAMs following IR on growth of tumour in vivo. IR up‐regulated PD‐L1 expression in macrophages, which was further augmented by ATM kinase inhibition. ATM inhibition increased IR‐induced DNA damage, which activated STING/interferon regulatory factor 3 (IRF3) signalling pathway and up‐regulated type I interferon (IFN‐I) expression in macrophages. IFN‐I bound to the IFN α receptor 1 on macrophages, activated the downstream JAK1 and STAT1/3 signalling and eventually led to PD‐L1 up‐expression. ATM inhibition augmented IR‐induced PD‐L1 expression in macrophages and CD8+ T cell infiltration, and promoted anti‐tumour efficacy in vivo. These results suggested that ATM inhibition promoted IR‐induced PD‐L1 expression through the activation of innate immunity in TAMs, which provided a novel approach to enhance the anti‐tumour efficacy of RT. [ABSTRACT FROM AUTHOR]

Myeloid‐derived suppressor cells (MDSC) induced cellular immune deficiency and bone marrow inflammatory microenvironment play an important role in the pathogenesis and progression of myelodysplastic syndrome (MDS), but the underlying mechanism remains unclear. Here, we revealed that immune checkpoint protein TIM3 and CEACAM1 were highly demonstrated on MDSC and CD8+ T cells in MDS patients. CD8+ T cells were reduced in number and function and presented a exhaustion state. The levels of pro‐inflammatory cytokines (IL‐1β, IL‐18) and CEACAM1 were raised in bone marrow supernatants and MDSC culture supernatants. Blocking or neutralizing TIM3/CEACAM1 and IL‐1β/IL‐18 partially reversed exhaustion of CD8+ T cells. Moreover, TIM3 correlated with NF‐κB /NLRP3 inflammatory pathway. The levels of NF‐κB/NLRP3/Caspase‐1/IL‐1β and IL‐18 were all increased in MDSC of MDS. Co‐culturing MDSC from MDS patients with rhCEACAM1 enhanced NF‐κB/NLRP3/Caspase‐1/IL‐1β and IL‐18 levels, whereas blocking TIM3 could partially reverse the above manifestations. These results indicated that TIM3/CEACAM1 pathway involved in CD8+ T cells exhaustion and might activate the NF‐κB/NLRP3/Caspase‐1 pathway in MDSC, increasing pro‐inflammatory cytokines secretion in MDS bone marrow microenvironment. This study provided a basis for applying immune checkpoint inhibitors that could simultaneously modulate pro‐inflammatory cytokine secretion and enhance anti‐tumour immune function in the treatment of MDS. [ABSTRACT FROM AUTHOR]

Two human natural anti‐carbohydrate antibodies appeared in critical evolutionary events that brought primates and hominins to brink of extinction. The first is the anti‐Gal antibody, produced in Old‐World monkeys (OWM), apes and humans. It binds the carbohydrate‐antigen 'α‐gal epitope' (Galα1‐3Galβ1‐4GlcNAc‐R) on carbohydrate‐chains (glycans) synthesized by non‐primate mammals, lemurs and New‐World monkeys (NWM). The second is anti‐N‐glycolylneuraminic‐acid (anti‐Neu5Gc) antibody binding Neu5Gc on glycans synthesized by OWM, apes and most non‐primate mammals. Ancestral OWM and apes synthesized α‐gal epitopes and were eliminated ~20–30 million‐years‐ago (mya). Only few accidentally mutated offspring lacking α‐gal epitopes, produced anti‐Gal and survived. Hominin‐populations living ~3 mya synthesized Neu5Gc and were eliminated, but few mutated offspring that accidently lost their ability to synthesize Neu5Gc, produced natural anti‐Neu5Gc antibody. These hominins survived and ultimately evolved into present‐day humans. It is argued that these two near‐extinction events were likely to be the result of epidemics caused by highly virulent and lethal enveloped viruses that killed parental‐populations. These viruses presented α‐gal epitopes or Neu5Gc synthesized in host‐cells of the parental‐populations. Mutated offspring survived the epidemics because they were protected from the lethal virus by the natural anti‐Gal or anti‐Neu5Gc antibodies they produced due to loss of immune‐tolerance to α‐gal epitopes or to Neu5Gc, respectively. [ABSTRACT FROM AUTHOR]

Obesity is generally associated with low‐grade inflammation. Adipose tissue macrophages (ATMs) orchestrate metabolic inflammation. The classical (M1‐like) or alternative (M2‐like) activation of ATMs is functionally coupled with the metabolic status of fat tissues. It has been found that T‐cell immunoglobulin‐ and mucin‐domain‐containing molecule‐4 (Tim‐4) inhibits inflammation by regulating macrophages. However, the exact role of Tim‐4 in macrophage polarization and obesity remains unknown. Here, we identified Tim‐4 as a critical switch governing macrophage M1/M2 polarization and energy homeostasis. Tim‐4 deletion led to spontaneous obesity in elder mice and promoted obesity severity of db/db mice. Obesity microenvironment enhanced the expression of Tim‐4 in white adipose tissue and ATMs. In vitro, we detected an increase in M1‐like cells and decrease in M2‐like cells in both peritoneal macrophages and bone marrow‐derived macrophages from Tim‐4 knockout mice. Mechanistically, we demonstrated that Tim‐4 promoted M2‐like macrophages polarization via suppressing nuclear factor kappa B (NF‐κB) signaling pathway. In addition, we found that Tim‐4 promoted TLR4 internalization, which might contribute to regulation of NF‐κB signaling. Collectively, these results indicated that Tim‐4 maintained adipose tissue homeostasis by regulating macrophage polarization via NF‐κB pathway, which would provide a new target for obesity intervention. [ABSTRACT FROM AUTHOR]