scholarly journals Cytokine-Mediated Crosstalk between Immune Cells and Epithelial Cells in the Gut

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 111
Author(s):  
Mousumi Mahapatro ◽  
Lena Erkert ◽  
Christoph Becker
Keyword(s):  
Immune System ◽  
Epithelial Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Association Studies ◽  
Cell Types ◽  
Mucosal Immune System ◽  
Cytokine Signaling ◽  
Genome Wide Association Studies ◽  
Small Proteins

Cytokines are small proteins that are secreted by a vast majority of cell types in the gut. They not only establish cell-to-cell interactions and facilitate cellular signaling, but also regulate both innate and adaptive immune responses, thereby playing a central role in genetic, inflammatory, and infectious diseases of the gut. Both, immune cells and gut epithelial cells, play important roles in intestinal disease development. The epithelium is located in between the mucosal immune system and the gut microbiome. It not only establishes an efficient barrier against gut microbes, but it also signals information from the gut lumen and its composition to the immune cell compartment. Communication across the epithelial cell layer also occurs in the other direction. Intestinal epithelial cells respond to immune cell cytokines and their response influences and shapes the microbial community within the gut lumen. Thus, the epithelium should be seen as a translator or a moderator between the microbiota and the mucosal immune system. Proper communication across the epithelium seems to be a key to gut homeostasis. Indeed, current genome-wide association studies for intestinal disorders have identified several disease susceptibility loci, which map cytokine signatures and their related signaling genes. A thorough understanding of this tightly regulated cytokine signaling network is crucial. The main objective of this review was to shed light on how cytokines can orchestrate epithelial functions such as proliferation, cell death, permeability, microbe interaction, and barrier maintenance, thereby safeguarding host health. In addition, cytokine-mediated therapy for inflammation and cancer are discussed.

scholarly journals Neuroinflammation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia and the Interest of Induced Pluripotent Stem Cells to Study Immune Cells Interactions With Neurons

2021 ◽  
Vol 14 ◽  
Author(s):  
Elise Liu ◽  
Léa Karpf ◽  
Delphine Bohl
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Immune System ◽  
Frontotemporal Dementia ◽  
Immune Cells ◽  
Immune Cell ◽  
Current Knowledge ◽  
Cell Types ◽  
Induced Pluripotent ◽  
Different Cell Types ◽  
Lateral Sclerosis

Inflammation is a shared hallmark between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). For long, studies were conducted on tissues of post-mortem patients and neuroinflammation was thought to be only bystander result of the disease with the immune system reacting to dying neurons. In the last two decades, thanks to improving technologies, the identification of causal genes and the development of new tools and models, the involvement of inflammation has emerged as a potential driver of the diseases and evolved as a new area of intense research. In this review, we present the current knowledge about neuroinflammation in ALS, ALS-FTD, and FTD patients and animal models and we discuss reasons of failures linked to therapeutic trials with immunomodulator drugs. Then we present the induced pluripotent stem cell (iPSC) technology and its interest as a new tool to have a better immunopathological comprehension of both diseases in a human context. The iPSC technology giving the unique opportunity to study cells across differentiation and maturation times, brings the hope to shed light on the different mechanisms linking neurodegeneration and activation of the immune system. Protocols available to differentiate iPSC into different immune cell types are presented. Finally, we discuss the interest in studying monocultures of iPS-derived immune cells, co-cultures with neurons and 3D cultures with different cell types, as more integrated cellular approaches. The hope is that the future work with human iPS-derived cells helps not only to identify disease-specific defects in the different cell types but also to decipher the synergistic effects between neurons and immune cells. These new cellular tools could help to find new therapeutic approaches for all patients with ALS, ALS-FTD, and FTD.

scholarly journals Chronic lymphocytic leukemia (CLL) risk is mediated by multiple enhancer variants within CLL risk loci

2020 ◽  
Vol 29 (16) ◽  
pp. 2761-2774
Author(s):  
Huihuang Yan ◽  
Shulan Tian ◽  
Geffen Kleinstern ◽  
Zhiquan Wang ◽  
Jeong-Heon Lee ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Immune Cell ◽  
Association Studies ◽  
Cell Types ◽  
Lymphocytic Leukemia ◽  
Type I ◽  
Genome Wide Association Studies ◽  
Gene Promoters ◽  
Functional Variants ◽  
Increased Risk

