Advances In Immunology[JOURNAL]
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200 papers
The Fate Choice Between Effector and Memory T Cell Lineages: Asymmetry, Signal Integration, and Feedback to Create Bistability.
Backer RA, Hombrink P, Helbig C … +1 more , Amsen D
Adv Immunol · 2018 · PMID 29455847 · Publisher ↗
CD8 T cells clear primary infections with intracellular pathogens and provide long-term immunity against reinfection. Two different types of CD8 T cells are responsible for these functions: short-lived effector T cells a...
CD8 T cells clear primary infections with intracellular pathogens and provide long-term immunity against reinfection. Two different types of CD8 T cells are responsible for these functions: short-lived effector T cells and memory T cells. The cellular relationship between these two types of CD8 T cells has been subject to much investigation. Both cell types can derive from a single naïve CD8 T cell precursor. Their generation requires a fate choice early during a T cell response. As a result, two populations of T cells emerge. One of these consists of terminally differentiated short-lived effector T cells. The other contains cells able to develop into long-lived memory T cells. A foundation for development of these two populations may be laid during the first division of an activated naïve T cell precursor, as a consequence of asymmetric segregation of fate-determining factors into the daughter cells. Nonetheless, the binary choice between the two lineages is strongly influenced by signals, which ensure that the differentiation process is matched with the needs posed by the infection. Here, we will discuss the genetic and metabolic programs governing differentiation of these two lineages as well as the processes leading to their induction and consolidation to create bistability. These processes involve extensive lateral inhibition between the programs as well as positive feedback between the genetic programs and the signaling pathways responsible for their induction. These features will be highlighted by discussing the role of the Notch signaling pathway in guiding the decision between the two lineages.
The Unusual Genetics and Biochemistry of Bovine Immunoglobulins.
Stanfield RL, Haakenson J, Deiss TC … +3 more , Criscitiello MF, Wilson IA, Smider VV
Adv Immunol · 2018 · PMID 29455846 · Full text
Antibodies are the key circulating molecules that have evolved to fight infection by the adaptive immune system of vertebrates. Typical antibodies of most species contain six complementarity-determining regions (CDRs), w...
Antibodies are the key circulating molecules that have evolved to fight infection by the adaptive immune system of vertebrates. Typical antibodies of most species contain six complementarity-determining regions (CDRs), where the third CDR of the heavy chain (CDR H3) has the greatest diversity and often makes the most significant contact with antigen. Generally, the process of V(D)J recombination produces a vast repertoire of antibodies; multiple V, D, and J gene segments recombine with additional junctional diversity at the V-D and D-J joints, and additional combinatorial possibilities occur through heavy- and light-chain pairing. Despite these processes, the overall structure of the resulting antibody is largely conserved, and binding to antigen occurs predominantly through the CDR loops of the immunoglobulin V domains. Bovines have deviated from this general paradigm by having few VH regions and thus little germline combinatorial diversity, but their antibodies contain long CDR H3 regions, with substantial diversity generated through somatic hypermutation. A subset of the repertoire comprises antibodies with ultralong CDR H3s, which can reach over 70 amino acids in length. Structurally, these unusual antibodies form a β-ribbon "stalk" and disulfide-bonded "knob" that protrude far from the antibody surface. These long CDR H3s allow cows to mount a particularly robust immune response when immunized with viral antigens, particularly to broadly neutralizing epitopes on a stabilized HIV gp140 trimer, which has been a challenge for other species. The unusual genetics and structural biology of cows provide for a unique paradigm for creation of immune diversity and could enable generation of antibodies against especially challenging targets and epitopes.
Single-Cell Resolution of T Cell Immune Responses.
Buchholz VR, Flossdorf M
Adv Immunol · 2018 · PMID 29455845 · Publisher ↗
Single antigen-specific B or T lymphocytes are the smallest functional units, into which an adaptive immune response can be dissected. Today, novel high-throughput technologies are providing researches with increasingly...
