Advances In Immunology[JOURNAL]
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200 papers
Airway mycosis in allergic airway disease.
Li E, Knight JM, Wu Y … +4 more , Luong A, Rodriguez A, Kheradmand F, Corry DB
Adv Immunol · 2019 · PMID 31296304 · Publisher ↗
The allergic airway diseases, including chronic rhinosinusitis (CRS), asthma, allergic bronchopulmonary mycosis (ABPM) and many others, comprise a heterogeneous collection of inflammatory disorders affecting the upper an...
The allergic airway diseases, including chronic rhinosinusitis (CRS), asthma, allergic bronchopulmonary mycosis (ABPM) and many others, comprise a heterogeneous collection of inflammatory disorders affecting the upper and lower airways and lung parenchyma that represent the most common chronic diseases of humanity. In addition to their shared tissue tropism, the allergic airway diseases are characterized by a distinct pattern of inflammation involving the accumulation of eosinophils, type 2 macrophages, innate lymphoid cells type 2 (ILC2), IgE-secreting B cells, and T helper type 2 (Th2) cells in airway tissues, and the prominent production of type 2 cytokines including interleukin (IL-) 33, IL-4, IL-5, IL-13, and many others. These factors and related inflammatory molecules induce characteristic remodeling and other changes of the airways that include goblet cell metaplasia, enhanced mucus secretion, smooth muscle hypertrophy, tissue swelling and polyp formation that account for the major clinical manifestations of nasal obstruction, headache, hyposmia, cough, shortness of breath, chest pain, wheezing, and, in the most severe cases of lower airway disease, death due to respiratory failure or disseminated, systemic disease. The syndromic nature of the allergic airway diseases that now include many physiological variants or endotypes suggests that distinct endogenous or environmental factors underlie their expression. However, findings from different perspectives now collectively link these disorders to a single infectious source, the fungi, and a molecular pathogenesis that involves the local production of airway proteinases by these organisms. In this review, we discuss the evidence linking fungi and their proteinases to the surprisingly wide variety of chronic airway and systemic disorders and the immune pathogenesis of these conditions as they relate to environmental fungi. We further discuss the important implications these new findings have for the diagnosis and future therapy of these common conditions.
Roles of cysteinyl leukotrienes and their receptors in immune cell-related functions.
Kanaoka Y, Austen KF
Adv Immunol · 2019 · PMID 31296303 · Publisher ↗
The cysteinyl leukotrienes (cys-LTs), leukotriene C, (LTC), LTD, and LTE, are lipid mediators of inflammation. LTC is the only intracellularly synthesized cys-LT through the 5-lipoxygenase and LTC synthase pathway and af...
The cysteinyl leukotrienes (cys-LTs), leukotriene C, (LTC), LTD, and LTE, are lipid mediators of inflammation. LTC is the only intracellularly synthesized cys-LT through the 5-lipoxygenase and LTC synthase pathway and after transport is metabolized to LTD and LTE by specific extracellular peptidases. Each cys-LT has a preferred functional receptor in vivo; LTD to the type 1 cys-LT receptor (CysLTR), LTC to CysLTR, and LTE to CysLTR (OXGR1 or GPR99). Recent studies in mouse models revealed that there are multiple regulatory mechanisms for these receptor functions and each receptor plays a distinct role as observed in different mouse models of inflammation and immune responses. This review focuses on the integrated host responses to the cys-LT/CysLTR pathway composed of sequential ligands with preferred receptors as seen from mouse models. It also discusses potential therapeutic targets for LTC synthase, CysLTR, and CysLTR.
Deconstructing the sex bias in allergy and autoimmunity: From sex hormones and beyond.
Laffont S, Guéry JC
Adv Immunol · 2019 · PMID 31296302 · Publisher ↗
Men and women differ in their susceptibility to develop autoimmunity and allergy but also in their capacity to cope with infections. Mechanisms responsible for this sexual dimorphism are still poorly documented and proba...