Abstract Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries. It has a strong genetic basis, showing a ~ 8-fold increased risk of CLL in first-degree relatives. Genome-wide association studies (GWAS) have identified 41 risk variants across 41 loci. However, for a majority of the loci, the functional variants and the mechanisms underlying their causal roles remain undefined. Here, we examined the genetic and epigenetic features associated with 12 index variants, along with any correlated (r2 ≥ 0.5) variants, at the CLL risk loci located outside of gene promoters. Based on publicly available ChIP-seq and chromatin accessibility data as well as our own ChIP-seq data from CLL patients, we identified six candidate functional variants at six loci and at least two candidate functional variants at each of the remaining six loci. The functional variants are predominantly located within enhancers or super-enhancers, including bi-directionally transcribed enhancers, which are often restricted to immune cell types. Furthermore, we found that, at 78% of the functional variants, the alternative alleles altered the transcription factor binding motifs or histone modifications, indicating the involvement of these variants in the change of local chromatin state. Finally, the enhancers carrying functional variants physically interacted with genes enriched in the type I interferon signaling pathway, apoptosis, or TP53 network that are known to play key roles in CLL. These results support the regulatory roles for inherited noncoding variants in the pathogenesis of CLL.

scholarly journals The Immune System of Mesothelioma Patients: A Window of Opportunity for Novel Immunotherapies

2021 ◽  
Author(s):  
Fabio Nicolini ◽  
Massimiliano Mazza
Keyword(s):  
Immune System ◽  
Immune Cells ◽  
Immune Cell ◽  
Current Knowledge ◽  
Cell Types ◽  
Screening Strategies ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Review Current

The interplay between the immune system and the pleural mesothelium is crucial both for the development of malignant pleural mesothelioma (MPM) and for the response of MPM patients to therapy. MPM is heavily infiltrated by several immune cell types which affect the progression of the disease. The presence of organized tertiary lymphoid structures (TLSs) witness the attempt to fight the disease in situ by adaptive immunity which is often suppressed by tumor expressed factors. In rare patients physiological, pharmacological or vaccine-induced immune response is efficient, rendering their plasma a valuable resource of anti-tumor immune cells and molecules. Of particular interest are human antibodies targeting antigens at the tumor cell surface. Here we review current knowledge regarding MPM immune infiltration, MPM immunotherapy and the harnessing of this response to identify novel biologics as biomarkers and therapeutics through innovative screening strategies.

scholarly journals Single-cell RNA sequencing reveals micro-evolution of the stickleback immune system

2021 ◽  
Author(s):  
Lauren E Fuess ◽  
Daniel I Bolnick
Keyword(s):  
Immune System ◽  
Single Cell ◽  
Immune Cells ◽  
Gasterosteus Aculeatus ◽  
Immune Cell ◽  
Expression Profiles ◽  
Cell Types ◽  
Model Systems ◽  
System Structure ◽  
Ecological Processes

Pathogenic infection is an important driver of many ecological processes. Furthermore, variability in immune function is an important driver of differential infection outcomes. New evidence would suggest that immune variation extends to broad cellular structure of immune systems. However, variability at such broad levels is traditionally difficult to detect in non-model systems. Here we leverage single cell transcriptomic approaches to document signatures of microevolution of immune system structure in a natural system, the three-spined stickleback (Gasterosteus aculeatus). We sampled nine adult fish from three populations with variability in resistance to a cestode parasite, Schistocephalus solidus, to create the first comprehensive immune cell atlas for G. aculeatus. Eight major immune cell types, corresponding to major vertebrate immune cells, were identified. We were also able to document significant variation in both abundance and expression profiles of the individual immune cell types, among the three populations of fish. This variability may contribute to observed variability in parasite susceptibility. Finally, we demonstrate that identified cell type markers can be used to reinterpret traditional transcriptomic data. Combined our study demonstrates the power of single cell sequencing to not only document evolutionary phenomena (i.e. microevolution of immune cells), but also increase the power of traditional transcriptomic datasets.

scholarly journals 67 Immunometabolism – emerging concepts and potential applications in livestock

2019 ◽  
Vol 97 (Supplement_3) ◽  
pp. 101-101
Author(s):  
Barry J Bradford
Keyword(s):  
Immune System ◽  
Communication Networks ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Whole Body ◽  
Phagocytic Cells ◽  
Adaptive Immune Cells ◽  
Potential Applications ◽  
Host Microbe Interactions

