Pivotal Role In Immunity Research Articles

FvFold: A model to predict antibody Fv structure using protein language model with residual network and Rosetta minimization

The immune system depends on antibodies (Abs) to recognize and attach to a wide range of antigens, playing a pivotal role in immunity. The precise prediction of the variable fragment (Fv) region of antibodies is vital for the progress of therapeutic and commercial applications, particularly in the treatment of diseases such as cancer. Although deep learning models exist for accurate antibody structure prediction, challenges persist, particularly in modeling complementarity-determining regions (CDRs) and the overall antibody Fv structures. Introducing the FvFold model, a deep learning approach harnessing the capabilities of the ProtT5-XL-UniRef50 protein language model which is capable of predicting accurate antibody Fv structure. Through evaluations on various benchmarks, our model outperforms existing models, demonstrating superior accuracy by achieving lower Root Mean Square Deviation (RMSD) in almost all loops and Orientational Coordinate Distance (OCD) values in the RosettaAntibody benchmark, Therapeutic benchmark and IgFold benchmark compared to the previous top-performing model.

Retron-Eco1 assembles NAD+-hydrolyzing filaments that provide immunity against bacteriophages

Retrons are toxin-antitoxin systems protecting bacteria against bacteriophages via abortive infection. The Retron-Eco1 antitoxin is formed by a reverse transcriptase (RT) and a non-coding RNA (ncRNA)/multi-copy single-stranded DNA (msDNA) hybrid that neutralizes an uncharacterized toxic effector. Yet, the molecular mechanisms underlying phage defense remain unknown. Here, we show that the N-glycosidase effector, which belongs to the STIR superfamily, hydrolyzes NAD+ during infection. Cryoelectron microscopy (cryo-EM) analysis shows that the msDNA stabilizes a filament that cages the effector in a low-activity state in which ADPr, a NAD+ hydrolysis product, is covalently linked to the catalytic E106 residue. Mutations shortening the msDNA induce filament disassembly and the effector's toxicity, underscoring the msDNA role in immunity. Furthermore, we discovered a phage-encoded Retron-Eco1 inhibitor (U56) that binds ADPr, highlighting the intricate interplay between retron systems and phage evolution. Our work outlines the structural basis of Retron-Eco1 defense, uncovering ADPr's pivotal role in immunity.

The gasdermin family: emerging therapeutic targets in diseases.

The gasdermin (GSDM) family has garnered significant attention for its pivotal role in immunity and disease as a key player in pyroptosis. This recently characterized class of pore-forming effector proteins is pivotal in orchestrating processes such as membrane permeabilization, pyroptosis, and the follow-up inflammatory response, which are crucial self-defense mechanisms against irritants and infections. GSDMs have been implicated in a range of diseases including, but not limited to, sepsis, viral infections, and cancer, either through involvement in pyroptosis or independently of this process. The regulation of GSDM-mediated pyroptosis is gaining recognition as a promising therapeutic strategy for the treatment of various diseases. Current strategies for inhibiting GSDMD primarily involve binding to GSDMD, blocking GSDMD cleavage or inhibiting GSDMD-N-terminal (NT) oligomerization, albeit with some off-target effects. In this review, we delve into the cutting-edge understanding of the interplay between GSDMs and pyroptosis, elucidate the activation mechanisms of GSDMs, explore their associations with a range of diseases, and discuss recent advancements and potential strategies for developing GSDMD inhibitors.

Anterograde trafficking of Toll-like receptors requires the cargo sorting adaptors TMED-2 and 7.

Toll-Like Receptors (TLRs) play a pivotal role in immunity by recognising conserved structural features of pathogens and initiating the innate immune response. TLR signalling is subject to complex regulation that remains poorly understood. Here we show that two small type I transmembrane receptors, TMED2 and 7, that function as cargo sorting adaptors in the early secretory pathway are required for transport of TLRs from the ER to Golgi. Protein interaction studies reveal that TMED7 interacts with TLR2, TLR4 and TLR5 but not with TLR3 and TLR9. On the other hand, TMED2 interacts with TLR2, TLR4 and TLR3. Dominant negative forms of TMED7 suppress the export of cell surface TLRs from the ER to the Golgi. By contrast TMED2 is required for the ER-export of both plasma membrane and endosomal TLRs. Together, these findings suggest that association of TMED2 and TMED7 with TLRs facilitates anterograde transport from the ER to the Golgi.