Men and women differ in their susceptibility to develop autoimmunity and allergy but also in their capacity to cope with infections. Mechanisms responsible for this sexual dimorphism are still poorly documented and probably multifactorial. This review discusses the recent development in our understanding of the cell-intrinsic actions of biological factors linked to sex, sex hormones and sex chromosome complement, on immune cells, which may account for the sex differences in the enhanced susceptibility of women to develop immunological disorders, such as allergic asthma or systemic lupus erythematosus (SLE). We choose to more specifically discuss the impact of sex hormones on the development and function of immune cell populations directly involved in type-2 immunity, and the role of the X-linked Toll like receptor 7 (TLR7) in anti-viral immunity and in SLE. We will also elaborate on the recent evidence demonstrating that TLR7 escapes from X chromosome inactivation in the immune cells of women, and how this may contribute to endow woman immune system with enhanced responsiveness to RNA-virus and susceptibility to SLE.
The airway epithelium in asthma.
Bonser LR, Erle DJ
Adv Immunol · 2019 · PMID 31296301 · Publisher ↗
Asthma is a genetically and phenotypically complex disease that has a major impact on global health. Signs and symptoms of asthma are caused by the obstruction of airflow through the airways. The epithelium that lines th...
Asthma is a genetically and phenotypically complex disease that has a major impact on global health. Signs and symptoms of asthma are caused by the obstruction of airflow through the airways. The epithelium that lines the airways plays a major role in maintaining airway patency and in host defense. The epithelium initiates responses to inhaled or aspirated substances, including allergens, viruses, and bacteria, and epithelial-derived cytokines are important in the recruitment and activation of immune cells in the airway. Changes in the structure and function of the airway epithelium are a prominent feature of asthma. Approximately half of individuals with asthma have evidence of active type 2 immune responses in the airway. In these individuals, epithelial cytokines promote type 2 responses, and responses to type 2 cytokines result in increased epithelial mucus production and other effects that cause airway obstruction. Recent work also implicates other epithelial responses, including interleukin-17, interferon and ER stress responses, that may contribute to asthma pathogenesis and provide new targets for therapy.
Cis- and trans-factors affecting AID targeting and mutagenic outcomes in antibody diversification.
Yeap LS, Meng FL
Adv Immunol · 2019 · PMID 30904133 · Publisher ↗
Antigen receptor diversification is a hallmark of adaptive immunity which allows specificity of the receptor to particular antigen. B cell receptor (BCR) or its secreted form, antibody, is diversified through antigen-ind...
Antigen receptor diversification is a hallmark of adaptive immunity which allows specificity of the receptor to particular antigen. B cell receptor (BCR) or its secreted form, antibody, is diversified through antigen-independent and antigen-dependent mechanisms. During B cell development in bone marrow, BCR is diversified via V(D)J recombination mediated by RAG endonuclease. Upon stimulation by antigen, B cell undergo somatic hypermutation (SHM) to allow affinity maturation and class switch recombination (CSR) to change the effector function of the antibody. Both SHM and CSR are initiated by activation-induced cytidine deaminase (AID). Repair of AID-initiated lesions through different DNA repair pathways results in diverse mutagenic outcomes. Here, we focus on discussing cis- and trans-factors that target AID to its substrates and factors that affect different outcomes of AID-initiated lesions. The knowledge of mechanisms that govern AID targeting and outcomes could be harnessed to elicit rare functional antibodies and develop ex vivo antibody diversification approaches with diversifying base editors.
Transcription factories in Igκ allelic choice and diversity.
Karki S, Banerjee S, Mclean K … +2 more , Dinner A, Clark MR
Adv Immunol · 2019 · PMID 30904132 · Full text
The vertebrate immune system is tasked with the challenge of responding to any pathogen the organism might encounter, and retaining memory of that pathogen in case of future infection. Recognition and memory of pathogens...
