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  • Prediction of cancer neoepitopes needs new rules
    Semin. Immunol. (IF 7.358) Pub Date : 2020-01-14
    Cory A. Brennick; Mariam M. George; Pramod K. Srivastava; Sukrut H. Karandikar

    Tumors are immunogenic and the non-synonymous point mutations harbored by tumors are a source of their immunogenicity. Immunologists have long been enamored by the idea of synthetic peptides corresponding to mutated epitopes (neoepitopes) as specific “vaccines” against tumors presenting those neoepitopes in context of MHC I. Tumors may harbor hundreds of point mutations and it would require effective prediction algorithms to identify candidate neoepitopes capable of eliciting potent tumor-specific CD8+ T cell responses. Our current understanding of MHC I-restricted epitopes come from the observance of CD8+ T cell responses against viral (vaccinia, lymphocytic choriomeningitis etc.) and model (chicken ovalbumin, hen egg lysozyme etc.) antigens. Measurable CD8+ T cell responses elicited by model or viral antigens are always directed against epitopes possessing strong binding affinity for the restricting MHC I alleles. Immense collective effort to develop methodologies combining genomic sequencing, bioinformatics and traditional immunological techniques to identify neoepitopes with strong binding affinity to MHC I has only yielded inaccurate prediction algorithms. Additionally, new evidence has emerged suggesting that neoepitopes, which unlike the epitopes of viral or model antigens have closely resembling wild-type counterparts, may not necessarily demonstrate strong affinity to MHC I. Our bearing need recalibration.

    更新日期:2020-01-15
  • MUCIN-4 (MUC4) is a novel tumor antigen in pancreatic cancer immunotherapy
    Semin. Immunol. (IF 7.358) Pub Date : 2020-01-14
    Shailendra K. Gautam; Sushil Kumar; Vi Dam; Dario Ghersi; Maneesh Jain; Surinder K. Batra

    Pancreatic cancer (PC) is a highly lethal malignancy with a dismal five-year survival rate. This is due to its asymptomatic nature, lack of reliable biomarkers, poor resectability, early metastasis, and high recurrence rate. Limited efficacies of current treatment modalities treatment-associated toxicity underscore the need for the development of immunotherapy-based approaches. For non-resectable, locally advanced metastatic PC, immunotherapy-based approaches including vaccines, antibody-targeted, immune checkpoint inhibition, CAR-T-cells, and adoptive T-cell transfer could be valuable additions to existing treatment modalities. Thus far, the vaccine candidates in PC have demonstrated modest immunological responses in different treatment modalities. The identification of tumor-associated antigens (TAA) and their successful implication in PC treatment is still a challenge. MUC4, a high molecular weight glycoprotein that functionally contributes to PC pathogenesis, is an attractive TAA. It is not detected in the normal pancreas; however, it is overexpressed in mouse and human pancreatic tumors. The recombinant MUC4 domain, as well as predicted immunogenic T-cell epitopes, elicited cellular and humoral anti-MUC4 response, suggesting its ulility as a vaccine candidate for PC therapy. Existence of PC-associated MUC4 splice variants, autoantibodies against overexpressed and aberrantly glycosylated MUC4 and presence of T-cell clones against the mutations present in MUC4 further reinforce its significance as a tumor antigen for vaccine development. Herein, we review the significance of MUC4 as a tumor antigen in PC immunotherapy and discuss both, the development and challenges associated with MUC4 based immunotherapy. Lastly, we will present our perspective on MUC4 antigenicity for the future development of MUC4-based PC immunotherapy.

    更新日期:2020-01-15
  • Post-translational modifications such as citrullination are excellent targets for cancer therapy
    Semin. Immunol. (IF 7.358) Pub Date : 2020-01-10
    V.A. Brentville; M. Vankemmelbeke; R.L. Metheringham; L.G. Durrant

    Under conditions of cellular stress, proteins can be post-translationally modified causing them to be recognized by the immune system. One such stress-induced post-translational modification (siPTM) is citrullination, the conversion of arginine residues to citrulline by peptidylarginine deiminase (PAD) enzymes. PAD enzymes are activated by millimolar concentrations of calcium which can occur during apoptosis, leading to precipitation of proteins, their subsequent uptake by B cells and stimulation of antibody responses. Detection of anti-citrullinated protein antibodies (ACPAs) is a diagnostic of rheumatoid arthritis (RA), where immune complexes stimulate inflammation around the joints. More recently, autophagy has been shown to play a role in the presentation of citrullinated peptides on MHC class II molecules to CD4+ helper T cells, suggesting that citrullination may be a way of alerting immune cells to cellular stress. Additionally, inflammation-induced IFNγ and concomitant MHC class II expression on target cells contributes to immune activation. Stressful conditions in the tumor microenvironment induce autophagy in cancer cells as a pro-survival mechanism. Cancer cells also over express PAD enzymes and in light of this the hypothesis that citrullinated peptides stimulate CD4+ T cell responses that would recognize these siPTM’s produced during autophagy has been investigated. The induction of potent citrullinated peptide-specific CD4 responses has been shown in both humans and HLA transgenic mouse models. Responses in mouse models resulted in potent anti-tumour responses against tumours expressing either constitutive or IFNγ-inducible MHC class II. The anti-tumour effect relied upon direct recognition of tumours by specific CD4 T cells suggesting that citrullinated peptides are attractive targets for cancer vaccines.

    更新日期:2020-01-11
  • Breast cancer stem cell antigens as targets for immunotherapy
    Semin. Immunol. (IF 7.358) Pub Date : 2020-01-10
    Elena Quaglino; Laura Conti; Federica Cavallo
    更新日期:2020-01-11
  • Tumor-associated O-glycans of MUC1: Carriers of the glyco-code and targets for cancer vaccine design
    Semin. Immunol. (IF 7.358) Pub Date : 2020-01-09
    Donella M. Beckwith; Maré Cudic

    The transformation from normal to malignant phenotype in human cancers is associated with aberrant cell-surface glycosylation. It has frequently been reported that MUC1, the heavily glycosylated cell-surface mucin, is altered in both, expression and glycosylation pattern, in human carcinomas of the epithelium. The presence of incomplete or truncated glycan structures, often capped by sialic acid, commonly known as tumor-associated carbohydrate antigens (TACAs), play a key role in tumor initiation, progression, and metastasis. Accumulating evidence suggests that expression of TACAs is associated with tumor escape from immune defenses. In this report, we will give an overview of the oncogenic functions of MUC1 that are exerted through TACA interactions with endogenous carbohydrate-binding proteins (lectins). These interactions often lead to creation of a pro-tumor microenvironment, favoring tumor progression and metastasis, and tumor evasion. In addition, we will describe current efforts in the design of cancer vaccines with special emphasis on synthetic MUC1 glycopeptide vaccines. Analysis of the key factors that govern structure-based design of immunogenic MUC1 glycopeptide epitopes are described. The role of TACA type, position, and density on observed humoral and cellular immune responses is evaluated.

