Disruptions in the Immune System

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A new siglec family member, siglec-10, is expressed in cells of the immune system and has signaling properties similar to CD33 Gena Whitney 1 , Shulin Wang 1 , Han Chang 2 , Ke-Yi Cheng 1 , Pin Lu 1 , Xia D. Zhou 1 , Wen-Pin Yang 2 , Murray McKinnon 1 and Malinda Longphre 1 1 Inflammation and Pulmonary Drug Discovery Department, and 2 Applied Genomics Department, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA The siglecs (sialic acid-binding Ig-like lectins) are a distinct subset of the Ig superfamily with adhesion-molecule-like structure. We describe here a novel member of the siglec protein family that shares a similar structure including five Ig-like domains, a transmembrane domain, and a cyto- plasmic tail containing two ITIM-signaling motifs. Siglec- 10 was identified through database mining of an asthmatic eosinophil EST library. Using the Stanford G3 radiation hybrid panel we were able to localize the genomic sequence of siglec-10 within the cluster of genes on chromosome 19q13.3-4 that encode other siglec family members. We have demonstrated that siglec-10 is an immune system- restricted membrane-bound protein that is highly expressed in peripheral blood leukocytes as demonstrated by Northern, RT-PCR and flow cytometry. Binding assays determined that the extracellular domain of siglec-10 was capable of binding to peripheral blood leukocytes. The cytoplasmic tail of siglec-10 contains four tyrosines, two of which are embedded in ITIM-signaling motifs (Y597 and Y667) and are likely involved in intracellular signaling. The ability of tyrosine kinases to phosphorylate the cytoplasmic tyrosines was evaluated by kinase assay using wild-type siglec-10 cytoplasmic domain and Y!F mutants. The majority of the phosphorylation could be attributed to Y597 and Y667. Further experiments with cell extracts suggest that Src homology region 2 domain-containing protein tyrosine phosphatase (SHP)-1 interacts with Y667 and SHP-2 interacts with Y667 in addition to another tyrosine. This is very similar to CD33, which also binds the phosphatases SHP-1 and SHP-2, therefore siglec-10, as CD33, may be characterized as an inhibitory receptor. Keywords: sialoadhesin; CD33; inhibitory receptor; phos- phatase; siglec. A recently defined group of immunoglobulin superfamily proteins expressed on a variety of cell types have been described as having binding properties that may mediate cell adhesion and cell signaling through recognition of sialyated cell surface glycans [1,2]. This protein family was recently termed siglec for sialic acid-binding Ig-like lectins and is comprised of sialoadhesin (siglec-1) [3], CD22 (siglec-2) [4], CD33 (siglec-3) [5], myelin-associated glycoprotein (MAG, siglec-4a) [6], Schwann cell myelin protein (SMP, siglec-4b) [4], OB-BP2 (siglec-5) [7], OB-BP1 (siglec-6) [8], siglec-7 [9], siglec-8 [10], and siglec-9 [11,12]. Although expression of certain siglecs (e.g. CD33) has long been observed and utilized for diagnosis of some malignant disorders [13], the precise biological functions of the siglec protein family are not well understood. However, because of their structure and expression patterns, siglec proteins are hypothesized to be involved in diverse biological processes such as hematopoiesis, neuronal development and immunity [2]. A trait shared by many of Disruptions in the Immune System Disruptions in the Immune System Bởi: OpenStaxCollege A functioning immune system is essential for survival, but even the sophisticated cellular and molecular defenses of the mammalian immune response can be defeated by pathogens at virtually every step In the competition between immune protection and pathogen evasion, pathogens have the advantage of more rapid evolution because of their shorter generation time and other characteristics For instance, Streptococcus pneumoniae (bacterium that cause pneumonia and meningitis) surrounds itself with a capsule that inhibits phagocytes from engulfing it and displaying antigens to the adaptive immune system Staphylococcus aureus (bacterium that can cause skin infections, abscesses, and meningitis) synthesizes a toxin called leukocidin that kills phagocytes after they engulf the bacterium Other pathogens can also hinder the adaptive immune system HIV infects TH cells via their CD4 surface molecules, gradually depleting the number of TH cells in the body; this inhibits the adaptive immune system’s capacity to generate sufficient responses to infection or tumors As a result, HIVinfected individuals often suffer from infections that would not cause illness in people with