Neuroinflammation and neuroimmunology in Alzheimer's disease: The role of T‐lymphocytes in Alzheimer's disease

AbstractAlzheimer's disease (AD) is the leading cause of dementia, with the number of patients with AD expected to double in the next quarter‐century. Brain deposition of amyloid‐β (Aβ) and tau proteins is a necessary but insufficient condition for AD pathogenesis. There is also growing evidence to suggest that chronic neuroinflammation due to excessive microglial activation and astrocyte dysfunction exacerbates the pathophysiology of AD, but the factors that disrupt these homeostatic processes remain unclear. Research into AD pathophysiology has shown interest in the changes in adaptive T‐cells, which play a pivotal role in immunity. The immune alterations in the peripheral circulation and increased blood–brain‐barrier permeability observed in patients with AD, even in the initial stages of the disease, require investigation of the immune mechanisms resulting from T‐cell infiltration into the central nervous system (CNS) during disease initiation and exacerbation. Since T‐cells play a two‐faceted role in the CNS immune response, including pathogenic and neuroprotective roles, the role of T‐cells in AD has been debated. Memory T‐cells reside in the brain and communicate with glial cells and neurons. In this review, the role of immune responses in AD is discussed, focusing on the contribution of T‐cells.

Engineering cytokine therapeutics.

Cytokines have pivotal roles in immunity, making them attractive as therapeutics for a variety of immune-related disorders. However, the widespread clinical use of cytokines has been limited by their short blood half-lives and severe side effects caused by low specificity and unfavourable biodistribution. Innovations in bioengineering have aided in advancing our knowledge of cytokine biology and yielded new technologies for cytokine engineering. In this Review, we discuss how the development of bioanalytical methods, such as sequencing and high-resolution imaging combined with genetic techniques, have facilitated a better understanding of cytokine biology. We then present an overview of therapeutics arising from cytokine re-engineering, targeting and delivery, mRNA therapeutics and cell therapy. We also highlight the application of these strategies to adjust the immunological imbalance in different immune-mediated disorders, including cancer, infection and autoimmune diseases. Finally, we look ahead to the hurdles that must be overcome before cytokine therapeutics can live up to their full potential.

Phagekines: Directed Evolution and Characterization of Functional Cytokines Displayed on Phages.

The current chapter focuses on the use of filamentous phages to display and modify biologically active cytokines, with special emphasis on directed evolution of novel variants showing improved receptor binding. Cytokines are essential protein mediators involved in cell-to-cell communication. Their functional importance and the complexity of their interactions with multichain receptors make cytokine engineering a promising tool for the discovery and optimization of therapeutic molecules. Protocols used at the laboratory are illustrated through examples of manipulation of interleukin-2 and interleukin-6, two members of the family of alpha-helix-bundle cytokines playing pivotal roles in immunity and inflammation.

Orai2 deficiency attenutates experimental colitis by facilitating the colonization of Akkermansia muciniphila

Orai2 is a component of store-operated Calcium channels (SOCCs) and exerts a pivotal role in immunity. In intestinal macrophages (Mφs), Orai2 deficiency influenced linoleic acid (LA)-arachidonic acid (ARA) derivatives by regulating Pla2g6 and Alox5. 16S rRNA sequencing showed that deleting Orai2 facilitated the prevalence of Akkermansia muciniphila, and untargeted metabolomics confirmed the suppressed level of leukotriene A. Moreover, Orai2 deficiency ameliorated the progression of experimental murine colitis, as shown by attenuated structural collapse of colon and pro-inflammatory cytokine concentrations, and rescued dysbiosis. The administration of a Pla2g6 inhibitor (Bromoenol lactone) not only inhibited the relative abundance of A. muciniphila in the feces of Orai2 knockout (Orai2−/−) mice, but also abolished the increased activity of Calcium-released activated Calcium channel (CRAC) in Orai2−/− intestinal Mφs, corroborating the involvement of Pla2g6 in Orai2 signaling. In conclusion, Orai2 deficiency increases Pla2g6 and hence facilitating A. muciniphila colonization, which might be a potential strategy to combat colitis.