Abstract Our understanding of the immune system emerged from the study of disease processes and the communication networks used by various cell types to respond to pathogens. As with many aspects of physiology, this initial view was colored by the techniques available at the time. With technical advances beginning in the 1990, research in sepsis and obesity began to identify critical interactions between the immune system and metabolism. Our current understanding of these interactions is informed by two active but largely distinct research communities. Many in the field of immunology are utilizing cellular metabolism tools to understand mitochondrial function and fuel use in response to activation of innate and adaptive immune cells, especially as these relate to cancer. From another vantage point, many metabolic physiologists are now seeking to understand the importance of tissue-resident immune cells and immune signaling molecules in metabolic homeostasis and pathologies. Beyond human health implications of recent findings, a number of immunometabolism insights have informed our understanding of livestock health. In inflammatory events, phagocytic cells are activated, and the dramatic increase in oxidative metabolism is driven primarily by glucose use. Metabolism of healthy animals is also influenced by secretions from immune cells. Studies in mice indicate that appropriate host/microbe interactions (balancing protection and tolerance) are mediated by a network of immune cell types in the gut, which is critical to both absorptive and barrier functions of the gut. Adipose tissue immune cells regulate lipolytic rate, insulin sensitivity, and perhaps whole-body inflammatory tone. Local immune cell impacts on metabolism of other organs, including the liver and pancreas, are also emerging. Immunity and metabolism are tightly interwoven, and the evolving understanding of these links may enable nutritional or pharmacological strategies to enhance resilience to disease and alter nutrient partitioning in livestock.

scholarly journals Can cancer GWAS variants modulate immune cells in the tumor microenvironment?

2018 ◽  
Author(s):  
Yi Zhang ◽  
Mohith Manjunath ◽  
Jialu Yan ◽  
Brittany A. Baur ◽  
Shilu Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Cells ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Immune Surveillance ◽  
Tumor Infiltrating Lymphocytes ◽  
Cell Types ◽  
Potential Effect ◽  
Chromatin Interaction ◽  
Genome Wide Association Studies

AbstractGenome-wide association studies (GWAS) have hitherto identified several genetic variants associated with cancer susceptibility, but the molecular functions of these risk modulators remain largely uncharacterized. Recent studies have begun to uncover the regulatory potential of non-coding GWAS SNPs by using epigenetic information in corresponding cancer cell types and matched normal tissues. However, this approach does not explore the potential effect of risk germline variants on other important cell types that constitute the microenvironment of tumor or its precursor. This paper presents evidence that the breast cancer-associated variant rs3903072 may regulate the expression of CTSW in tumor infiltrating lymphocytes. CTSW is a candidate tumor-suppressor gene, with expression highly specific to immune cells and also positively correlated with breast cancer patient survival. Integrative analyses suggest a putative causative variant in a GWAS-linked enhancer in lymphocytes that loops to the 3’ end of CTSW through three-dimensional chromatin interaction. Our work thus poses the possibility that a cancer-associated genetic variant might regulate a gene not only in the cell of cancer origin, but also in immune cells in the microenvironment, thereby modulating the immune surveillance by T lymphocytes and natural killer cells and affecting the clearing of early cancer initiating cells.

scholarly journals Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Xiangyu Ge ◽  
Mojca Frank-Bertoncelj ◽  
Kerstin Klein ◽  
Amanda McGovern ◽  
Tadeja Kuret ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Cellular Proliferation ◽  
Immune Cell ◽  
Association Studies ◽  
Synovial Fibroblasts ◽  
Cell Types ◽  
Joint Involvement ◽  
Genome Wide Association Studies ◽  
Causal Genes

Abstract Background Genome-wide association studies have reported more than 100 risk loci for rheumatoid arthritis (RA). These loci are shown to be enriched in immune cell-specific enhancers, but the analysis so far has excluded stromal cells, such as synovial fibroblasts (FLS), despite their crucial involvement in the pathogenesis of RA. Here we integrate DNA architecture, 3D chromatin interactions, DNA accessibility, and gene expression in FLS, B cells, and T cells with genetic fine mapping of RA loci. Results We identify putative causal variants, enhancers, genes, and cell types for 30–60% of RA loci and demonstrate that FLS account for up to 24% of RA heritability. TNF stimulation of FLS alters the organization of topologically associating domains, chromatin state, and the expression of putative causal genes such as TNFAIP3 and IFNAR1. Several putative causal genes constitute RA-relevant functional networks in FLS with roles in cellular proliferation and activation. Finally, we demonstrate that risk variants can have joint-specific effects on target gene expression in RA FLS, which may contribute to the development of the characteristic pattern of joint involvement in RA. Conclusion Overall, our research provides the first direct evidence for a causal role of FLS in the genetic susceptibility for RA accounting for up to a quarter of RA heritability.

scholarly journals The impact of cell type and context-dependent regulatory variants on human immune traits

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Zepeng Mu ◽  
Wei Wei ◽  
Benjamin Fair ◽  
Jinlin Miao ◽  
Ping Zhu ◽  
...  
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Association Studies ◽  
Genetic Effects ◽  
Genome Wide Association Studies ◽  
Cell Type ◽  
Functional Interpretation ◽  
Immune Traits ◽  
Human Immune ◽  
The Impact