Single antigen-specific B or T lymphocytes are the smallest functional units, into which an adaptive immune response can be dissected. Today, novel high-throughput technologies are providing researches with increasingly complex information on the diverse phenotypic signatures of individual lymphocytes. With a focus on T cells, we summarize here, how computational approaches are becoming increasingly important to identify the relevant developmental boundaries and connections between these high-dimensional lymphocyte states. We then describe how these insights may be further expanded by novel experimental approaches that allow to map the fate of individual T cells and their progeny in vivo and in vitro. Finally, we highlight how these experiments have uncovered a probabilistic regulatory structure of T cell immune responses and briefly discuss, how two distinct theoretical frameworks used to describe this structure may be merged to best capture single T cell behavior in computational terms.
Preface.
Shukla AK
Adv Immunol · 2017 · PMID 28950953 · Publisher ↗
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P2Y Receptors in Immune Response and Inflammation.
Le Duc D, Schulz A, Lede V … +4 more , Schulze A, Thor D, Brüser A, Schöneberg T
Adv Immunol · 2017 · PMID 28950952 · Publisher ↗
Metabotropic pyrimidine and purine nucleotide receptors (P2Y receptors) are expressed in virtually all cells with implications in very diverse biological functions, including the well-established platelet aggregation (P2...
Metabotropic pyrimidine and purine nucleotide receptors (P2Y receptors) are expressed in virtually all cells with implications in very diverse biological functions, including the well-established platelet aggregation (P2Y12), but also immune regulation and inflammation. The classical P2Y receptors bind nucleotides and are encoded by eight genes with limited sequence homology, while phylogenetically related receptors (e.g., P2Y12-like) recognize lipids and peptides, but also nucleotide derivatives. Growing lines of evidence suggest an important function of P2Y receptors in immune cell differentiation and maturation, migration, and cell apoptosis. Here, we give a perspective on the P2Y receptors' molecular structure and physiological importance in immune cells, as well as the related diseases and P2Y-targeting therapies. Extensive research is being undertaken to find modulators of P2Y receptors and uncover their physiological roles. We anticipate the medical applications of P2Y modulators and their immune relevance.
Roles of NHERF Family of PDZ-Binding Proteins in Regulating GPCR Functions.
Broadbent D, Ahmadzai MM, Kammala AK … +4 more , Yang C, Occhiuto C, Das R, Subramanian H
Adv Immunol · 2017 · PMID 28950951 · Publisher ↗
Multicellular organisms are equipped with an array of G-protein-coupled receptors (GPCRs) that mediate cell-cell signaling allowing them to adapt to environmental cues and ultimately survive. This is mechanistically poss...
Multicellular organisms are equipped with an array of G-protein-coupled receptors (GPCRs) that mediate cell-cell signaling allowing them to adapt to environmental cues and ultimately survive. This is mechanistically possible through complex intracellular GPCR machinery that encompasses a vast network of proteins. Within this network, there is a group called scaffolding proteins that facilitate proper localization of signaling proteins for a quick and robust GPCR response. One protein family within this scaffolding group is the PSD-95/Dlg/ZO-1 (PDZ) family which is important for GPCR localization, internalization, recycling, and downstream signaling. Although the PDZ family of proteins regulate the functions of several receptors, this chapter focuses on a subfamily within the PDZ protein family called the Na/H exchanger regulatory factors (NHERFs). Here we extensively review the predominantly characterized roles of NHERFs in renal phosphate absorption, intestinal ion regulation, cancer progression, and immune cell functions. Finally, we discuss the future perspectives and possible clinical application of targeting NHERFs in several disorders.
Emerging Roles of Regulators of G Protein Signaling (RGS) Proteins in the Immune System.
Druey KM
Adv Immunol · 2017 · PMID 28950950 · Publisher ↗
The regulators of G protein signaling (RGS) proteins are a large, evolutionarily conserved group of intracellular proteins expressed in every cell type and tissue throughout the body including the immune system. Through...