Trace elements and Immunity: A brief overview

Trace elements or micronutrients play a vital role in the human body. They are required as cofactors and function with enzymes to catalyze various biochemical reactions. Around 14 trace elements are found in the human body which are crucial to various physiological and biological functions in the cells. Some of these elements have therapeutic potential. Impaired immunity and increased susceptibility to infections are a few responses that develop under nutritional deficiency of these trace elements. A comprehensive literature search was accomplished on PubMed, SCOPUS and Google Scholar to identify articles on trace elements and their pivotal role in immunity. Antibody responses, cell-mediated immunity and natural killer (NK) cell activity are few of the immune processes likely to be influenced by trace element levels. Elements such as zinc, selenium and other trace elements activate the cytokine-mediated immune response by triggering the synthesis of TH1 cells and proinflammatory cytokines. In addition, some trace elements possess antiviral properties, interfering with the entry and replication of the viruses. Based on the above perspectives and the significance of trace elements in immunity, the current review was undertaken to shed light on the role of trace elements important in immunity.

Psychobiotics: feeding the gut to nurture the brain

Undoubtedly, the gut microbiome has emerged as a key influencer of countless human biological processes. Our resident bacteria, viruses, fungi, and archaea colonise virtually all body sites and play pivotal roles in immunity, energy metabolism, and gastrointestinal health. Their influence even extends to the brain, affecting cognitive processes and mental wellbeing. The question is, could we improve brain functioning and behaviour by shifting the landscape of the microbiome?

Serum‑derived exosomes from house dust mite‑sensitized guinea pigs contribute to inflammation in BEAS‑2B cells via the TLR4‑NF‑κB pathway.

Airway epithelial cells, which are the first physical defense barrier against allergens, play a pivotal role in immunity, airway inflammation and airway remodeling. The damage and dysfunction of these cells trigger the development of airway inflammatory diseases. Exosomes, which exist in various bodily fluids, mediate cell-cell communication and participate in the immune response process. The present study aimed to investigate whether serum exosomes play a pro-inflammatory role in bronchial epithelial cells (BEAS-2B cells) and, if so, explore the underlying molecular mechanisms. A guinea pig model of House dust mite (HDM)-induced asthma was established by sensitizing the rodents with HDM and PBS, and serum-derived exosomes were harvested. It was found that serum-derived exosomes from HDM-sensitized guinea pigs displayed higher levels of exosomal markers than those from controls. Additionally, western blot analysis and reverse transcription-quantitative PCR indicated that serum-derived exosomes from HDM-sensitized guinea pigs carried heat shock protein 70 and triggered an inflammatory response in BEAS-2B cells via the toll-like receptor 4 (TLR4)-NF-κB pathway. However, TAK-242, an inhibitor of the expression of TLR4, blocked the activation of the TLR4-NF-κB pathway. These findings provided a novel mechanism for exosome-mediated inflammatory responses and a new perspective for the intervention of inflammatory airway disorders.

An Emerging Role for Chloroplasts in Disease and Defense.

Chloroplasts are key players in plant immune signaling, contributing to not only de novo synthesis of defensive phytohormones but also the generation of reactive oxygen and nitrogen species following activation of pattern recognition receptors or resistance (R) proteins. The local hypersensitive response (HR) elicited by R proteins is underpinned by chloroplast-generated reactive oxygen species. HR-induced lipid peroxidation generates important chloroplast-derived signaling lipids essential to the establishment of systemic immunity. As a consequence of this pivotal role in immunity, pathogens deploy effector complements that directly or indirectly target chloroplasts to attenuate chloroplast immunity (CI). Our review summarizes the current knowledge of CI signaling and highlights common pathogen chloroplast targets and virulence strategies. We address emerging insights into chloroplast retrograde signaling in immune responses and gaps in our knowledge, including the importance of understanding chloroplast heterogeneity and chloroplast involvement in intraorganellular interactions in host immunity.