    更新日期:2020-01-09
  • Primary immunoprevention of adult onset cancers by vaccinating against retired tissue-specific self-proteins
    Semin. Immunol. (IF 7.358) Pub Date : 2020-01-08
    Vincent K. Tuohy; Justin M. Johnson; Suparna Mazumder

    Despite the enormous success of childhood prophylactic vaccination against diseases caused by pathogens, there is currently no similar preventive vaccine program against diseases confronted with age like breast cancer and ovarian cancer. With the exception of the annual influenza vaccine, current recommendations for adult vaccination are for either primary vaccines not received during childhood or for booster vaccinations to maintain the immunity against pathogens already induced during childhood. Here we describe a strategy to provide prophylactic pre-emptive immunity against the development of adult onset cancers not associated with any definitive etiopathogenic agent. We propose that safe and effective pre-emptive immunity may be induced in cancer-free subjects by vaccination against immunodominant tissue-specific self-proteins that are ‘retired’ from expression in normal tissues as part of the normal aging process but are expressed in tumors that emerge with age. Primary immunoprevention of adult onset cancers like breast cancer and ovarian cancer represents a great challenge and an even greater unmet need for our current healthcare.

    更新日期:2020-01-09
  • Regulation of the complement system and immunological tolerance in pregnancy
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-19
    Laura Teirilä, Jenni Heikkinen-Eloranta, Juha Kotimaa, Seppo Meri, A. Inkeri Lokki
    更新日期:2019-11-19
  • Regulation of regulators: Role of the complement factor H-related proteins
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-19
    Marcell Cserhalmi, Alexandra Papp, Bianca Brandus, Barbara Uzonyi, Mihály Józsi

    The complement system, while being an essential and very efficient effector component of innate immunity, may cause damage to the host and result in various inflammatory, autoimmune and infectious diseases or cancer, when it is improperly activated or regulated. Factor H is a serum glycoprotein and the main regulator of the activity of the alternative complement pathway. Factor H, together with its splice variant factor H-like protein 1 (FHL-1), inhibits complement activation at the level of the central complement component C3 and beyond. In humans, there are also five factor H-related (FHR) proteins, whose function is poorly characterized. While data indicate complement inhibiting activity for some of the FHRs, there is increasing evidence that FHRs have an opposite role compared with factor H and FHL-1, namely, they enhance complement activation directly and also by competing with the regulators FH and FHL-1. This review summarizes the current stand and recent data on the roles of factor H family proteins in health and disease, with focus on the function of FHR proteins.

    更新日期:2019-11-19
  • The C1q Receptors: Focus on gC1qR/p33 (C1qBP, p32, HABP-1)1
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-16
    Berhane Ghebrehiwet, Brian V. Geisbrecht, Xin Xu, Anne G. Savitt, Ellinor I.B. Peerschke

    In the past several years, a number of C1q binding surface proteins or receptors have been described. This is not of course surprising considering the complexity of the C1q molecule and its ability to bind to a wide range of cellular and plasma proteins via both its collagen-like [cC1q] region and its heterotrimeric globular heads [gC1q] each of which in turn is capable of binding a specific ligand. However, while each of these “receptor” molecules undoubtedly plays a specific function within its restricted microenvironment, and therefore merits full attention, this review nonetheless, will singularly focus on the structure and function of gC1qR–a multi-functional and multi-compartmental protein, which plays an important role in inflammation, infection, and cancer. Although first identified as a receptor for C1q, gC1qR has been shown to bind to a plethora of proteins found in plasma, on the cell surface and on pathogenic microorganisms. The plasma proteins that bind to gC1qR are mostly blood coagulation proteins and include high molecular weight kininogen [HK], Factor XII [Hageman factor], fibrinogen, thrombin [FII], and multimeric vitronectin. This suggests that gC1qR can play an important role in modulating not only of fibrin formation, particularly at local sites of immune injury and/or inflammation, but by activating the kinin/kallikrein system, it is also able to generate, bradykinin, a powerful vasoactive peptide that is largely responsible for the swelling seen in angioedema. Another important function of gC1qR is in cancer, where it has been shown to play a role in tumor cell survival, growth and metastatic invasion by interacting with critical molecules in the tumor cell microenvironment including those of the complement system and kinin system. Finally, by virtue of its ability to interact with a growing list of pathogen-associated molecules, including bacterial and viral ligands, gC1qR is becoming recognized as an important pathogen recognition receptor [PRR]. Given the numerous roles it plays in a growing list of disease settings, gC1qR has now become a potential target for the development of monoclonal antibody-based and/or small molecule-based therapies.

    更新日期:2019-11-18
  • Immune induction of airway remodeling
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-14
    Giuseppe Guida, Anna Maria Riccio

    Airway remodeling is accepted to be a determining component within the natural history of asthma. It is a phenomenon characterized by changes in the airways structures that marches in parallel with and can be influenced by airway inflammation, floating at the interface between both natural and adaptive immunity and physical and mechanical cells behavior. In this review we aimed to highlight the comprehensive, yet not exhaustive, evidences of how immune cells induce, regulate and adapt to the recognized markers of airway remodeling. Mucous cell hyperplasia, epithelial dysfunction and mesenchymal transition, extracellular matrix protein synthesis and restructuration, fibroblast to myofibroblast transition, airway smooth muscle proliferation, bioactive and contractile properties, and vascular remodeling encompass complex physiopathological mechanisms that can be induced, suppressed or regulated by different cellular and molecular pathways. Growth factors, cytokines, chemokines and adhesion molecules expressed or derived either from the immune network of cells infiltrating the asthmatic airways and involving T helper lymphocytes, immune lymphoid cells, dendritic cells, eosinophils, neutrophils, mast cells or by the structural components such as epithelial cells, fibroblasts, myocytes, airway smooth muscle cells concur with protein cellular matrix component and metalloproteases in modifying the airway structure in a detrimental way. The consequences in lung function decline, fixed airway obstruction and clinical severity of the disease suggest the possibility of identify among the immune molecular pathway of remodeling some biological parameters or signal pathway to be either a good tracer for monitoring the disease evolution or a target for hypothetical phenotypes and endotypes. In the era of personalized medicine, a biomarker of remodeling might predict a response to small-molecule inhibitors or biologicals potentially targeting a fundamental aspect of asthma pathogenesis that impacts on the low responsiveness to airway inflammation directed treatments.

    更新日期:2019-11-18
  • Severe asthma phenotypes and endotypes
    Semin. Immunol. (IF 7.358) Pub Date : 2019-08-27
    Ioana Agache

    Current management of severe asthma relying either on guidelines (bulk approach) or on disease phenotypes (stratified approach) did not improve the burden of the disease. Several severe phenotypes are described: clinical, functional, morphological, inflammatory, molecular and microbiome-related. However, phenotypes do not necessarily relate to or give insights into the underlying pathogenetic mechanisms which are described by the disease endotypes. Based on the major immune-inflammatory pathway involved type-2 high, type-2 low and mixed endotypes are described for severe asthma, with several shared pathogenetic pathways such as genetic and epigenetic, metabolic, neurogenic and remodelling subtypes. The concept of multidimensional endotyping as un unbiased approach to severe asthma is discussed, together with new tools and targets facilitating the shift from the stratified to the precision medicine approach.