The regulators of G protein signaling (RGS) proteins are a large, evolutionarily conserved group of intracellular proteins expressed in every cell type and tissue throughout the body including the immune system. Through their signature GTPase-activating protein (GAP) activity on heterotrimeric G proteins and interactions with signaling complexes and membrane constituents (e.g., lipids), RGS proteins determine the intensity and duration of G protein-coupled receptor-induced responses. They may also have a function in generating intracellular signaling gradients necessary for the directional migration of leukocytes to inflamed tissues containing local accumulations of chemoattractants. Although physiological functions of most RGS proteins in leukocytes and lymphoid organs are largely unknown, it appears thus far that deficiency of individual RGS proteins in mice does not affect homeostatic immune responses in the absence of immunogenic challenge and/or microbial infection. Although aberrant expression of some RGS proteins has been linked to dysregulated immunity and/or neoplasia in humans, there are no human diseases attributed to specific RGS dysfunction. Here, we highlight mostly published work describing expression and functions of the core group of RGS proteins that were among the first discovered, in both innate and adaptive immune processes, with particular emphasis on cell trafficking.
G Protein-Coupled Kinin Receptors and Immunity Against Pathogens.
Scharfstein J, Ramos PIP, Barral-Netto M
Adv Immunol · 2017 · PMID 28950949 · Publisher ↗
For decades, immunologists have considered the complement system as a paradigm of a proteolytic cascade that, acting cooperatively with the immune system, enhances host defense against infectious organisms. In recent yea...
For decades, immunologists have considered the complement system as a paradigm of a proteolytic cascade that, acting cooperatively with the immune system, enhances host defense against infectious organisms. In recent years, advances made in thrombosis research disclosed a functional link between activated neutrophils, monocytes, and platelet-driven thrombogenesis. Forging a physical barrier, the fibrin scaffolds generated by synergism between the extrinsic and intrinsic (contact) pathways of coagulation entrap microbes within microvessels, limiting the systemic spread of infection while enhancing the clearance of pathogens by activated leukocytes. Insight from mice models of thrombosis linked fibrin formation via the intrinsic pathway to the autoactivation of factor XII (FXII) by negatively charged "contact" substances, such as platelet-derived polyphosphates and DNA from neutrophil extracellular traps. Following cleavage by FXIIa, activated plasma kallikrein (PK) initiates inflammation by liberating the nonapeptide bradykinin (BK) from an internal domain of high molecular weight kininogen (HK). Acting as a paracrine mediator, BK induces vasodilation and increases microvascular permeability via activation of endothelial B2R, a constitutively expressed subtype of kinin receptor. During infection, neutrophil-driven extravasation of plasma fuels inflammation via extravascular activation of the kallikrein-kinin system (KKS). Whether liberated by plasma-borne PK, tissue kallikrein, and/or microbial-derived proteases, the short-lived kinins activate immature dendritic cells via B2R, thus linking the infection-associated innate immunity/inflammation to the adaptive arm of immunity. As inflammation persists, a GPI-linked carboxypeptidase M removes the C-terminal arginine from the primary kinin, converting the B2R agonist into a high-affinity ligand for B1R, a GPCR subtype that is transcriptionally upregulated in injured/inflamed tissues. As reviewed here, lessons taken from studies of kinin receptor function in experimental infections have shed light on the complex proteolytic circuits that, acting at the endothelial interface, reciprocally couple immunity to the proinflammatory KKS.
Canonical and Noncanonical Signaling Roles of β-Arrestins in Inflammation and Immunity.
Ahmadzai MM, Broadbent D, Occhiuto C … +3 more , Yang C, Das R, Subramanian H
Adv Immunol · 2017 · PMID 28950948 · Publisher ↗
β-Arrestins are a highly conserved family of cytosolic adaptor proteins that contribute to many immune functions by orchestrating the desensitization and internalization of cell-surface G protein-coupled receptors (GPCRs...
β-Arrestins are a highly conserved family of cytosolic adaptor proteins that contribute to many immune functions by orchestrating the desensitization and internalization of cell-surface G protein-coupled receptors (GPCRs) via well-studied canonical interactions. In cells of the innate and adaptive immune system, β-arrestins also subserve a parallel but less understood role in which they propagate, rather than terminate, intracellular signal transduction cascades. Because β-arrestins are promiscuous in their binding, they are capable of interacting with several different GPCRs and downstream effectors; in doing so, they vastly expand the repertoire of cellular responses evoked by agonist binding and the scope of responses that may contribute to inflammation during infectious and sterile insults. In this chapter, we attempt to provide an overview of the canonical and noncanonical roles of β-arrestins in inflammatory diseases.