De novo generation of macrophage from placenta-derived hemogenic endothelium.

Macrophages play pivotal roles in immunity, hematopoiesis, and tissue homeostasis. In mammals, macrophages have been shown to originate from yolk-sac-derived erythro-myeloid progenitors and aorta-gonad-mesonephros (AGM)-derived hematopoietic stem cells. However, whether macrophages can arise from other embryonic sites remains unclear. Here, using single-cell RNA sequencing, we profile the transcriptional landscape of mouse fetal placental hematopoiesis. We uncover and experimentally validate that a CD44+ subpopulation of placental endothelial cells (ECs) exhibits hemogenic potential. Importantly, lineage tracing using the newly generated Hoxa13 reporter line shows that Hoxa13-labeled ECs can produce placental macrophages, named Hofbauer cell (HBC)-like cells. Furthermore, we identify two subtypes of HBC-like cells, and cell-cell interaction analysis identifies their potential roles in angiogenesis and antigen presentation, separately. Our study provides a comprehensive understanding of placental hematopoiesis and highlights the placenta as a source of macrophages, which has important implications for both basic and translational research.

Microbiota and their Influence in the Human Body

Scientists have invested considerable resources in the study of the microbiota of the human body. These microorganisms play pivotal roles in immunity and disease. Of which, probiotics are live beneficial microorganisms that keep your intestinal or lung microbiota healthy, and occupy a special role in combating the infections. Thus, it is critical to understand their contributions to these processes. Technology can facilitate advanced studies of the microbiota, including how it develops and its positive and negatives effects on the immune system. This paper investigates how several factors (e.g. birth delivery mode, metabolic activities, types of microorganisms, and immune system interactions) affect the microbiota, particularly in early life. The paper also discusses how gastrointestinal microbes in particular may be associated with certain disease processes, such as those related to schizophrenia, autism, and diabetes. Clinical studies show that certain probiotic strains, like Lactobacillus rhamnosus GG and Bifidobacterium animalis ssp. lactis help to prevent infection of pathogenic organisms (both bacterial and viral). This research may yield crucial contributions to disease prevention and public health. The dysbiosis may result in changes in the acquired immunity later on. The probiotic strains can prevent viral replication during SARS-CoV-2 or COVID-19 infection by reducing proinflammatory cytokines. There has been much interest into the intestinal flora as proposed by the diversity, volume, and proposed role in disease. Future research in the field of microbiome should be done in order to uncover their association to gut virome by noting both their influence on each other and relevant health and disease.

The role of miR-183 cluster in immunity

MicroRNAs (miRNAs) are essential factors of an extensively conserved post-transcriptional process to regulate gene expression. MiRNAs play a pivotal role in immunity, including controlling the differentiation of various immune cells as well as their immunological functions. The miR-183 cluster, which is comprised of miR-183, -96 and −182, is a miRNA family with sequence homology. These miRNAs are usually transcribed together as a polycistronic miRNA cluster during development and are required for maturation of sensory organs. In comparison to defined sensory-specific role of these miRNAs in normal development, they are frequently over-expressed in several non-sensory diseases, including autoimmune diseases and cancers. Because individual miRNAs of miR-183 cluster have both common and unique targets within functionally interrelated pathways, they can show cooperative or opposing effects on biological processes, implying the complexity of this miR cluster-mediated gene regulation. Therefore, a better understanding of the molecular regulation of miR-183 cluster expression and its downstream networks is important for the therapeutic applications. In this review, we will discuss the characteristics of miR-183 cluster and a wide variety of evidence on its function in immune system. Newer knowledge summarized here will help readers understand the versatile role of miR-183 cluster in this field.

IL-33/ST2 Axis in Organ Fibrosis.