    更新日期:2019-11-18
  • Senescent cell clearance by the immune system: Emerging therapeutic opportunities
    Semin. Immunol. (IF 7.358) Pub Date : 2019-05-11
    Larissa G.P. Langhi Prata, Inna G. Ovsyannikova, Tamara Tchkonia, James L. Kirkland

    Senescent cells (SCs) arise from normal cells in multiple organs due to inflammatory, metabolic, DNA damage, or tissue damage signals. SCs are non-proliferating but metabolically active cells that can secrete a range of pro-inflammatory and proteolytic factors as part of the senescence-associated secretory phenotype (SASP). Senescent cell anti-apoptotic pathways (SCAPs) protect SCs from their own pro-apoptotic SASP. SCs can chemo-attract immune cells and are usually cleared by these immune cells. During aging and in multiple chronic diseases, SCs can accumulate in dysfunctional tissues. SCs can impede innate and adaptive immune responses. Whether immune system loss of capacity to clear SCs promotes immune system dysfunction, or conversely whether immune dysfunction permits SC accumulation, are important issues that are not yet fully resolved. SCs may be able to assume distinct states that interact differentially with immune cells, thereby promoting or inhibiting SC clearance, establishing a chronically pro-senescent and pro-inflammatory environment, leading to modulation of the SASP by the immune cells recruited and activated by the SASP. Therapies that enhance immune cell-mediated clearance of SCs could provide a lever for reducing SC burden. Such therapies could include vaccines, small molecule immunomodulators, or other approaches. Senolytics, drugs that selectively eliminate SCs by transiently disabling their SCAPs, may prove to alleviate immune dysfunction in older individuals and thereby accelerate immune-mediated clearance of SCs. The more that can be understood about the interplay between SCs and the immune system, the faster new interventions may be developed to delay, prevent, or treat age-related dysfunction and the multiple senescence-associated chronic diseases and disorders.

    更新日期:2019-11-18
  • IL-10 producing regulatory and helper T-cells in systemic lupus erythematosus
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-15
    J. Geginat, M. Vasco, M. Gerosa, S.W. Tas, M. Pagani, F. Grassi, R.A. Flavell, Pl. Meroni, S. Abrignani

    Systemic lupus erythematosus (SLE) is a highly heterogeneous autoimmune disease characterised by the production of pathogenic autoantibodies against nuclear self-antigens. The anti-inflammatory and tolerogenic cytokine Interleukin-10 appears to play a paradoxical pathogenic role in SLE and is therefore currently therapeutically targeted in clinical trials. It is generally assumed that the pathogenic effect of IL-10 in SLE is due to its growth and differentiation factor activity on autoreactive B-cells, but effects on other cells might also play a role. To date, a unique cellular source of pathogenic IL-10 in SLE has not been identified. In this review, we focus on the contribution of different CD4+T-cell subsets to IL-10 and autoantibody production in SLE. In particular, we discuss that IL-10 produced by different subsets of adaptive regulatory T-cells, follicular helper T-cells and extra-follicular B-helper T-cells is likely to have different effects on autoreactive B-cell responses. A better understanding of the role of IL-10 in B-cell responses and lupus would allow to identify the most promising therapies for individual SLE patients in the future.

    更新日期:2019-11-15
  • PROPERTIES AND FUNCTIONS OF THE NOVEL TYPE I INTERFERON EPSILON
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-14
    Zoe R.C. Marks, Nicole Campbell, Nicole A. deWeerd, San S. Lim, Linden J. Gearing, Nollaig M. Bourke, Paul J. Hertzog

    Interferon epsilon (IFNε) is a type I IFN with unusual patterns of expression and therefore, function. It is constitutively expressed by reproductive tract epithelium and regulated by hormones during estrus cycle, reproduction, and menopause and by exogenous hormones. The IFNe protein is encoded by a gene in the type I IFN locus, binds to IFNAR1 and 2 which are required for signaling via the JAK STAT pathway. Its affinity for binding receptors and transducing signals is less potent than IFNα or β subtypes in vitro. Nevertheless, in vivo experiments indicate its efficacy in regulating mucosal immune responses and protecting from bacterial and viral infections. These studies demonstrate a different mechanism of action to type I IFNs. In this organ system with dynamic fluxes in cellularity, requirement to tolerate an implanted fetus, and be protected from disease, there is co-option of a special IFN from a family of effective immunoregulators, with unique controls and modified potency to make it a safe and effective constitutive reproductive tract cytokine.

    更新日期:2019-11-14
  • Title: IL-10-producing T cells and their dual functions
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-14
    Tanja Bedke, Franziska Muscate, Shiwa Soukou, Nicola Gagliani, Samuel Huber

    Interleukin (IL)-10 is considered a prototypical anti-inflammatory cytokine, which significantly contributes to the maintenance and reestablishment of immune homeostasis. However, this classical view fails to fully describe the pleiotropic roles of IL-10. Indeed, IL-10 can also promote immune responses, e.g. by supporting B-cell and CD8+ T-cell activation. The reasons for these seemingly opposing functions are unclear to a large extent. Recent and previous studies suggest that the cellular source and the microenvironment impact the function of IL-10. However, studies addressing the mechanisms which determine whether IL-10 promotes inflammation or controls it have just begun. This review first summarizes the recent findings on the heterogeneity of IL-10 producing T cells and their impact on the target cells. Finally, we will propose two possible explanations for the dual functions of IL-10.

    更新日期:2019-11-14
  • Immunological biomarkers in severe asthma
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-14
    Dharani Narendra, John Blixt, Nicola A. Hanania

    Severe asthma is heterogeneous in its clinical presentation, underlying pathophysiology, course and response to therapy. Clinical and physiological assessment of severe asthma is often inadequate in predicting underlying disease mechanisms and or response to medications. With the emergence of novel targeted therapies in severe asthma, the need for reproducible, easily measured biomarkers became obvious but only few are currently available for clinical use. These biomarkers along with the clinical presentation of the patient play an important role in identifying phenotypes and endotypes, predicting the clinical course and prognosis and improving the precision therapeutic approach to asthma.

    更新日期:2019-11-14
  • Functions and regulation of T cell-derived interleukin-10
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-12
    Christian Neumann, Alexander Scheffold, Sascha Rutz

    Interleukin (IL)-10 is an essential anti-inflammatory cytokine and functions as a negative regulator of immune responses to microbial antigens. IL-10 is particularly important in maintaining the intestinal microbe-immune homeostasis. Loss of IL-10 promotes the development of inflammatory bowel disease (IBD) as a consequence of an excessive immune response to the gut microbiota. IL-10 also functions more generally to prevent excessive inflammation during the course of infection. Although IL-10 can be produced by virtually all cells of the innate and adaptive immune system, T cells constitute a non-redundant source for IL-10 in many cases. The various roles of T cell-derived IL-10 will be discussed in this review. Given that IL-10 is at the center of maintaining the delicate balance between effective immunity and tissue protection, it is not surprising that IL-10 expression is highly dynamic and tightly regulated. We summarize the environmental signals and molecular pathways that regulate IL-10 expression. While numerous studies have provided us with a deep understanding of IL-10 biology, the majority of findings have been made in murine models, prompting us to highlight gaps in our knowledge about T cell-derived IL-10 in the human system.