G Protein-Coupled Receptor Kinases in the Inflammatory Response and Signaling.
Steury MD, McCabe LR, Parameswaran N
Adv Immunol · 2017 · PMID 28950947 · Full text
G protein-coupled receptor kinases (GRKs) are serine/threonine kinases that regulate a large and diverse class of G protein-coupled receptors (GPCRs). Through GRK phosphorylation and β-arrestin recruitment, GPCRs are des...
G protein-coupled receptor kinases (GRKs) are serine/threonine kinases that regulate a large and diverse class of G protein-coupled receptors (GPCRs). Through GRK phosphorylation and β-arrestin recruitment, GPCRs are desensitized and their signal terminated. Recent work on these kinases has expanded their role from canonical GPCR regulation to include noncanonical regulation of non-GPCR and nonreceptor substrates through phosphorylation as well as via scaffolding functions. Owing to these and other regulatory roles, GRKs have been shown to play a critical role in the outcome of a variety of physiological and pathophysiological processes including chemotaxis, signaling, migration, inflammatory gene expression, etc. This diverse set of functions for these proteins makes them popular targets for therapeutics. Role for these kinases in inflammation and inflammatory disease is an evolving area of research currently pursued in many laboratories. In this review, we describe the current state of knowledge on various GRKs pertaining to their role in inflammation and inflammatory diseases.
GPCR Signaling in C. elegans and Its Implications in Immune Response.
Gupta A, Singh V
Adv Immunol · 2017 · PMID 28950946 · Publisher ↗
The ability to sense environmental cues is central to the survival of living organisms. G-protein-coupled receptors (GPCRs) are, by far, the most diverse class of sensory receptors and play an important role in surveilla...
The ability to sense environmental cues is central to the survival of living organisms. G-protein-coupled receptors (GPCRs) are, by far, the most diverse class of sensory receptors and play an important role in surveillance. As Caenorhabditis elegans lives in soil and feeds on bacteria, it must have strategies to differentiate between nutritious vs pathogenic bacteria. In C. elegans, lacking professional immune cells, GPCRs play a very important role in defense responses, for survival against pathogens. Here, we review a rich body of research to show that C. elegans uses GPCRs in different tissues for immune surveillance, immune homeostasis, as well as behavioral responses. Nematode sensory neurons and GPCRs can sense both pathogen-associated molecules as well as damage-associated molecular patterns during infection. Both fight and flight responses, activated upon exposure to pathogens, are driven by GPCRs and trimeric G proteins in the sensory neurons.
Adhesion GPCRs in Regulating Immune Responses and Inflammation.
Lin HH, Hsiao CC, Pabst C … +3 more , Hébert J, Schöneberg T, Hamann J
Adv Immunol · 2017 · PMID 28950945 · Publisher ↗
The adhesion family comprises one of the five major clades of G protein-coupled receptors (GPCRs). Unlike conventional GPCRs, adhesion GPCRs (aGPCRs) have extended ectodomains with various protein folds that facilitate p...
The adhesion family comprises one of the five major clades of G protein-coupled receptors (GPCRs). Unlike conventional GPCRs, adhesion GPCRs (aGPCRs) have extended ectodomains with various protein folds that facilitate protein-protein interactions and, hence, putative cellular adhesive functions. Juxtaposed to the seven-pass transmembrane domain is a GPCR autoproteolysis-inducing domain that enables autoproteolytic cleavage of the receptor, resulting in a bipartite structure of many aGPCRs. aGPCRs are widely distributed and play critical roles in many developmental processes; yet, the underlying mechanisms of activation and signal transduction have emerged only recently. About one-third of the 33 human aGPCRs are expressed in hematopoietic stem, progenitor, or mature cells, where they define distinct cellular populations. Recent studies have demonstrated roles of aGPCR in the control of innate effector functions and the susceptibility for and onset of (auto)inflammatory conditions. We here discuss the current knowledge about aGPCRs in the regulation of immune responses and inflammation.
Emerging Roles for MAS-Related G Protein-Coupled Receptor-X2 in Host Defense Peptide, Opioid, and Neuropeptide-Mediated Inflammatory Reactions.