The vertebrate immune system is tasked with the challenge of responding to any pathogen the organism might encounter, and retaining memory of that pathogen in case of future infection. Recognition and memory of pathogens are encoded within the adaptive immune system and production of T and B lymphocytes with diverse antigen receptor repertoires. In B lymphocytes, diversity is generated by sequential recombination between Variable (V), Diversity (D) and Joining (J) gene segments in the immunoglobulin heavy chain gene (Igh) and subsequent V-J recombination in immunoglobulin light chain genes (Igκ followed by Igλ). However, the process by which particular V, D and J segments are selected during recombination, and stochasticity is maintained to ensure antibody repertoire diversity, is still unclear. In this review, we focus on Igκ and recent findings regarding the relationships between gene structure, the generation of diversity and allelic choice. Surprisingly, the nuclear environment in which each Igκ allele resides, including transcription factories assembled on the nuclear matrix, plays critical roles in both gene regulation and in shaping the diversity of Vκ genes accessible to recombination. These findings provide a new paradigm for understanding Igκ recombination and Vκ diversity in the context of B lymphopoiesis.
Signaling control of antibody isotype switching.
Chen Z, Wang JH
Adv Immunol · 2019 · PMID 30904131 · Full text
Class switch recombination (CSR) generates isotype-switched antibodies with distinct effector functions essential for mediating effective humoral immunity. CSR is catalyzed by activation-induced deaminase (AID) that init...
Class switch recombination (CSR) generates isotype-switched antibodies with distinct effector functions essential for mediating effective humoral immunity. CSR is catalyzed by activation-induced deaminase (AID) that initiates DNA lesions in the evolutionarily conserved switch (S) regions at the immunoglobulin heavy chain (Igh) locus. AID-initiated DNA lesions are subsequently converted into DNA double stranded breaks (DSBs) in the S regions of Igh locus, repaired by non-homologous end-joining to effect CSR in mammalian B lymphocytes. While molecular mechanisms of CSR are well characterized, it remains less well understood how upstream signaling pathways regulate AID expression and CSR. B lymphocytes express multiple receptors including the B cell antigen receptor (BCR) and co-receptors (e.g., CD40). These receptors may share common signaling pathways or may use distinct signaling elements to regulate CSR. Here, we discuss how signals emanating from different receptors positively or negatively regulate AID expression and CSR.
Multilayer regulation of CD4 T cell subset differentiation in the era of single cell genomics.
Sungnak W, Wang C, Kuchroo VK
Adv Immunol · 2019 · PMID 30904130 · Publisher ↗
CD4 T cells are major immune cell types that mediate effector responses appropriate for diverse incoming threats. These cells have been categorized into different subsets based on how they are induced, expression of spec...
CD4 T cells are major immune cell types that mediate effector responses appropriate for diverse incoming threats. These cells have been categorized into different subsets based on how they are induced, expression of specific master transcription factors, and the resulting effector cell phenotypes as defined by expression of signature cytokines. However, recent studies assessing the expression of gene modules in single CD4 T cells, rather than expression of one or a few signature genes, have provided a more complex picture in which the canonical model does not fit as cleanly as proposed. Here, we review the concepts of lineage commitment, plasticity and functional heterogeneity in the context of this greater complexity. We then apply our current understanding of CD4 T cell subsets to discuss outstanding questions regarding follicular helper T cells and follicular regulatory T cells with respect to their shared features with other known CD4 T cell subsets.
The Fly Way of Antiviral Resistance and Disease Tolerance.
Chow J, Kagan JC
Adv Immunol · 2018 · PMID 30366519 · Full text
Like humans, insects face the threat of viral infection. Despite having repercussions on human health and disease, knowledge gaps exist for how insects cope with viral pathogens. Drosophila melanogaster serves as an idea...
Like humans, insects face the threat of viral infection. Despite having repercussions on human health and disease, knowledge gaps exist for how insects cope with viral pathogens. Drosophila melanogaster serves as an ideal insect model due to its genetic tractability. When encountering a pathogen, two major approaches to fight disease are resistance strategies and tolerance strategies. Disease resistance strategies promote the health of the infected host by reducing pathogen load. Multiple disease resistance mechanisms have been identified in Drosophila: RNA interference, Jak/STAT signaling, Toll signaling, IMD signaling, and autophagy. Disease tolerance mechanisms, in contrast, do not reduce pathogen load directly, but rather mitigate the stress and damage incurred by infection. The main benefit of tolerance mechanisms may therefore be to provide the host with time to engage antiviral resistance mechanisms that eliminate the threat. In this review, antiviral resistance mechanisms used by Drosophila will be described and compared to mammalian antiviral mechanisms. Disease tolerance will then be explained in a broader context as this is a burgeoning field of study.