    更新日期:2019-11-13
  • Complement dysregulation in glomerulonephritis
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-09
    Kati Kaartinen, Adrian Safa, Soumya Kotha, Giorgio Ratti, Seppo Meri

    Glomerulonephritis (GN) refers to a group of renal diseases affecting the glomeruli due to the damage mediated by immunological mechanisms. A large proportion of the disease manifestations are caused by disturbances in the complement system. They can be due to genetic errors, autoimmunity, microbes or abnormal immunoglobulins, like modified IgA or paraproteins. The common denominator in most of the problems is an overactive or misdirected alternative pathway complement activation. An assessment of kidney function, amount of proteinuria and hematuria are crucial elements to evaluate, when glomerulonephritis is suspected. However, the cornerstones of the diagnoses are renal biopsy and careful examination of the complement abnormality. Differential diagnostics between the various forms of GN is not possible based on clinical features, as they may vary greatly. This review describes the known mechanisms of complement dysfunction leading to different forms of primary GN (like IgA glomerulonephritis, dense deposit disease, C3 glomerulonephritis, post-infectious GN, membranous GN) and differences to atypical hemolytic uremic syndrome. It also covers the basic elements of etiology-directed therapy and prognosis of the most common forms of GN. Common principles in the management of GN include treatment of hypertension and reduction of proteinuria, some require immunomodulating treatment. Complement inhibition is an emerging treatment option. A thorough understanding of the basic disease mechanism and a careful follow-up are needed for optimal therapy.

    更新日期:2019-11-11
  • Complement activation and regulation in rheumatic disease
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-09
    Douwe J. Dijkstra, Jivan V. Joeloemsingh, Ingeborg M. Bajema, Leendert A. Trouw

    Complement is a key component of the innate immune defence and in addition forms a bridge to the adaptive immune responses. As such complement is of vital importance for efficient protection against infections. However, the activity of the complement system can also aberrantly be directed against the tissues of the body itself and contribute to organ damage in a variety of diseases. In several rheumatic diseases complement activation is suggested to play a pronounced role. This review will highlight the role of both complement activation and complement regulation in rheumatic disease. A contribution of complement to the disease process is often suggested based on the presence of complement activation fragments in the target tissues or the presence of complement activation fragments in the circulation. The role that complement plays in different rheumatic diseases is often unknown but is thought to contribute to tissue damage as a consequence of autoantibody mediated immune complex formation and deposition. In addition reduced complement inhibition mediated by endogenous complement regulators can also enhance complement activity and tissue damage. In observational studies, it is difficult to distinguish whether complement activation is a result of enhanced activation or decreased regulation. Until recently, strong conclusions on the relative importance of complement activation to the pathology were largely restricted to animal experiments. Usage of complement targeting therapeutics in humans will hopefully give us the opportunity to study the actual contribution of complement activation towards disease progression and tissue damage in rheumatic disease into more detail.

    更新日期:2019-11-11
  • Il-10 producing T and B cells in allergy
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-08
    Tadech Boonpiyathad, Pattraporn Satitsuksanoa, Mübeccel Akdis, Cezmi A. Akdis

    The molecular and cellular mechanisms of allergen tolerance in humans have been intensively studied in the past few decades. The demonstration of epitope-specific T cell tolerance, particularly mediated by the immune suppressor functions of IL-10 led to a major conceptual change in this area more than 20 years ago. Currently, the known essential components of allergen tolerance include the induction of allergen-specific regulatory of T and B cells, the immune suppressive function of secreted factors, such as IL-10, IL-35, IL-1 receptor antagonist and TGF-β, immune suppressive functions of surface molecules such as CTLA-4 and PD-1, the production IgG4 isotype allergen-specific blocking antibodies, and decreased allergic inflammatory responses by mast cells, basophils, and eosinophils in inflamed tissues. In this review, we explain the importance of the role of IL-10 in allergen tolerance.

    更新日期:2019-11-08
  • Allergen immunotherapy (AIT) in asthma
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-08
    J. Christian Virchow

    Bronchial asthma remains one of the most common chronic diseases with a high degree of morbidity and still a considerable mortality with an increasing prevalence in many countries. Although remarkable progress has been made in the past decades in the medical treatment for asthma, curative or disease modifying approaches are still limited to allergen immunotherapy (AIT). Despite a plethora of potential immunological actions observed during AIT, the precise mechamisms that might exert beneficial effects especially in asthma remain unclear. Clinical studies in the past have suggested clinical benefits in symptom control and medication use with a small reduction in allergen-specific and non-specific bronchial hyperresponsiveness but these results were mainly derived from small, frequently suboptimally designed studies which were poorly comparable. Only recently have larger, dose ranging studies with well standardized allergens with patient relevant endpoints such as corticosteroid requirements for asthma control or the onset of exacerbations following inhaled corticosteroid (ICS) withdrawal corroborated the potential clinical effects of AIT in asthma, suggesting that it might replace some of the controller effects of ICS. In addition, newer, up-do-date designed studies support previous data that in patient populations at risk to develop asthma AIT might have a role in secondary prevention. Further studies on the long term effects as well as comparative studies are needed to further corroborate the role of AIT in the prevention and the control of asthma are needed.

    更新日期:2019-11-08
  • Complement dysregulation in the central nervous system during development and disease
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-07
    John D. Lee, Liam G. Coulthard, Trent M. Woodruff

    The complement cascade is an important arm of the immune system that plays a key role in protecting the central nervous system (CNS) from infection. Recently, it has also become clear that complement proteins have fundamental roles in the developing and aging CNS that are distinct from their roles in immunity. During neurodevelopment, complement signalling is involved in diverse processes including neural tube closure, neural progenitor proliferation and differentiation, neuronal migration, and synaptic pruning. In acute neurotrauma and ischamic brain injury, complement drives inflammation and neuronal death, but also neuroprotection and regeneration. In diseases of the aging CNS including dementias and motor neuron disease, chronic complement activation is associated with glial activation, and synapse and neuron loss. Proper regulation of complement is thus essential to allow for an appropriately developed CNS and prevention of excessive damage following neurotrauma or during neurodegeneration. This review provides a comprehensive overview of the evidence for functional roles of complement in brain formation, and its dysregulation during acute and chronic disease. We also provide working models for how complement can lead to neurodevelopmental disorders such as schizophrenia and autism, and either protect, or propagate neurodegenerative diseases including Alzheimer’s disease and amyotrophic lateral sclerosis.