healthy immune systems but which can cause devastating illness to immunecompromised individuals Maladaptive responses of immune cells and molecules themselves can also disrupt the proper functioning of the entire system, leading to host cell damage that could become fatal Immunodeficiency Failures, insufficiencies, or delays at any level of the immune response can allow pathogens or tumor cells to gain a foothold and replicate or proliferate to high enough levels that the immune system becomes overwhelmed Immunodeficiency is the failure, insufficiency, or delay in the response of the immune system, which may be acquired or inherited Immunodeficiency can be acquired as a result of infection with certain pathogens (such as HIV), chemical exposure (including certain medical treatments), malnutrition, or possibly by extreme stress For instance, radiation exposure can destroy populations of lymphocytes and elevate an individual’s susceptibility to infections and cancer Dozens of genetic disorders result in immunodeficiencies, including Severe Combined Immunodeficiency (SCID), Bare lymphocyte syndrome, and MHC II 1/6 Disruptions in the Immune System deficiencies Rarely, primary immunodeficiencies that are present from birth may occur Neutropenia is one form in which the immune system produces a below-average number of neutrophils, the body’s most abundant phagocytes As a result, bacterial infections may go unrestricted in the blood, causing serious complications Hypersensitivities Maladaptive immune responses toward harmless foreign substances or self antigens that occur after tissue sensitization are termed hypersensitivities The types of hypersensitivities include immediate, delayed, and autoimmunity A large proportion of the population is affected by one or more types of hypersensitivity Allergies The immune reaction that results from immediate hypersensitivities in which an antibody-mediated immune response occurs within minutes of exposure to a harmless antigen is called an allergy In the United States, 20 percent of the population exhibits symptoms of allergy or asthma, whereas 55 percent test positive against one or more allergens Upon initial exposure to a potential allergen, an allergic individual synthesizes antibodies of the IgE class via the typical process of APCs presenting processed antigen to TH cells that stimulate B cells to produce IgE This class of antibodies also mediates the immune response to parasitic worms The constant domain of the IgE molecules interact with mast cells embedded in connective tissues This process primes, or sensitizes, the tissue Upon subsequent exposure to the same allergen, IgE molecules on mast cells bind the antigen via their variable domains and stimulate the mast cell to release the modified amino acids histamine and serotonin; these chemical mediators then recruit eosinophils which mediate allergic responses [link] shows an example of an allergic response to ragweed pollen The effects of an allergic reaction range from mild symptoms like sneezing and itchy, watery eyes to more severe or even life-threatening reactions involving intensely itchy welts or hives, airway contraction with severe respiratory distress, and plummeting blood pressure This extreme reaction is known as anaphylactic shock If not treated with epinephrine to counter the blood pressure and breathing effects, this condition can be fatal 2/6 Disruptions in the Immune System On first exposure to an allergen, an IgE antibody is synthesized by plasma cells in response to a harmless antigen The IgE molecules bind to mast cells, and on secondary exposure, the mast cells release histamines and other modulators that affect the symptoms of allergy (credit: modification ...http://jbiol.com/content/8/7/61 Stockinger: Journal of Biology 2009, 8:61 Abstract The aryl hydrocarbon receptor is a ligand-activated trans crip- tional regulator that binds dioxin and other exogenous contami- nants and is responsible for their toxic effects, including immuno- suppression. New evidence suggests, however, that the aryl hydrocarbon receptor has a physiological role in the immune system, and the immunosuppressive effects of dioxin may reflect a more subtle disruption of the regulatory inter actions between immune cells. The aryl hydrocarbon receptor (AhR), also called the dioxin receptor, is a transcriptional regulator best known for mediating the toxicity of environmental contaminants, most notably halogenated polycyclic aromatic hydro- carbons such as dioxin. AhR has been studied extensively for its pathological role in response to environmental pollution, and there is a wealth of knowledge regarding its signalling