Tumor Necrosis Factor Receptor Superfamily in T Cell Priming and Effector Function.
Muller J, Baeyens A, Dustin ML
Adv Immunol · 2018 · PMID 30366518 · Publisher ↗
The tumor necrosis factor receptor superfamily (TNFRSF) and their ligands mediate lymphoid tissue development and homeostasis in addition to key aspects of innate and adaptive immune responses. T cells of the adaptive im...
The tumor necrosis factor receptor superfamily (TNFRSF) and their ligands mediate lymphoid tissue development and homeostasis in addition to key aspects of innate and adaptive immune responses. T cells of the adaptive immune system express a number of TNFRSF members that are used to receive signals at different instructive stages and produce several tumor necrosis factor superfamily (TNFSF) members as effector molecules. There is also one example of a TNFRSF member serving as a ligand for negative regulatory checkpoint receptors. In most cases, the ligands in afferent and efferent phases are membrane proteins and thus the interaction with TNFRSF members must take place in immunological synapses and other modes of cell-cell interaction. A particular feature of the TNFRSF-mediated signaling is the prominent use of linear ubiquitin chains as scaffolds for signaling complexes that activate nuclear factor κ-B and Fos/Jun transcriptional regulators. This review will focus on the signaling mechanisms triggered by TNFRSF members in their role as costimulators of early and late phases of T cell instruction and the delivery mechanism of TNFSF members through the immunological synapses of helper and cytotoxic effector cells.
New Insights Into the Biology of CD8 Regulatory T Cells.
Nakagawa H, Wang L, Cantor H … +1 more , Kim HJ
Adv Immunol · 2018 · PMID 30366517 · Publisher ↗
Regulatory T cells are central mediators of immune regulation and play an essential role in the maintenance of immune homeostasis in the steady state and under pathophysiological conditions. Disruption of CD8 Treg-depend...
Regulatory T cells are central mediators of immune regulation and play an essential role in the maintenance of immune homeostasis in the steady state and under pathophysiological conditions. Disruption of CD8 Treg-dependent recognition of Qa-1-restricted self-antigens can result in dysregulated immune responses, tissue damage, autoimmune disease and cancer. Recent progress in studies on regulatory T cells of the CD8 lineage has provided new biological insight into this specialized regulatory T cell subpopulation. Identification of the Helios transcription factor as an essential control element for the differentiation and function of CD8 regulatory T cells has led to a better understanding of the unique genetic program of these cells. Recent analyses of T-cell receptor usage and antigen recognition by Qa-1-restricted CD8 Treg have provided additional insight into the unusual biological function of this regulatory CD8 lineage. Here we summarize recent advances in our understanding of CD8 regulatory T cells with emphasis on lineage commitment, differentiation and stability.
RAG Chromatin Scanning During V(D)J Recombination and Chromatin Loop Extrusion are Related Processes.
Lin SG, Ba Z, Alt FW … +1 more , Zhang Y
Adv Immunol · 2018 · PMID 30249335 · Publisher ↗
An effective adaptive immune system depends on the ability of developing B and T cells to generate diverse immunoglobulin (Ig) and T cell receptor repertoires, respectively. Such diversity is achieved through a programme...
An effective adaptive immune system depends on the ability of developing B and T cells to generate diverse immunoglobulin (Ig) and T cell receptor repertoires, respectively. Such diversity is achieved through a programmed somatic recombination process whereby germline V, D, and J segments of antigen receptor loci are assembled to form the variable region V(D)J exons of Ig and TCRs. Studies of this process, termed V(D)J recombination, have provided key insights into our understanding of a variety of general gene regulatory and DNA repair processes over the last several decades. V(D)J recombination is initiated by the RAG endonuclease which generates DNA double-stranded breaks at the borders of V, D, and J segments. In this review, we cover recent work that has elucidated RAG structure and work that revealed that RAG has a novel chromatin scanning activity, likely mediated by chromatin loop extrusion, that contributes to its ability to locate V, D, J gene segment substrates within large chromosomal loop domains bounded by CTCF-binding elements (CBEs). This latter function, coupled with the role CBE-based chromatin loop domains and subdomains within them play in focusing V(D)J recombination activity within antigen receptor loci, provide mechanistic explanations for long-standing questions regarding V(D)J segment usage diversification and in limiting potentially deleterious off-target RAG-initiated recombination events genome-wide. This review will focus mainly on studies of the mouse Ig heavy chain locus, but the principles described also apply to other Ig loci and to TCR loci in mice and humans.