Ali H
Adv Immunol · 2017 · PMID 28950944 · Publisher ↗
Mast cells (MCs) are tissue-resident immune cells that contribute to host defense but are best known for their roles in allergic and inflammatory diseases. In humans, MCs are divided into two subtypes based on the protea...
Mast cells (MCs) are tissue-resident immune cells that contribute to host defense but are best known for their roles in allergic and inflammatory diseases. In humans, MCs are divided into two subtypes based on the protease content of their secretory granules. Thus, human lung MCs contain only tryptase and are known as MC, whereas skin MCs contain both tryptase and chymase and are known as MC. Patients with severe asthma display elevated MCs in the lung, which undergo phenotypic change from MC to MC. Although the human genome contains four Mas related G protein coupled receptor X (MRGPRX) genes, an important feature of MC is that they selectively express MRGPRX2. It is activated by antimicrobial host defense peptides such as human β-defensins and the cathelicidin LL-37 and likely contributes to host defense. MRGPRX2 is also a receptor for the neuropeptide substance P, major basic protein, eosinophil peroxidase, opioids, and many FDA-approved cationic drugs. Increased expression of MRGPRX2 or enhanced downstream signaling likely contributes to chronic inflammatory diseases such as rosacea, atopic dermatitis, chronic urticaria, and severe asthma. In this chapter, I will discuss the expression profile and function of MRGPRX1-4 and review the emerging roles of MRGPRX2 on host defense, chronic inflammatory diseases, and drug-induced pseudoallergic reactions. I will also examine the novel aspects of MRGPRX2 signaling in MCs as it related to degranulation and review the mechanisms of its regulation.
β2-Adrenoceptor Function in Asthma.
Amrani Y, Bradding P
Adv Immunol · 2017 · PMID 28950943 · Publisher ↗
β2-adrenoceptor agonists, often used in combination with corticosteroids, have been extensively used for the treatment of asthma. However, concerns have been raised regarding their adverse effects and safety including po...
β2-adrenoceptor agonists, often used in combination with corticosteroids, have been extensively used for the treatment of asthma. However, concerns have been raised regarding their adverse effects and safety including poor asthma control, life-threatening exacerbations, exacerbations that often require hospitalization, and asthma-related deaths. The question as to whether these adverse effects relate to the loss of their bronchoprotective action remains an interesting possibility. In the chapter, we will review the experimental evidence that describes the different potential factors and associated mechanisms that can blunt the therapeutic action of β2-adrenoceptor agonists in asthma. We show here evidence that various key inflammatory cytokines, growth factors, some respiratory viruses, certain allergens, unknown factors present in serum from atopic asthmatics have the capacity to impair β2-adrenoceptor function in airway smooth muscle, the main target of these drugs. More importantly, we present our latest research describing the role played by mast cells in impairing β2-adrenoceptor function. Although no definitive conclusion could be made regarding the implication of one single mechanism, receptor uncoupling, or receptor desensitization due to phosphorylation represents the main inhibitory pathways associated with a loss of β2-adrenoceptor function in airway smooth muscle. Targeting the pathways leading to β2-adrenoceptor dysfunction will likely provide novel therapies to improve the efficacy of β2-agonists in asthma.
A Mechanistic Understanding of Pyroptosis: The Fiery Death Triggered by Invasive Infection.
Liu X, Lieberman J
Adv Immunol · 2017 · PMID 28826530 · Full text
Immune cells and skin and mucosal epithelial cells recognize invasive microbes and other signs of danger to sound alarms that recruit responder cells and initiate an immediate "innate" immune response. An especially powe...