Interleukin 33 (IL-33) is highly expressed in barrier sites, acting via the suppression of tumorigenicity 2 receptor (ST2). IL-33/ST2 axis has long been known to play a pivotal role in immunity and cell homeostasis by promoting wound healing and tissue repair. However, it is also involved in the loss of balance between extensive inflammation and tissue regeneration lead to remodeling, the hallmark of fibrosis. The aim of the current review is to critically evaluate the available evidence regarding the role of the IL-33/ST2 axis in organ fibrosis. The role of the axis in tissue remodeling is better understood considering its crucial role reported in organ development and regeneration. Generally, the IL-33/ST2 signaling pathway has mainly anti-inflammatory/anti-proliferative effects; however, chronic tissue injury is responsible for pro-fibrogenetic responses. Regarding pulmonary fibrosis mature IL-33 enhances pro-fibrogenic type 2 cytokine production in an ST2- and macrophage-dependent manner, while full-length IL-33 is also implicated in the pulmonary fibrotic process in an ST2-independent, Th2-independent fashion. In liver fibrosis, evidence indicate that when acute and massive liver damage occurs, the release of IL-33 might act as an activator of tissue-protective mechanisms, while in cases of chronic injury IL-33 plays the role of a hepatic fibrotic factor. IL-33 signaling has also been involved in the pathogenesis of acute and chronic pancreatitis. Moreover, IL-33 could be used as an early marker for ulcer-associated activated fibroblasts and myofibroblast trans-differentiation; thus one cannot rule out its potential role in inflammatory bowel disease-associated fibrosis. Similarly, the upregulation of the IL-33/ST2 axismay contribute to tubular cell injury and fibrosis via epithelial to mesenchymal transition (EMT) of various cell types in the kidneys. Of note, IL-33 exerts a cardioprotective role via ST2 signaling, while soluble ST2 has been demonstrated as a marker of myocardial fibrosis. Finally, IL-33 is a crucial cytokine in skin pathology responsible for abnormal fibroblast proliferation, leukocyte infiltration and morphologic differentiation of human endothelial cells. Overall, emerging data support a novel contribution of the IL-33/ST2 pathway in tissue fibrosis and highlight the significant role of the Th2 pattern of immune response in the pathophysiology of organ fibrosis.

Ancient Origin of the CARD-Coiled Coil/Bcl10/MALT1-Like Paracaspase Signaling Complex Indicates Unknown Critical Functions.

The CARD–coiled coil (CC)/Bcl10/MALT1-like paracaspase (CBM) signaling complexes composed of a CARD–CC family member (CARD-9, -10, -11, or -14), Bcl10, and the type 1 paracaspase MALT1 (PCASP1) play a pivotal role in immunity, inflammation, and cancer. Targeting MALT1 proteolytic activity is of potential therapeutic interest. However, little is known about the evolutionary origin and the original functions of the CBM complex. Type 1 paracaspases originated before the last common ancestor of planulozoa (bilaterians and cnidarians). Notably in bilaterians, Ecdysozoa (e.g., nematodes and insects) lacks Bcl10, whereas other lineages have a Bcl10 homolog. A survey of invertebrate CARD–CC homologs revealed such homologs only in species with Bcl10, indicating an ancient common origin of the entire CBM complex. Furthermore, vertebrate-like Syk/Zap70 tyrosine kinase homologs with the ITAM-binding SH2 domain were only found in invertebrate organisms with CARD–CC/Bcl10, indicating that this pathway might be related to the original function of the CBM complex. Moreover, the type 1 paracaspase sequences from invertebrate organisms that have CARD–CC/Bcl10 are more similar to vertebrate paracaspases. Functional analysis of protein–protein interactions, NF-κB signaling, and CYLD cleavage for selected invertebrate type 1 paracaspase and Bcl10 homologs supports this scenario and indicates an ancient origin of the CARD–CC/Bcl10/paracaspase signaling complex. By contrast, many of the known MALT1-associated activities evolved fairly recently, indicating that unknown functions are at the basis of the protein conservation. As a proof-of-concept, we provide initial evidence for a CBM- and NF-κB-independent neuronal function of the Caenorhabditis elegans type 1 paracaspase malt-1. In conclusion, this study shows how evolutionary insights may point at alternative functions of MALT1.