The First B-Cell Tolerance Checkpoint in Mice and Humans: Control by AID.
Kuraoka M, Meffre E, Kelsoe G
Adv Immunol · 2018 · PMID 30249334 · Publisher ↗
Activation-induced cytidine deaminase (AID) expression in the germinal center response drives the immunoglobulin class-switch recombination and V(D)J hypermutation necessary for efficacious, high-affinity antibody respon...
Activation-induced cytidine deaminase (AID) expression in the germinal center response drives the immunoglobulin class-switch recombination and V(D)J hypermutation necessary for efficacious, high-affinity antibody responses. That AID is expressed in developing lymphocytes is less well known, but represents an evolutionarily conserved pattern of lymphocyte development that is represented in all vertebrate species. Here we review the role of early, developmentally regulated AID expression in mice and humans and its role in establishing the first B-cell tolerance checkpoint. This newly recognized component of central tolerance requires coordinate signaling by poly- or autoreactive B-cell antigen receptors and endosomal Toll-like receptors. These signals synergize to upregulate AID expression in immature and transitional B cells to levels that approach that of germinal center B cells with the result of caspase 3-mediated cell death. In this review, we discuss the origins and mechanism of this interesting collaboration between adaptive and innate receptors to purge the primary B-cell repertoire of self-reactivity and how it may be related to receptor editing, the other major mechanism for central tolerance.
The Microglial Response to Neurodegenerative Disease.
Song WM, Colonna M
Adv Immunol · 2018 · PMID 30249333 · Publisher ↗
Microglia are a subset of tissue macrophages that constitute the major immune cell type of the central nervous system. These cells have long been known to change their morphology and functions in response to various neur...
Microglia are a subset of tissue macrophages that constitute the major immune cell type of the central nervous system. These cells have long been known to change their morphology and functions in response to various neurological insults. Recently, a plethora of unbiased transcriptomics studies have revealed that across a broad spectrum of neurodegeneration-like disease models, microglia adopt a similar activation signature and perform similar functions. Despite these commonalities in response, the role of microglia has been described as both positive and negative in different murine disease models. In humans, genetic association studies have revealed strong connections between microglia genes and various neurodegenerative diseases, and mechanistic investigations of these mutations have added another layer of complexity. Here, we provide an overview of studies that have built a case for a common microglial response to neurodegeneration and discuss pathways that may be important to initiate and sustain this response; delineate the multifaceted functions of activated microglia spanning different diseases; and discuss insights from studying genes associated with disease in humans. We argue that strong evidence causally links activated microglia function to neurodegeneration and discuss what seems to be a conflict between mouse models and human genetics.
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes.
Comrie WA, Lenardo MJ
Adv Immunol · 2018 · PMID 29731008 · Full text
Proper regulation of the immune system is required for protection against pathogens and preventing autoimmune disorders. Inborn errors of the immune system due to inherited or de novo germline mutations can lead to the l...
Proper regulation of the immune system is required for protection against pathogens and preventing autoimmune disorders. Inborn errors of the immune system due to inherited or de novo germline mutations can lead to the loss of protective immunity, aberrant immune homeostasis, and the development of autoimmune disease, or combinations of these. Forward genetic screens involving clinical material from patients with primary immunodeficiencies (PIDs) can vary in severity from life-threatening disease affecting multiple cell types and organs to relatively mild disease with susceptibility to a limited range of pathogens or mild autoimmune conditions. As central mediators of innate and adaptive immune responses, T cells are critical orchestrators and effectors of the immune response. As such, several PIDs result from loss of or altered T cell function. PID-associated functional defects range from complete absence of T cell development to uncontrolled effector cell activation. Furthermore, the gene products of known PID causal genes are involved in diverse molecular pathways ranging from T cell receptor signaling to regulators of protein glycosylation. Identification of the molecular and biochemical cause of PIDs can not only guide the course of treatment for patients, but also inform our understanding of the basic biology behind T cell function. In this chapter, we review PIDs with known genetic causes that intrinsically affect T cell function with particular focus on perturbations of biochemical pathways.