components as well as its structural features and pharmacological effects. Although many aspects of AhR- mediated toxicity have been described, the molecular mechanisms underlying these are not well understood. AhR is conserved across vertebrate and invertebrate species, playing a role, for instance, in the development of the nervous system in Caenorhabditis elegans, while in Drosophila the AhR homolog spineless is involved in development of antennae and legs as well as in aspects of color vision [1].The intrinsic physiological functions of AhR in mammals have been delineated from the phenotype of the AhR knockout mouse [2-4]. These mice show reduced fertility, smaller livers, possibly resulting from vascular defects [1], and portal fibrosis. The strong conser- vation of AhR in so many species as well as the mutant phenotype suggest that it has roles beyond those of mediat- ing toxicity of pollutants. More recently it has been suggested that dioxin-mediated toxicity may, in fact, reflect disruption of the endogenous function of this receptor by inducing sustained and inappropriate AhR signaling due to the stability of the toxin, and thus causing dysregulation of physiological functions [5]. Toxic effects of dysregulation are particularly likely in the immune system where highly complex interactions between hematopoietic cells and their environment dictate the outcome of challenge by pathogens, and indeed dioxin has been known for decades to be immunotoxic, though information on possible underlying mechanisms is sparse [6]. Indications of immune defects have been described in one of the three AhR knockout strains, but not the others, prompting suggestions that differences in background or infectious agents in the environment might have played a role. However, immune challenges such as influenza or Listeria monocytogenes applied to AhR knockout mice have so far yielded little insight into the mechanism of changes that have been reported in the responses of specific subsets of immune cells, or the induction of specific subsets of immune cells [7]. More recent experiments on the expression of AhR in the lymphocytes of the immune system have begun to suggest that ligands of AhR have roles in the immune system that do not conform to the notion of immunosuppression. The lymphocytes of the adaptive immune system fall into two major classes - B cells, which secrete antibodies, and T cells, which act on other cells and, broadly speaking, either activate other cells of the immune system (cells that do this belong to a class known as CD4 T cells, or T helper cells) or destroy infected cells (most cells that do this belong to a class known as CD8 T cells). CD4 T cells are further subdivided into four clearly defined subsets with distinct functions that are mediated by the distinct cytokines they secrete and that act on other immune cells (Figure 1), including B cells, which they activate to secrete antibody. All CD4 T cells to some extent regulate one 215 APC = antigen presenting cell; IL = interleukin; MHC = major histocompatibility complex; TCR = T-cell receptor; TGF-β = transforming growth factor beta; Th = T helper cell; Tr1 = T regulatory 1; T R = CD4 + CD25 + T regulatory cell. Available online http://arthritis-research.com/content/6/5/215 Introduction The ability of the immune system to distinguish between self-antigens and nonself-antigens, and between harmful and innocuous foreign antigens, is critical to the maintenance of immune homeostasis. Failure to maintain tolerance to self-antigens or innocuous antigen results in the development of autoimmune or allergic disease, respectively. To achieve this state of immune tolerance, the immune system has evolved a variety of mechanisms. These include deletion of self-reactive clones in the thymus through a process referred to as negative selection, or central tolerance [1]. Central tolerance is imperfect, however, and self-reactive T cells do appear in the periphery. Likewise, the immune system is continuously distinguishing between innocuous and pathogenic foreign antigens. To deal with these situations the immune system has evolved a system of induced peripheral tolerance. Two well-characterized mechanisms of peripheral tolerance are the death of self-reactive T cells via negative selection and the induction of a state of nonresponsiveness, or anergy [2]. A third, less well-characterized, mechanism is the active suppression of T-cell responses. This latter mechanism involves a recently described T-cell subset, known as regulatory T cells, which are induced in the periphery in an antigen-specific fashion [3,4]. The present review will discuss the various