    更新日期:2019-11-07
  • Immune regulation and cytotoxic T cell activation of IL-10 agonists – Preclinical and clinical experience
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-06
    Martin Oft

    The expansion and activation of tumor antigen reactive CD8+ T cells are primary goals of immunotherapies for cancer. IL-10 is an anti-inflammatory cytokine with an essential role in the development and proliferation of regulatory T cells, restricting myeloid and chronic inflammatory T cell responses. However, IL-10 is also essential for the expansion of antigen activated, tumor specific CD8+ T cells, leading to spontaneous tumor development in IL-10 deficient patients and mice. IL-10 induces IFNγ and cytotoxic mediators in antigen activated T cells. In clinical trials, monotherapy with recombinant, pegylated IL-10 (Pegilodecakin) induced objective responses in cancer patients. Patients receiving pegilodecakin had a systemic increase of IFNγ and granzymes, proliferation and expansion of immune checkpoint positive CD8+ T cells. Combination of pegilodecakin with anti-PD-1 appeared to improve on the efficacy of the single agents.

    更新日期:2019-11-07
  • Immunologic mechanisms in asthma
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-06
    Tadech Boonpiyathad, Zeynep Celebi Sözener, Pattraporn Satitsuksanoa, Cezmi A. Akdis

    Asthma is a chronic airway disease, which affects more than 300 million people. The pathogenesis of asthma exhibits marked heterogeneity with many phenotypes defining visible characteristics and endotypes defining molecular mechanisms. With the evolution of novel biological therapies, patients, who do not-respond to conventional asthma therapy require novel biologic medications, such as anti-IgE, anti-IL-5 and anti-IL4/IL13 to control asthma symptoms. It is increasingly important for physicians to understand immunopathology of asthma and to characterize asthma phenotypes. Asthma is associated with immune system activation, airway hyperresponsiveness (AHR), epithelial cell activation, mucus overproduction and airway remodeling. Both innate and adaptive immunity play roles in immunologic mechanisms of asthma. Type 2 asthma with eosinophilia is a common phenotype in asthma. It occurs with and without visible allergy. The type 2 endotype comprises; T helper type 2 (Th2) cells, type 2 innate lymphoid cells (ILC2), IgE-secreting B cells and eosinophils. Eosinophilic nonallergic asthma is ILC2 predominated, which produces IL-5 to recruit eosinophil into the mucosal airway. The second major subgroup of asthma is non-type 2 asthma, which contains heterogeneous group of endoypes and phenotypes, such as exercise-induced asthma, obesity induced asthma, etc. Neutrophilic asthma is not induced by allergens but can be induced by infections, cigarette smoke and pollution. IL-17 which is produced by Th17 cells and type 3 ILCs, can stimulate neutrophilic airway inflammation. Macrophages, dendritic cells and NKT cells are all capable of producing cytokines that are known to contribute in allergic and nonallergic asthma. Bronchial epithelial cell activation and release of cytokines, such as IL-33, IL-25 and TSLP play a major role in asthma. Especially, allergens or environmental exposure to toxic agents, such as pollutants, diesel exhaust, detergents may affect the epithelial barrier leading to asthma development. In this review, we focus on the immunologic mechanism of heterogenous asthma phenotypes.

    更新日期:2019-11-06
  • IL-10-producing regulatory B cells and plasmocytes: Molecular mechanisms and disease relevance
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-01
    Catia Cerqueira, Benoît Manfroi, Simon Fillatreau

    It has long been assumed that the functions of B cells reflected the roles of antibodies. However, B cells also decisively influence immunity via antibody-independent mechanisms including the presentation of antigen to T cells and the secretion of cytokines. In fact, B cell depletion therapy improves the course of autoimmune diseases such as multiple sclerosis by removing pro-inflammatory cytokine-producing B cells rather than by reducing autoantibody levels. Remarkably, B cells can also produce anti-inflammatory cytokines, and subsequently suppress immunity, providing protection from autoimmune diseases while interfering with beneficial responses against pathogens and cancers. A major mediator of this B cell regulatory function is their secretion of IL-10. There is considerable interest in identifying the mechanisms inducing the expression of IL-10 in B cells during the course of their activation. Here, we review the molecular mechanisms controlling IL-10 expression in B cells, and the evidence that IL-10-producing B cells play a protective role in human autoimmune diseases, underlying the relevance of this immunosuppressive axis for therapy.

    更新日期:2019-11-01
  • Epigenetic and transcriptional mechanisms for the regulation of IL-10
    Semin. Immunol. (IF 7.358) Pub Date : 2019-10-30
    Huiyuan Zhang, Vijay Kuchroo

    IL-10 is a critical immunoregulatory cytokine expressed in virtually all immune cell types. Maintaining a delicate balance between effective immune response and tolerance requires meticulous and dynamic control of IL-10 expression both epigenetically and transcriptionally. In this Review, we describe the epigenetic mechanisms controlling IL-10 expression, including chromatin remodeling, 3D chromatin loops, histone modification and DNA methylation. We discuss the role of transcription factors in directing chromatin modifications, with a special highlight on the emerging concept of pioneer transcription factors in setting up the chromatin landscape in T helper cells for IL-10 induction. Besides summarizing the recent progress on transcriptional regulation in specialized IL-10 producers such as type 1 regulatory T cells, regulatory B cells and regulatory innate lymphoid cells, we also discuss common transcriptional mechanisms for IL-10 regulation that are shared with other IL-10 producing cells.

    更新日期:2019-11-01
  • Editorial to the ASTHMA Issue.
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-18
    Giorgio Walter Canonica

    更新日期:2019-11-01
  • Too much of a good thing: Detrimental effects of interferon.
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-28
    Nancy C Reich

    Healthy tissues of the body express relatively low basal levels of interferons. However, following detection of microbial invasion by sentinel receptors, a cascade of events initiates leading to the transcriptional induction of interferon genes. Interferons are secreted and act primarily as paracrine cytokines to bind neighboring cell surface receptors. Binding to interferon receptors activates a signal pathway to the nucleus inducing a set of interferon-stimulated genes. The biological activity of these genes confers the unique antiviral and innate immune response of interferons. The rapid induction of interferons is critical to survival, and equally critical is the recovery from this defensive state. Either an aberrant response to infection or an inherited genetic disorder that leads to sustained or increased interferon levels can tip the balance towards pathogenesis.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Interferon signaling in cancer. Non-canonical pathways and control of intracellular immune checkpoints.
    Semin. Immunol. (IF 7.358) Pub Date : null
    Diana Saleiro,Leonidas C Platanias

    The interferons (IFNs) are cytokines with important antineoplastic and immune modulatory effects. These cytokines have been conserved through evolution as important elements of the immune surveillance against cancer. Despite this, defining their precise and specific roles in the generation of antitumor responses remains challenging. Emerging evidence suggests the existence of previously unknown roles for IFNs in the control of the immune response against cancer that may redefine our understanding on how these cytokines function. Beyond the engagement of classical JAK-STAT signaling pathways that promote transcription and expression of gene products, the IFNs engage multiple other signaling cascades to generate products that mediate biological responses and outcomes. There is recent emerging evidence indicating that IFNs control the expression of both traditional immune checkpoints like the PD-L1/PD1 axis, but also less well understood "intracellular" immune checkpoints whose targeting may define new approaches for the treatment of malignancies.