Abstract Background The vast majority of trait-associated variants identified using genome-wide association studies (GWAS) are noncoding, and therefore assumed to impact gene regulation. However, the majority of trait-associated loci are unexplained by regulatory quantitative trait loci (QTLs). Results We perform a comprehensive characterization of the putative mechanisms by which GWAS loci impact human immune traits. By harmonizing four major immune QTL studies, we identify 26,271 expression QTLs (eQTLs) and 23,121 splicing QTLs (sQTLs) spanning 18 immune cell types. Our colocalization analyses between QTLs and trait-associated loci from 72 GWAS reveals that genetic effects on RNA expression and splicing in immune cells colocalize with 40.4% of GWAS loci for immune-related traits, in many cases increasing the fraction of colocalized loci by two fold compared to previous studies. Notably, we find that the largest contributors of this increase are splicing QTLs, which colocalize on average with 14% of all GWAS loci that do not colocalize with eQTLs. By contrast, we find that cell type-specific eQTLs, and eQTLs with small effect sizes contribute very few new colocalizations. To investigate the 60% of GWAS loci that remain unexplained, we collect H3K27ac CUT&Tag data from rheumatoid arthritis and healthy controls, and find large-scale differences between immune cells from the different disease contexts, including at regions overlapping unexplained GWAS loci. Conclusion Altogether, our work supports RNA splicing as an important mediator of genetic effects on immune traits, and suggests that we must expand our study of regulatory processes in disease contexts to improve functional interpretation of as yet unexplained GWAS loci.

scholarly journals Skin-resident immune cells actively coordinate their distribution with epidermal cells during homeostasis

2021 ◽  
Author(s):  
Sangbum Park ◽  
Catherine Matte-Martone ◽  
David G Gonzalez ◽  
Elizabeth A Lathrop ◽  
Dennis P May ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Cell Density ◽  
Immune Cells ◽  
Immune Cell ◽  
Basal Layer ◽  
Cell Types ◽  
Epidermal Cells ◽  
Cell Junctions ◽  
Epithelial Stem Cells

Our organs consist of multiple cell types that ensure proper architecture and function. How different cell types coexist and interact to maintain their homeostasis in vivo remain elusive. The skin epidermis comprises mostly epithelial cells, but also harbors Langerhans cells (LCs) and Dendritic Epidermal T cells (DETCs). In response to injury or infection, LCs and DETCs become activated and play critical immunological roles. During homeostasis, they coexist with epithelial cells in the basal layer of the epidermis. Whether, and how, distributions of LCs and DETCs are regulated during homeostasis is unclear. Here, we addressed this question by tracking LCs, DETCs and epithelial basal cells over time within the skin of live adult mice. We show that LCs and DETCs maintain their overall position despite continuous turnover of neighboring basal epithelial stem cells. Moreover, LCs and DETCs rapidly and maximally explore basal epithelial cell junctions through their dendritic extensions. Altering the epithelial cell density triggers corresponding changes in the immune cell density, but not vice versa, suggesting that epithelial cells determine immune tissue composition in the epidermis. Moreover, LCs and DETCs are organized in a tiling pattern that is actively maintained. When LCs or DETCs are ectopically removed, neighboring epidermal LCs or DETCs, respectively, move into the emptied spaces and re-establish the tiling pattern. Finally, LCs require the GTPase Rac1 to maintain their positional stability, density and tiling pattern. Overall, we discovered that epidermal cells regulate the density of immune cells during homeostasis, and that immune cells actively maintain a non-random spatial distribution, reminiscent of neuronal self-avoidance. We propose that these cellular mechanisms provide the epidermis with an optimal response to environmental insults.

scholarly journals The immune response after noise damage in the cochlea is characterized by a heterogeneous mix of adaptive and innate immune cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Vikrant Rai ◽  
Megan B. Wood ◽  
Hao Feng ◽  
Nathan. M. Schabla ◽  
Shu Tu ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Cells ◽  
Noise Exposure ◽  
Immune Cell ◽  
Organ Of Corti ◽  
Adaptive Immune System ◽  
Cell Types ◽  
Cell Gene Expression ◽  
Noise Damage

Abstract Cells of the immune system are present in the adult cochlea and respond to damage caused by noise exposure. However, the types of immune cells involved and their locations within the cochlea are unclear. We used flow cytometry and immunostaining to reveal the heterogeneity of the immune cells in the cochlea and validated the presence of immune cell gene expression by analyzing existing single-cell RNA-sequencing (scRNAseq) data. We demonstrate that cell types of both the innate and adaptive immune system are present in the cochlea. In response to noise damage, immune cells increase in number. B, T, NK, and myeloid cells (macrophages and neutrophils) are the predominant immune cells present. Interestingly, immune cells appear to respond to noise damage by infiltrating the organ of Corti. Our studies highlight the need to further understand the role of these immune cells within the cochlea after noise exposure.

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