TLR-2, IL-10 and IL-17-mediated immunity in experimental chemotherapy murine model of systemic candidiasis; cyclophosphamides' impact and roles

The majority of immune components such as Toll-like receptor (TLR)-2, interleukin (IL)-17, neutrophils, and IL-10 play pivotal roles in immunity to Candida albicans (C. albicans) through identifying and launching inflammatory and regulatory responses. Chemotherapy is one of the most potent risk factors for systemic candidiasis through inducing immunosuppression (mostly cyclophosphamide induced immunosuppression) and there is a sensible lack of study around the immunity to C. albicans in such a situation. In this study, following the establishment of infection and immunosuppression in Balb/c mice model, the mRNA/protein levels of TLR-2, IL-10, IL-17, and Myeloperoxidase (MPO) in serum/kidney were measured using Real-time PCR and ELISA respectively. The survival of mice was checked daily and organ fungal burden was calculated and the histology samples were prepared. Results indicated that the mRNA and protein levels of IL-10, IL-17 and MPO were significantly elevated in immunosuppressed-infected mice (P < 0.05). Conversely, the mRNA level of TLR-2 in this mice were significantly decreased (P < 0.05). We conclude that, I. cyclophosphamide could induce only a minor state of immunosuppression through depletion of serum neutrophils. II. TLR-2 does not have important roles in developing immune responses in immunosuppressed mice model of systemic candidiasis. Our findings can be applicable for further experimental investigations on patients in clinics for deep understanding of pathogenesis of systemic candidiasis, which could be useful to further broaden our insights for targeted therapy, especially targeting TLR-2 and IL-17, based on siRNA, miRNA or monoclonal antibodies.

Abstract A147: Differential transcriptional profiling of tumor cell populations

Abstract Tumors compass remarkably diverse cell populations as a result of genetic and environmental influences. Macrophages are a type of white blood cell with pivotal roles in immunity and tissue homeostasis that were reported to constitute up to 50% of the tumor mass. Macrophages also present a central line of defense against cancer by preventing inflammation as well as specific elimination of tumor cells. However, tumors can manipulate macrophages to switch their function from tumor-suppressing to tumor-supporting. Tumor-supporting macrophages are pro-angiogenic, immunosuppressive and aid the neoplastic progression. My aim is to characterize the core transcriptional network of “supporting” or “repressing” tumor associated macrophages in mice and humans. At phase 1 of the project, I am testing methods to differentially analyze cell populations from tumors with minimal perturbations as well as ways to reduce input for GROseq and RNAseq analysis. Citation Format: Sascha H. Duttke, Christopher K. Glass. Differential transcriptional profiling of tumor cell populations [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A147.

Impaired Expression of Cytokines as a Result of Viral Infections with an Emphasis on Small Ruminant Lentivirus Infection in Goats.

Knowing about the genes involved in immunity, and being able to identify the factors influencing their expressions, helps in gaining awareness of the immune processes. The qPCR method is a useful gene expression analysis tool, but studies on immune system genes are still limited, especially on the caprine immune system. Caprine arthritis encephalitis, a disease caused by small ruminant lentivirus (SRLV), causes economic losses in goat breeding, and there is no therapy against SRLV. The results of studies on vaccines against other viruses are promising. Moreover, the Marker-Assisted Selection strategy against SRLV is possible, as has been shown in sheep breeding. However, there are still many gaps in our knowledge on the caprine immune response to infection. All types of cytokines play pivotal roles in immunity, and SRLV infection influences the expression of many cytokines in different types of cells. This information encouraged the authors to examine the results of studies conducted on SRLV and other viral infections, with an emphasis on the expression of cytokine genes. This review attempts to summarize the results of studies on the expression of cytokines in the context of the SRLV infection.