    更新日期:2019-11-01
  • Type III IFNs: Beyond antiviral protection.
    Semin. Immunol. (IF 7.358) Pub Date : null
    Sergei V Kotenko,Amariliz Rivera,Dane Parker,Joan E Durbin

    The unexpected discovery of a novel family of antiviral mediators, type III IFNs or IFN-λs, challenged the widely accepted primacy of type I IFNs in antiviral immunity, and it is now well recognized that the IFN-λ-based antiviral system plays a major role in antiviral protection of epithelial barriers. The recent characterization of previously unknown IFN-λ-mediated activities has prompted further reassessment of the role of type I IFNs in innate and adaptive immune and inflammatory responses. Since type I and type III IFNs are co-produced in response to a variety of stimuli, it is likely that many physiological processes are simultaneously and coordinately regulated by these cytokines in pathological conditions, and likely at steady state, as baseline expression of both IFN types is maintained by microbiota. In this review, we discuss emerging differences in the production and signaling of type I and type III IFNs, and summarize results of recent studies describing the involvement of type III IFNs in anti-bacterial and anti-fungal, as well as antiviral, defenses.

    更新日期:2019-11-01
  • Global virus outbreaks: Interferons as 1st responders.
    Semin. Immunol. (IF 7.358) Pub Date : null
    Ben X Wang,Eleanor N Fish

    Outbreaks of severe virus infections with the potential to cause global pandemics are increasing. In many instances these outbreaks have been newly emerging (SARS coronavirus), re-emerging (Ebola virus, Zika virus) or zoonotic (avian influenza H5N1) virus infections. In the absence of a targeted vaccine or a pathogen-specific antiviral, broad-spectrum antivirals would function to limit virus spread. Given the direct antiviral effects of type I interferons (IFNs) in inhibiting the replication of both DNA and RNA viruses at different stages of their replicative cycles, and the effects of type I IFNs on activating immune cell populations to clear virus infections, IFNs-α/β present as ideal candidate broad-spectrum antivirals.

    更新日期:2019-11-01
  • Introduction to special issue on interferons.
    Semin. Immunol. (IF 7.358) Pub Date : 2019-11-02
    Eleanor Fish

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Advances in T-cell co-receptor biology and cancer immunotherapy.
    Semin. Immunol. (IF 7.358) Pub Date : 2019-10-13
    Christopher E Rudd

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • AIDing antibody diversity by error-prone mismatch repair.
    Semin. Immunol. (IF 7.358) Pub Date : 2012-06-19
    Richard Chahwan,Winfried Edelmann,Matthew D Scharff,Sergio Roa

    The creation of a highly diverse antibody repertoire requires the synergistic activity of a DNA mutator, known as activation-induced deaminase (AID), coupled with an error-prone repair process that recognizes the DNA mismatch catalyzed by AID. Instead of facilitating the canonical error-free response, which generally occurs throughout the genome, DNA mismatch repair (MMR) participates in an error-prone repair mode that promotes A:T mutagenesis and double-strand breaks at the immunoglobulin (Ig) genes. As such, MMR is capable of compounding the mutation frequency of AID activity as well as broadening the spectrum of base mutations; thereby increasing the efficiency of antibody maturation. We here review the current understanding of this MMR-mediated process and describe how the MMR signaling cascade downstream of AID diverges in a locus dependent manner and even within the Ig locus itself to differentially promote somatic hypermutation (SHM) and class switch recombination (CSR) in B cells.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • A systems approach to dissecting immunity and inflammation.
    Semin. Immunol. (IF 7.358) Pub Date : 2004-01-31
    Alan Aderem,Kelly D Smith

    The immune and inflammatory responses are extraordinarily complex, involving the dynamic interaction of a wide array of tissues, cells, and molecules. Traditional approaches are by and large reductionist, shying away from complexity, but providing detailed knowledge of circumscribed physiologic, cellular and molecular entities. The sequencing of the human genome, in concert with emerging genomic and proteomic technologies permits the definition of a complete and dynamic parts list of the immune and inflammatory systems. When harnessed with powerful new computational approaches, this will for the first time provide a comprehensive description of these complex biological processes.

    更新日期:2019-11-01
  • Sensing infection in Drosophila: Toll and beyond.
    Semin. Immunol. (IF 7.358) Pub Date : 2004-01-31
    Dominique Ferrandon,Jean-Luc Imler,Jules A Hoffmann

    Drosophila has evolved a potent immune system that is somewhat adapted to the nature of infections through the selective activation of either one of two NF-kappa B-like signalling pathways, the Toll and IMD (Immune deficiency) pathways. In contrast to the mammalian system, the Toll receptor does not act as a pattern recognition receptor (PRR) but as a cytokine receptor. The sensing of microbial infections is achieved by at least four PRRs that belong to two distinct families: the peptidoglycan recognition proteins (PGRPs) and the Gram-negative binding proteins (GNBPs)/beta-glucan recognition proteins (beta GRPs).

    更新日期:2019-11-01
  • The role of Toll-like receptors in combating mycobacteria.
    Semin. Immunol. (IF 7.358) Pub Date : 2004-01-31
    Stephan R Krutzik,Robert L Modlin

    In the battle against infections with mycobacteria, the body employs components of both the innate and adaptive arms of the immune system. Toll-like receptors (TLRs) mediate the activation of cells of the innate immune system leading to dynamic functions including direct anti-microbial activity, induction of cytokine secretion, triggering dendritic cell maturation, and triggering apoptosis. Furthermore, TLR activation is capable of modulating the adaptive immune response with a bias towards a Th1 T-cell response. However, the activation of TLRs by mycobacteria may also provide a means of immune evasion. Therefore, the modulation of TLR activation can influence the ability to properly destroy invading pathogens such as mycobacteria.

    更新日期:2019-11-01
  • Toll-like receptors and dendritic cells: for whom the bug tolls.
    Semin. Immunol. (IF 7.358) Pub Date : 2004-01-31
    Caetano Reis e Sousa

    Recognition of molecular signatures of potential pathogens via toll-like receptors (TLRs) activates dendritic cells (DC), leading to the initiation of adaptive immunity. TLR signalling in DC causes an increase in display of MHC peptide ligands for T cell recognition, upregulation of co-stimulatory molecules important for T cell clonal expansion and secretion of immunomodulatory cytokines, which direct T cell differentiation into effectors. Remarkably, ligation of distinct TLRs can trigger differential cytokine production in a single DC type or result in different cytokines in distinct DC sub-types. Studying the complexity of DC responses to TLR ligands illuminates the link between innate recognition and adaptive immunity, paving the way for improved vaccines and strategies to induce tolerance to autoantigens or allografts.

    更新日期:2019-11-01
  • Toll-like receptors and acquired immunity.
    Semin. Immunol. (IF 7.358) Pub Date : 2004-01-31
    Chandrashekhar Pasare,Ruslan Medzhitov

    Toll-like receptors are a family of pattern recognition receptors (PRRs) that evolved to detect microbial infection. These receptors recognize conserved molecular products derived from different classes of microorganisms, including Gram-positive and -negative bacteria, fungi, protozoa and viruses. Following recognition of ligands TLRs initiate signaling events that result in acute innate responses. In addition, TLRs are responsible for initiation of adaptive immune responses against pathogen-derived antigens primarily through triggering dendritic cell activation. Control of adaptive immunity by TLRs is a complex phenomenon and much needs to be understood about how different TLRs tailor the outcome of adaptive immune responses to the advantage of the host. Although TLRs have evolved to induce protective immune responses, under some circumstances, activation of these receptors may lead to autoimmune diseases.