types of regulatory T cells, as well as the mechanisms that have been described for their generation. Natural versus acquired regulatory T cells Several classes of regulatory T cells, capable of suppressing antigen-specific immune responses, have been identified and characterized. These subsets can be distinguished in a variety of ways; including whether suppression is cell-contact mediated or is mediated through soluble factors such as IL-10 and transforming Review Regulating the immune system: the induction of regulatory T cells in the periphery Jane H Buckner 1 and Steven F Ziegler 2 1 Diabetes Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA 2 Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA Corresponding author: Steven F Ziegler, sziegler@vmresearch.org Received: 31 Mar 2004 Revisions requested: 12 May 2004 Revisions received: 19 Jul 2004 Accepted: 21 Jul 2004 Published: 11 Aug 2004 Arthritis Res Ther 2004, 6:215-222 (DOI 10.1186/ar1226) © 2004 BioMed Central Ltd Abstract The immune system has evolved a variety of mechanisms to achieve and maintain tolerance both centrally and in the periphery. Central tolerance is achieved through negative selection of autoreactive T cells, while peripheral tolerance is achieved primarily via three mechanisms: activation- induced cell death, anergy, and the induction of regulatory T cells. Three forms of these regulatory T cells have been described: those that function via the production of the cytokine IL-10 (T regulatory 1 cells), transforming growth factor beta (Th3 cells), and a population of T cells that suppresses proliferation via a cell-contact-dependent mechanism (CD4 + CD25 + T R cells). The present review focuses on the third form of peripheral tolerance — the induction of regulatory T cells. The review will address the induction of the three types of regulatory T cells, the mechanisms by which they suppress T-cell responses in the periphery, the role they play in immune homeostasis, and the potential these cells have as therapeutic agents in immune-mediated disease. Keywords: interleukin-10, regulatory T cell, suppression, transforming growth factor beta, tolerance 216 Arthritis Research & Therapy Vol 6 No 5 Buckner and Ziegler growth factor Genome BBiioollooggyy 2008, 99:: 315 Meeting report GGeennee rreegguullaattiioonn aanndd ssiiggnnaall ttrraannssdduuccttiioonn iinn tthhee iimmmmuunnee ssyysstteemm Tiffany Horng, Shalini Oberdoerffer and Anjana Rao Address: Department of Pathology, Harvard Medical School, Immune Disease Institute, Boston, Massachusetts 02115, USA. Correspondence: Tiffany Horng. Email: horng@idi.harvard.edu Published: 10 July 2008 Genome BBiioollooggyy 2008, 99:: 315 (doi:10.1186/gb-2008-9-7-315) The electronic version of this article is the complete one and can be found online at http://genomebiology.com/2008/9/7/315 © 2008 BioMed Central Ltd A report of the meeting ‘Gene Expression and Signaling in the Immune System’, Cold Spring Harbor, USA, 22-26 April 2008. Major themes at this year’s Cold Spring Harbor meeting on gene expression and signaling in the immune system included transcriptional control of leukocyte development and differentiation, antigen receptor gene assembly and modification, signal transduction by antigen receptors in control of lymphocyte biology, signal transduction in regula- tion of inflammatory gene expression and the analysis of chromatin structure and other epigenetic mechanisms in control of gene expression. MMeettaabboolliicc rreegguullaattiioonn iinn llyymmpphhooccyyttee aaccttiivvaattiioonn The link between metabolism and regulation of lymphocyte activity was addressed by Doreen Cantrell (University of Dundee, UK), who presented data regarding the role of phosphatidylinositol-3-OH kinase (PI3K) signaling in regulating T-cell biology. She has used an in vitro model of murine CD8 T-cell differentiation in which the strength of PI3K signaling is varied, by culture with either of the cytokines interleukin (IL)-2 or IL-15, or with pharmacological inhibitors of the PI3K pathway. She showed that high levels of PI3K signaling (as in the IL-2 cultures) produced large cells with an effector phenotype, while low levels (as with IL-15) resulted in small, memory- like cells. This reflected regulation of two major functional programs: metabolism, through control of protein synthesis, and trafficking, through regulated expression of the chemokine receptor CCR7 and the selectin molecule CD62L. Cantrell suggested that this enables the PI3K pathway to match cellular metabolic demands with migration in vivo, such that high levels of PI3K signaling would support energy-demanding effector T-cell functions in