Chemokines: Critical Regulators of Memory T Cell Development, Maintenance, and Function.
Rahimi RA, Luster AD
Adv Immunol · 2018 · PMID 29731007 · Full text
Memory T cells are central to orchestrating antigen-specific recall responses in vivo. Compared to naïve T cells, memory T cells respond more quickly to cognate peptide:MHC with a shorter lag time for entering the cell c...
Memory T cells are central to orchestrating antigen-specific recall responses in vivo. Compared to naïve T cells, memory T cells respond more quickly to cognate peptide:MHC with a shorter lag time for entering the cell cycle and exerting effector functions. However, it is now well established that this enhanced responsiveness is not the only mechanism whereby memory T cells are better equipped than naïve T cells to rapidly and robustly induce inflammation. In contrast to naïve T cells, memory T cells are composed of distinct subsets with unique trafficking patterns and localizations. Tissue-resident memory T cells persist in previously inflamed tissue and function as first responders to cognate antigen reexposure. In addition, a heterogeneous group of circulating memory T cells augment inflammation by either rapidly migrating to inflamed tissue or responding to cognate antigen within secondary lymphoid organs and producing additional effector T cells. Defining the mechanisms regulating T cell positioning and trafficking and how this influences the development, maintenance, and function of memory T cell subsets is essential to improving vaccine design as well as treatment of immune-mediated diseases. In this chapter, we will review our current knowledge of how chemokines, critical regulators of cell positioning and migration, govern memory T cell biology in vivo. In addition, we discuss areas of uncertainty and future directions for further delineating how T cell localization influences memory T cell biology.
Unexpected Roles for Intracellular Complement in the Regulation of Th1 Responses.
West EE, Afzali B, Kemper C
Adv Immunol · 2018 · PMID 29731006 · Publisher ↗
The complement system is generally recognized as an evolutionarily ancient and critical part of innate immunity required for the removal of pathogens that have breached the protective host barriers. It was originally def...
The complement system is generally recognized as an evolutionarily ancient and critical part of innate immunity required for the removal of pathogens that have breached the protective host barriers. It was originally defined as a liver-derived serum surveillance system that induces the opsonization and killing of invading microbes and amplifies the general inflammatory reactions. However, studies spanning the last four decades have established complement also as a vital bridge between innate and adaptive immunity. Furthermore, recent work on complement, and in particular its impact on human T helper 1 (Th1) responses, has led to the unexpected findings that the complement system also functions within cells and that it participates in the regulation of basic processes of the cell, including metabolism. These recent new insights into the unanticipated noncanonical activities of this ancient system suggest that the functions of complement extend well beyond mere host protection and into cellular physiology.
Molecular Aspects of Allergens and Allergy.
Valenta R, Karaulov A, Niederberger V … +16 more , Gattinger P, van Hage M, Flicker S, Linhart B, Campana R, Focke-Tejkl M, Curin M, Eckl-Dorna J, Lupinek C, Resch-Marat Y, Vrtala S, Mittermann I, Garib V, Khaitov M, Valent P, Pickl WF
Adv Immunol · 2018 · PMID 29731005 · Publisher ↗
Immunoglobulin E (IgE)-associated allergy is the most common immune disorder. More than 30% of the population suffer from symptoms of allergy which are often severe, disabling, and life threatening such as asthma and ana...