    更新日期:2019-11-01
  • Signal transduction pathways mediated by the interaction of CpG DNA with Toll-like receptor 9.
    Semin. Immunol. (IF 7.358) Pub Date : 2004-01-31
    Fumihiko Takeshita,Ihsan Gursel,Ken J Ishii,Koichi Suzuki,Mayda Gursel,Dennis M Klinman

    Synthetic oligodeoxynucleotides (ODN) expressing non-methylated "CpG motifs" patterned after those present in bacterial DNA have characteristic immunomodulatory effects. CpG DNA is recognized as a pathogen-associated molecular pattern, and triggers a rapid innate immune response. CpG ODN are being harnessed for a variety of therapeutic uses, including as immune adjuvants, for cancer therapy, as anti-allergens, and as immunoprotective agents. The signal transduction pathway mediated by the engagement of CpG DNA with Toll-like receptor 9 (TLR9) is shared with other members of the TLR family. Recent studies demonstrate that formation and maturation of CpG DNA-containing endosomes are regulated by phosphatidylinositol 3 kinases and the Ras-associated GTP-binding protein, Rab5, which are essential for the initiation of TLR9-mediated signaling.

    更新日期:2019-11-01
  • Endotoxin recognition molecules, Toll-like receptor 4-MD-2.
    Semin. Immunol. (IF 7.358) Pub Date : 2004-01-31
    Kensuke Miyake

    Toll-like receptors (TLRs) are innate pathogen recognition molecules for microbial products. Lipopolysaccharide (LPS), a membrane constituent of Gram-negative bacteria, is one of the most potent microbial products. LPS is recognized by TLR4 and MD-2. TLR4 is a transmembrane protein, the extracellular domain of which is composed of a protein motif called leucine-rich repeats (LRR). MD-2 is an extracellular molecule that is associated with the extracellular LRR of TLR4. MD-2 has a role in cell surface expression of TLR4 and interaction with LPS. TLR4-MD-2 contributes to containment of infections by Gram-negative bacteria by activating immune responses.

    更新日期:2019-11-01
  • TLR signaling pathways.
    Semin. Immunol. (IF 7.358) Pub Date : 2004-01-31
    Kiyoshi Takeda,Shizuo Akira

    Toll-like receptors (TLRs) have been established to play an essential role in the activation of innate immunity by recognizing specific patterns of microbial components. TLR signaling pathways arise from intracytoplasmic TIR domains, which are conserved among all TLRs. Recent accumulating evidence has demonstrated that TIR domain-containing adaptors, such as MyD88, TIRAP, and TRIF, modulate TLR signaling pathways. MyD88 is essential for the induction of inflammatory cytokines triggered by all TLRs. TIRAP is specifically involved in the MyD88-dependent pathway via TLR2 and TLR4, whereas TRIF is implicated in the TLR3- and TLR4-mediated MyD88-independent pathway. Thus, TIR domain-containing adaptors provide specificity of TLR signaling.

    更新日期:2019-11-01
  • Toll receptor families: structure and function.
    Semin. Immunol. (IF 7.358) Pub Date : 2004-01-31
    S Akira

    更新日期:2019-11-01
  • Exploring the immunogenome with bioinformatics.
    Semin. Immunol. (IF 7.358) Pub Date : 2003-12-24
    Bernard de Bono,John Trowsdale

    A better description of the immune system can be afforded if the latest developments in bioinformatics are applied to integrate sequence with structure and function. Clear guidelines for the upgrade of the bioinformatic capability of the immunogenetics laboratory are discussed in the light of more powerful methods to detect homology, combined approaches to predict the three dimensional properties of a protein and a robust strategy to represent the biological role of a gene.

    更新日期:2019-11-01
  • Informatics and the immune system: the expanding IL-1 and B7 protein families.
    Semin. Immunol. (IF 7.358) Pub Date : 2003-12-24
    Ethan P Grant,Anthony J Coyle,Jose-Carlos Gutierrez-Ramos

    Remarkable advances in our knowledge of the genome sequence have led to the creation of databases that afford the opportunity to discover genes based on the presence of specific sequence motifs. The application of this strategy to the identification of proteins in families of immunological interest has had a visible impact on the sizes of the interleukin 1/18 and the CD28/B7 costimulatory molecule families, among many others. This accelerated pace of discovery presents a new challenge to match the rate of discovery with biological understanding of the functions of these extended protein families.

    更新日期:2019-11-01
  • Membrane proteins with immunoglobulin-like domains--a master superfamily of interaction molecules.
    Semin. Immunol. (IF 7.358) Pub Date : 2003-12-24
    A Neil Barclay

    Recent genomic analysis has shown that proteins with immunoglobulin superfamily (IgSF) domains are extremely abundant and their number has increased markedly in evolution correlating with the development of the adaptive immune system. The IgSF domain is particularly good at being recognised and is involved in many different kinds of interactions. Thus, analysis of the properties of these domains can act as a paradigm for thinking about the roles of newly identified gene products. This review summarises the identification, function and properties of IgSF domains including, their size, variety of interactions, their strength of binding, role of glycosylation and organisation with other proteins.

    更新日期:2019-11-01
  • Serial analysis of gene expression provides new insights into regulatory T cells.
    Semin. Immunol. (IF 7.358) Pub Date : 2003-12-24
    Stephen P Cobbold,Elizabeth Adams,Luis Graca,Herman Waldmann

    It is now possible to induce donor-specific transplantation tolerance in adult rodents using a number of therapeutic strategies. Such peripheral tolerance is maintained by regulatory CD4+ T cells, not only in transplantation models, but also in autoimmunity. Differential gene expression analyses have been used to identify potential new markers for regulatory T cells, aiming to reveal new insights into their mechanisms of action, and to find novel targets for therapeutic manipulation of the immune system.

    更新日期:2019-11-01
  • Genomics and immunology.
    Semin. Immunol. (IF 7.358) Pub Date : 2003-12-24
    Adrian C Hayday,Daniel J Pennington,Vicki M Giuggio

    更新日期:2019-11-01
  • SHP-1: a regulator of neutrophil apoptosis.
    Semin. Immunol. (IF 7.358) Pub Date : 2003-10-18
    Shida Yousefi,Hans-Uwe Simon

    The Src homology domain 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1) has been implicated in the regulation of differentiation, proliferation, and activation of hematopoietic cells. In this review, we discuss the potential role of SHP-1 in modulating apoptosis pathways in neutrophils. Low enzymatic SHP-1 was associated with increased neutrophil survival in vitro and SHP-1-deficient mice were reported to develop severe neutrophilic inflammatory responses. In contrast, high expression of this phosphatase was observed in neutropenic patients. Moreover, when neutrophils were exposed to Fas ligand, TNF-alpha, or TRAIL, the anti-apoptotic effects of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), or IFN-gamma were blocked, most likely by SHP-1-mediated inactivation of anti-apoptotic signaling molecules. In summary, the current available data point to an important role of SHP-1 in the regulation of neutrophil apoptosis.