Immune cells and skin and mucosal epithelial cells recognize invasive microbes and other signs of danger to sound alarms that recruit responder cells and initiate an immediate "innate" immune response. An especially powerful alarm is triggered by cytosolic sensors of invasive infection that assemble into multimolecular complexes, called inflammasomes, that activate the inflammatory caspases, leading to maturation and secretion of proinflammatory cytokines and pyroptosis, an inflammatory death of the infected cell. Work in the past year has defined the molecular basis of pyroptosis. Activated inflammatory caspases cleave Gasdermin D (GSDMD), a cytosolic protein in immune antigen-presenting cells and epithelia. Cleavage separates the autoinhibitory C-terminal fragment from the active N-terminal fragment, which moves to the cell membrane, binds to lipids on the inside of the cell membrane, and oligomerizes to form membrane pores that disrupt cell membrane integrity, causing death and leakage of small molecules, including the proinflammatory cytokines and GSDMD itself. GSDMD also binds to cardiolipin on bacterial membranes and kills the very bacteria that activate the inflammasome. GSDMD belongs to a family of poorly studied gasdermins, expressed in the skin and mucosa, which can also form membrane pores. Spontaneous mutations that disrupt the binding of the N- and C-terminal domains of other gasdermins are associated with alopecia and asthma. Here, we review recent studies that identified the roles of the inflammasome, inflammatory caspases, and GSDMD in pyroptosis and highlight some of the outstanding questions about their roles in innate immunity, control of infection, and sepsis.
Complement System in Neural Synapse Elimination in Development and Disease.
Presumey J, Bialas AR, Carroll MC
Adv Immunol · 2017 · PMID 28826529 · Publisher ↗
Recent discoveries implicate the classical complement cascade in normal brain development and in disease. Complement proteins C1q, C3, and C4 participate in synapse elimination, tagging inappropriate synaptic connections...
Recent discoveries implicate the classical complement cascade in normal brain development and in disease. Complement proteins C1q, C3, and C4 participate in synapse elimination, tagging inappropriate synaptic connections between neurons for removal by phagocytic microglia that exist in a special, highly phagocytic state during the synaptic pruning period. Several neurodevelopmental disorders, such as schizophrenia and autism, are thought to be caused by an imbalance in synaptic pruning, and recent studies suggest that dysregulation of complement could promote this synaptic pruning imbalance. Moreover, in the mature brain, complement can be aberrantly activated in early stages of neurodegenerative diseases to stimulate synapse loss. Similar pathways can also be activated in response to inflammation, as in West Nile Virus infection or in lupus, where peripheral inflammation can promote microglia-mediated synapse loss. Whether synapse loss in disease is a true reactivation of developmental synaptic pruning programs remains unclear; nonetheless, complement proteins represent potential therapeutic targets for both neurodevelopmental and neurodegenerative diseases.
Chemokine-Driven CD4 T Cell Homing: New Concepts and Recent Advances.
Gregor CE, Foeng J, Comerford I … +1 more , McColl SR
Adv Immunol · 2017 · PMID 28826528 · Publisher ↗
CD4 T cells are critical regulators of the adaptive immune system and have diverse roles in regulating responses to the broad array of microbes encountered. Appropriate execution of their effector function requires preci...
CD4 T cells are critical regulators of the adaptive immune system and have diverse roles in regulating responses to the broad array of microbes encountered. Appropriate execution of their effector function requires precise and coordinated migration of these cells to specific lymphoid niches and peripheral sites. This migration is largely controlled by dynamic expression of chemokine receptors and the discrete functions of distinct subsets of CD4 T cells can often be determined from their expression of specific chemokine receptors. In this chapter, we discuss recent advances in the subset-specific homing of distinct T helper populations, focusing on new insights stemming from the increased diversity and plasticity now observed among CD4 T cells as well as how chemokine receptors can govern T cell-fate decisions. We also discuss current understanding of CD4 memory T cells with reference to their diversification based on chemokine receptor expression.
Chromosome 17q21 Genes ORMDL3 and GSDMB in Asthma and Immune Diseases.
Das S, Miller M, Broide DH
Adv Immunol · 2017 · PMID 28826527 · Publisher ↗
Chromosome 17q21 contains a cluster of genes including ORMDL3 and GSDMB, which have been highly linked to asthma in genome-wide association studies. ORMDL3 is localized to the endoplasmic reticulum and regulates downstre...