the periphery, whereas low levels would direct T cells back to the nutrient-rich environment of the lymph node. The intracellular signaling protein Slp2 is also involved in regulating energy metabolism in lymphocytes. Joaquin Madrenas (University of Western Ontario, London, Ontario) suggested that induction of Slp2 in activated mouse T cells and B cells is necessary to meet the increased metabolic demands associated with the transition from the quiescent, G0-arrested state to actively proliferating and differentiating lymphocytes. He showed that induction of Slp2 led to an increase in the amount of mitochondrial membrane and the number of mitochondria, and consistent with this, an increase in ATP stores. Conversely, Slp2 downregulation inhibited T-cell activation, as assessed by IL-2 production. Ectopic expression of Slp2 also protected T cells from apoptosis triggered by the cell-autonomous, mitochondria-dependent pathway. There- fore, while its exact role in mitochondrial regulation is not clear, Slp2 may be critical for diverse aspects of lymphocyte activation, including energy metabolism and survival. SSiiggnnaall ttrraannssdduuccttiioonn iinn pprroo iinnffllaammmmaattoorryy ggeennee eexxpprreessssiioonn The NF-κB family of transcription factors critically regulates pro-inflammatory gene expression in response to a range of stimuli. Alexander Hoffmann (University of California, San Diego, USA) reported that one member, NF-κB2/p100, can function as a novel noncanonical inhibitor in the IκB family, by mediating retention ROLE OF THE IMMUNE SYSTEM IN TUMOR PROGRESSION TOH PANG KIAT, BENJAMIN (B.Sc. (Hons.), NUS) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY NUS Graduate School for Integrative Sciences and Engineering NATIONAL UNIVERSITY OF SINGAPORE 2011 Acknowledgements I would like to acknowledge my supervisor, Jean-Pierre Abastado, for his continued help and support throughout the course of my PhD. He has been a great mentor and guide from whom I have learnt a great deal. I would also like to thank my thesis advisory committee members, Ren Ee Chee and Laurent Renia, for their guidance and help. I would like to show my appreciation to all members of the Tumor Immunology Laboratory in the Singapore Immunology Network (SIgN). Special thanks go to Karen Khoo, Jeremy Wang and Jo Keeble for their help and discussions about the work presented in this thesis. Next, I would like to thank my collaborators for their help in this project. Laurent Renia (SIgN) for the NIMP-R14 antibody, Ng Lai Guan (SIgN) for providing me with the IL8R-KO and tdTomato mice, Esther Koh for help in the cell tracking software, Poon Lai Fong (SIgN) for help with cell sorting, Josephine Lum (SIgN) for the microarray work and Wong Wing Cheong (BII) for the analysis of the microarray data. Special thanks to Masashi Kato (Chubu University, Aichi, Japan) and Armelle Prevost-Blondel (Institut Cochin, Paris, France) for providing the RET mice. I would also like to thank Jean-Paul Thiery (IMCB) and Sim Wen Jing (IMCB) for their help and discussion regarding the EMT assays. Last but not least, I would like to thank my family for their support, especially my wife, who painstakingly helped with the editing of this thesis. i Table of Contents Acknowledgements . i Summary v List of Tables . vi List of Figures . vii List of Appendices . ix List of Videos . ix List of Publications .x List of Abbreviations xi Introduction .1 Inflammation, immunity and cancer Immunosurveillance theory .2 Immunoediting theory Roles of immune cells Melanoma Diagnosis and treatment .11 Melanoma and the immune system 15 Objectives 16 Experimental Procedures .18 Mice . 18 In vivo PMN-MDSCs depletion . 18 Flow cytometry analysis 19 Isolation of PMN-MDSCs and macrophages 20 Microarray analysis 21 Cytospin and May-Grunwald/Giemsa stain . 22 Tumor cell detection by qRT-PCR 23 Low density microarray . 23 Immunohistochemistry and calculations 24 Migration assay 25 Tumor proliferation assay 26 ii OVA-specific T cell proliferation assay 27 E-Cadherin assays 27 MT assay 28 Statistics ... response against insulin-producing cells of the 4/6 Disruptions in the Immune System pancreas Patients with this autoimmunity must be injected with insulin that originates from other sources... erythematosus, a diffuse autoantibody response to the individual’s own DNA and proteins results in various systemic diseases As illustrated in [link], systemic lupus erythematosus may affect the. .. exposure to the same allergen, IgE molecules on mast cells bind the antigen via their variable domains and stimulate the mast cell to release the modified amino acids histamine and serotonin; these