    更新日期:2019-11-01
  • The CD95 type I/type II model.
    Semin. Immunol. (IF 7.358) Pub Date : 2003-10-18
    Bryan C Barnhart,Elizabeth C Alappat,Marcus E Peter

    CD95 (APO-1/Fas) has become the prototype of a death domain containing receptor and is the best studied member of the death receptors that activate the extrinsic apoptosis pathway. This pathway is initiated by recruitment and activation of caspase-8, an initiator caspase, in the death-inducing signaling complex (DISC) followed by direct cleavage of downstream effector caspases. In contrast, the intrinsic apoptosis pathway starts from within the cell either by direct activation of caspases or through intracellular changes such as DNA damage resulting in the release of a number of pro-apoptotic factors from the intermembrane space of mitochondria. The release of these factors results in the activation of another initiator caspase, caspase-9, and ultimately in the activation of effector caspases in a protein complex called the apoptosome. In recent years, it has become apparent that there is cross talk between the extrinsic and intrinsic pathway. In the death receptor pathway of apoptosis induction, the best characterized connection between the two pathways is the Bcl-2 family member Bid which translocates to mitochondria after cleavage by caspase-8 causing pro-apoptotic changes. Cells that die through CD95 without help from mitochondria are called Type I cells, whereas cells in which CD95-mediated death relies mostly on the intrinsic pathway are called Type II. This review focuses on recent developments in the delineation of the biochemistry and the physiological function of the two CD95 pathways.

    更新日期:2019-11-01
  • From antigen to activation: specific signal transduction pathways linking antigen receptors to NF-kappaB.
    Semin. Immunol. (IF 7.358) Pub Date : 2003-10-18
    Jürgen Ruland,Tak W Mak

    A precise balance between cellular apoptosis and cellular survival is essential for the proper functioning of the immune system. Whereas apoptosis eliminates self-reactive or supernumerary lymphocytes, survival signaling that counteracts apoptotic programs is needed to allow B and T lymphocytes that recognize pathogens to become activated and expand in response to infection. A major regulator of lymphocyte survival and activation is the transcription factor NF-kappaB. Controlled activation of NF-kappaB is essential for normal innate and adaptive immune responses, and dysregulated NF-kappaB signaling in lymphocytes contributes to diseases ranging from chronic inflammation and autoimmunity to lymphoma. The core NF-kappaB activating machinery composed of the NF-kappaB, IkappaB and IKK proteins is relatively well-characterized, but it is less clear how distinct upstream stimuli activate NF-kappaB in a tissue-, time- and signal-specific manner. In this review, we discuss recent insights into the specific signal transduction pathways leading to NF-kappaB activation that are triggered by engagement of the antigen receptors of T and B cells. We focus mainly on T cell receptor (TCR)-mediated NF-kappaB activation and draw parallels to B cell receptor (BCR)-mediated NF-kappaB activation where appropriate.

    更新日期:2019-11-01
  • Fas (CD95/Apo-1) ligand regulation in T cell homeostasis, cell-mediated cytotoxicity and immune pathology.
    Semin. Immunol. (IF 7.358) Pub Date : 2003-10-18
    Thomas Brunner,Christoph Wasem,Ralph Torgler,Igor Cima,Sabine Jakob,Nadia Corazza

    Members of the tumor necrosis factor (TNF) superfamily are crucially involved in the regulation of T cell activation, homeostasis and cytotoxicity. In particular, Fas ligand (FasL), expressed by activated T lymphocytes, induces cell-mediated cytotoxicity and may also be responsible for apoptotic suicide. Tight regulation of this death-inducing ligand is a prerequisite for proper immune defense and homeostasis. In this review, we will discuss various aspects of FasL regulation in cell-mediated cytotoxicity, immune homeostasis and the immunopathology of diseases.

    更新日期:2019-11-01
  • The role of Rel/NF-kappaB transcription factors in B lymphocyte survival.
    Semin. Immunol. (IF 7.358) Pub Date : 2003-10-18
    Steve Gerondakis,Andreas Strasser

    Among the transcriptional mediators of the various signal transduction pathways that have been shown to regulate lymphocyte apoptosis, Rel/NF-kappaB transcription factors have emerged as key regulators of B cell survival during their differentiation and in their activation by antigens or mitogens. The aim of this review is to bring together recent findings on Rel/NF-kappaB regulation of B cell survival and to present an integrated model of how these transcription factors control apoptosis in a signal and differentiation-stage specific manner. In addition to providing a contemporary view of Rel/NF-kappaB regulated B cell survival, the model described here is aimed to serve as a paradigm for how Rel/NF-kappaB family members control survival in different cell types during differentiation and in response to the plethora of signals that impinge on this master transcriptional regulatory pathway.

    更新日期:2019-11-01
  • Function and regulation of the CD95 (APO-1/Fas) ligand in the immune system.
    Semin. Immunol. (IF 7.358) Pub Date : 2003-10-18
    Min Li-Weber,Peter H Krammer

    CD95/CD95L mediated apoptosis is an important mechanism of immune homeostasis. It is instrumental for termination of an immune response and mainly be involved in peripheral tolerance. Dysregulation of the CD95/CD95L system leads to severe diseases. In this review, we present a survey of the role of the CD95/CD95L system in the immune system and, particularly, focus on the signals and transcription factors (NF-AT, Egr, NF-kappaB, AP-1, c-Myc, Nur77, IRFs, SP-1, ALG-4, ROR(gamma)t, and CIITA) involved in CD95L expression. It should also be evident from this review that a profound insight into the molecular mechanisms of CD95L activation should allow to explore potential therapeutic means to treat CD95/CD95L-dependent diseases.

    更新日期:2019-11-01
  • Cell death in the thymus--it' s all a matter of contacts.
    Semin. Immunol. (IF 7.358) Pub Date : 2003-10-18
    Lisa M Minter,Barbara A Osborne

    Apoptosis, or programmed cell death, plays a critical role in shaping the T cell repertoire, deleting unproductive as well as potentially autoreactive T cells. Our understanding of how thymocyte apoptosis is regulated is continually evolving, as new essential modulators of this process are discovered. A conundrum that remains, however, is how signaling through essentially the same receptors and cascades evokes distinct biological responses: death by neglect, positive or negative selection. We hypothesize that the immunological synapse (IS) may be critical to transducing survival signals during thymocyte development, and suggest that factors affecting IS assembly may also influence T cell selection.

    更新日期:2019-11-01
  • Cell death during lymphocyte development and activation.
    Semin. Immunol. (IF 7.358) Pub Date : 2003-10-18
    Ignacio Moreno de Alborán,María S Robles,Alexandra Bras,Esther Baena,Carlos Martínez-A

    The development and homeostasis of the immune system requires an exquisite balance between cell proliferation and cell death. In this review, we discuss several in vivo and in vitro models that have been developed to help understand the importance of apoptosis during B and T cell development and activation.

    更新日期:2019-11-01
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