Chromosome 17q21 contains a cluster of genes including ORMDL3 and GSDMB, which have been highly linked to asthma in genome-wide association studies. ORMDL3 is localized to the endoplasmic reticulum and regulates downstream pathways including sphingolipids, metalloproteases, remodeling genes, and chemokines. ORMDL3 inhibits serine palmitoyl-CoA transferase, the rate-limiting enzyme for sphingolipid biosynthesis. In addition, ORMDL3 activates the ATF6α branch of the unfolded protein response which regulates SERCA2b and IL-6, pathways of potential importance to asthma. The SNP-linking chromosome 17q21 to asthma is associated with increased ORMDL3 and GSDMB expression. Mice expressing either increased levels of human ORMDL3, or human GSDMB, have an asthma phenotype characterized by increased airway responsiveness and increased airway remodeling (increased smooth muscle and fibrosis) in the absence of airway inflammation. GSDMB regulates expression of 5-LO and TGF-β1 which are known pathways involved in the pathogenesis of asthma. GSDMB is one of four members of the GSDM family (GSDMA, GSDMB, GSDMC, and GSDMD). GSDMD (located on chromosome 8q24 and not linked to asthma) has emerged as a key mediator of pyroptosis. GSDMD is a key component of the NLPR3 inflammasome and is required for its activation. GSDMD undergoes proteolytic cleavage by caspase-1 to release its N-terminal fragment, which in turn mediates pyroptosis and IL-1β secretion. Chromosome 17q21 has not only been linked to asthma but also to type 1 diabetes, inflammatory bowel disease, and primary biliary cirrhosis suggesting that future insights into the biology of genes located in this region will increase our understanding of these diseases.
Tissue-Specific Diversity and Functions of Conventional Dendritic Cells.
Pakalniškytė D, Schraml BU
Adv Immunol · 2017 · PMID 28413024 · Publisher ↗
Dendritic cells (DCs) are versatile controllers of immunity, which sense infection or tissue damage and, accordingly, initiate innate and adaptive effector responses. In recent years, it has become evident that DCs exist...
Dendritic cells (DCs) are versatile controllers of immunity, which sense infection or tissue damage and, accordingly, initiate innate and adaptive effector responses. In recent years, it has become evident that DCs exist as an independent hematopoietic lineage comprising several developmentally distinct and functionally specialized subsets that are strategically located in all organs to defend the organism against invading pathogens. Here, we review the diversity of DC subtypes found across tissues and discuss our current understanding of the tissue-specific functions of these cell types.
A Chemoattractant-Guided Walk Through Lymphopoiesis: From Hematopoietic Stem Cells to Mature B Lymphocytes.
Lim VY, Zehentmeier S, Fistonich C … +1 more , Pereira JP
Adv Immunol · 2017 · PMID 28413023 · Full text
B lymphocytes develop from hematopoietic stem cells (HSCs) in specialized bone marrow niches composed of rare mesenchymal lineage stem/progenitor cells (MSPCs) and sinusoidal endothelial cells. These niches are defined b...
B lymphocytes develop from hematopoietic stem cells (HSCs) in specialized bone marrow niches composed of rare mesenchymal lineage stem/progenitor cells (MSPCs) and sinusoidal endothelial cells. These niches are defined by function and location: MSPCs are mostly perisinusoidal cells that together with a small subset of sinusoidal endothelial cells express stem cell factor, interleukin-7 (IL-7), IL-15, and the highest amounts of CXCL12 in bone marrow. Though rare, MSPCs are morphologically heterogeneous, highly reticular, and form a vast cellular network in the bone marrow parenchyma capable of interacting with large numbers of hematopoietic cells. HSCs, downstream multipotent progenitor cells, and common lymphoid progenitor cells utilize CXCR4 to fine-tune access to critical short-range growth factors provided by MSPCs for their long-term maintenance and/or multilineage differentiation. In later stages, developing B lymphocytes use CXCR4 to navigate the bone marrow parenchyma, and predominantly cannabinoid receptor-2 for positioning within bone marrow sinusoids, prior to being released into peripheral blood circulation. In the final stages of differentiation, transitional B cells migrate to the spleen where they preferentially undergo further rounds of differentiation until selection into the mature B cell pool occurs. This bottleneck purges up to 97% of all developing B cells in a peripheral selection process that is heavily controlled not only by the intensity of BCR signaling and access to BAFF but also by the proper functioning of the B cell motility machinery.
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