Immunoglobulin E (IgE)-associated allergy is the most common immune disorder. More than 30% of the population suffer from symptoms of allergy which are often severe, disabling, and life threatening such as asthma and anaphylaxis. Population-based birth cohort studies show that up to 60% of the world population exhibit IgE sensitization to allergens, of which most are protein antigens. Thirty years ago the first allergen-encoding cDNAs have been isolated. In the meantime, the structures of most of the allergens relevant for disease in humans have been solved. Here we provide an update regarding what has been learned through the use of defined allergen molecules (i.e., molecular allergology) and about mechanisms of allergic disease in humans. We focus on new insights gained regarding the process of sensitization to allergens, allergen-specific secondary immune responses, and mechanisms underlying allergic inflammation and discuss open questions. We then show how molecular forms of diagnosis and specific immunotherapy are currently revolutionizing diagnosis and treatment of allergic patients and how allergen-specific approaches may be used for the preventive eradication of allergy.
Eosinophil Development, Disease Involvement, and Therapeutic Suppression.
Fulkerson PC, Rothenberg ME
Adv Immunol · 2018 · PMID 29731004 · Publisher ↗
Human eosinophils have characteristic morphologic features, including a bilobed nucleus and cytoplasmic granules filled with cytotoxic and immunoregulatory proteins that are packaged in a specific manner. Eosinophil prod...
Human eosinophils have characteristic morphologic features, including a bilobed nucleus and cytoplasmic granules filled with cytotoxic and immunoregulatory proteins that are packaged in a specific manner. Eosinophil production in the bone marrow is exquisitely regulated by timely expression of a repertoire of transcription factors that work together via collaborative and hierarchical interactions to direct eosinophil development. In addition, proper granule formation, which occurs in a spatially organized manner, is an intrinsic checkpoint that must be passed for proper eosinophil production to occur. In eosinophil-associated disorders, eosinophils and their progenitors can be recruited in large numbers into tissues where they can induce proinflammatory organ damage in response to local signals. Eosinophils are terminally differentiated and do not proliferate once they leave the bone marrow. The cytokine IL-5 specifically enhances eosinophil production and, along with other mediators, promotes eosinophil activation. Indeed, eosinophil depletion with anti-IL-5 or anti-IL-5Rα is now proven to be clinically beneficial for several eosinophilic disorders, most notably severe asthma, and several therapeutics targeting eosinophil viability and production are now in development. Significant progress has been made in our understanding of eosinophil development and the consequences of tissue eosinophilia. Future research efforts focused on basic eosinophil immunobiology and translational efforts to assist in the diagnosis, treatment selection, and resolution of eosinophil-associated disorders will likely be informative and clinically helpful.
Caveolin-1: The Unnoticed Player in TCR and BCR Signaling.
Fiala GJ, Minguet S
Adv Immunol · 2018 · PMID 29455848 · Publisher ↗
T and B lymphocytes are key players of the adaptive immune system. They recognize pathogenic cues via the T cell antigen receptor (TCR) and the B cell antigen receptor (BCR) to get activated and execute their protective...
T and B lymphocytes are key players of the adaptive immune system. They recognize pathogenic cues via the T cell antigen receptor (TCR) and the B cell antigen receptor (BCR) to get activated and execute their protective function. TCR and BCR signaling are initiated at the plasma membrane and subsequently propagated into the cell, ultimately leading to cell activation and a protective immune response. However, inappropriate activation of T and B cells can be detrimental to the host resulting in autoimmune disorders, immunodeficiencies, and cancer. The TCR and BCR are located at the plasma membrane, which composition is highly heterogenic. Membrane compartmentalization based on specific lipid-lipid and protein-lipid interactions has raised the interest of the scientific community, converting the plasma membrane into an active player in the initiation of signaling and adding an additional layer of regulation to our current understanding of the functioning of antigen receptors. Caveolin-1 is an integral membrane protein and a crucial component of caveolae. It has been long thought that lymphocytes lack Caveolin-1 expression, due to the absence of detectable caveolae in lymphocytes and the failure to detect Caveolin-1 in T and B cell lines. However, Caveolin-1 is expressed at low levels in primary lymphocytes, and recent studies have shown the importance of Caveolin-1 for the basal membrane organization of the BCR and the TCR as well as their reorganization upon activation. Here, we review our current understanding of the initial signaling events of TCR and BCR activation with respect to receptor compartmentalization on the plasma membrane and with special emphasis on the previously unnoticed role of Caveolin-1.
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