Immune System and Immunology Final Exam Review PDF

Immune System & Immunology Fundamental Principles Carlos A. Barrero, M.D Assistant Professor Pharmaceutical Sciences Department Proteomics and Metabolomics Facility Moulder Center for Drug Discovery Research Temple University - School of Pharmacy ...

Immune System & Immunology Fundamental Principles Carlos A. Barrero, M.D Assistant Professor Pharmaceutical Sciences Department Proteomics and Metabolomics Facility Moulder Center for Drug Discovery Research Temple University - School of Pharmacy  Immune System as a System of Systems Human Physiology http://anatomyandphysiologyi.com Characteristics of the Immune System  Specificity: Fine distinctions  Diversity: Broad repertoire  Memory: Accelerate next response  Homeostasis: Demobilization after clearance  Tolerance: Distinguish self from foreign Immune System Functions  Types of adaptive immunity In humoral immunity, B lymphocytes secrete antibodies that prevent infections by and eliminate extracellular microbes. In cell-mediated immunity, helper T lymphocytes activate microbes or cytotoxic T lymphocytes directly destroy infected cells. Humoral immunity is the aspect of immunity that is mediated by macromolecules – including secreted antibodies, complement proteins, and certain antimicrobial peptides – located in extracellular fluids. Cellular Immunity  What is the Immune System?  The immune system is composed of the innate immunity which occurs in the early phase of a reaction and the adaptive immunity which occurs in the later phase.  Summary Immune Cells Role Phagocytes and killing for microorganisms. Macrophage Activation of T cells and initiation of immune response. Phagocytes and killing for microorganisms. Neutrophils Activation of T cells and initiation of adaptive immune Dendritic Cells responses Expulsion of parasites from body through release of Mast Cells granules containing histamine and other active agents Basophils Controlling immune responses to parasites Killing of antibody-coated parasites through release of Eosinophils granule contents  Lymphocytes Classes of Lymphocytes Roles Neutralization of microbe, B Lymphocyte phagocytosis, complement activation Activation of macrophages Inflammation Helper T Lymphocyte Activation of (proliferation and differentiation) of T and B lymphocytes Cytotoxic T Lymphocyte Killing of infected cell Regulatory T Lymphocyte Suppression of immune response Natural Killer (NK) Cells Killing of infected cell Immune system cells with different functions all derive from hematopoietic stem cells Immune cells all originate from a common hematopoietic stem cell (HSC) in the bone marrow. HSCs are pluripotent, meaning that a single HSC can generate all different types of mature blood cells. HSCs are also self-renewing because each time they divide, at least one daughter cell maintains the properties of a stem cell while the other can differentiate along a particular lineage https://stemcells.nih.gov/info/Regenerative_Medicine/2006Chapter2.htm Innate and Adaptive Immunity 11 Innate Immunity This immunity provides the early line of defense against microbes It consists of cellular and biochemical defense mechanisms that are in place even before infection and will respond rapidly to infections. These mechanisms react to microbes (PAMPs: Pathogen-Associated Molecular Patterns) and to the products of injured cells (DAMPs: Damage- Associated Molecular Patterns), and they respond in essentially the same way to repeated infections. The response of this immunity is very specific for structure that are common to groups of related microbes and may not distinguish fine difference between microbes. 12 Innate and Adaptive Immunity Every individual’s immune system is able to recognize, respond to, and eliminate many foreign (non-self) antigens but does not usually react against that individual’s own (self) antigens and tissues. Different mechanisms are used by the innate and adaptive immune systems to prevent reactions against healthy host cells. 13 Adaptive Immunity  This immunity is stimulated by exposure to infectious agents and increase in magnitude and defensive capabilities with each successive exposure to a particular microbe.  Adaptive immunity can recognize and react to a number of microbial and nonmicrobial substances  It can also distinguish between different, even closely related, microbes and molecules, which is why its also called specific immunity  Also called acquired immunity because of its potent protective responses are acquired by experience The main components of adaptive immunity are lymphocytes which secrete products such as antibodies. Lymphocytes can then be separated into: B lymphocytes secrete antibodies T lymphocytes are involved in cell mediated immunity Foreign substances that induce specific immune responses or are recognized by lymphocytes or antibodies are called antigens 14 Clonal Expansion  Lymphocytes specific for an antigen undergo considerable proliferation after exposure to that antigen.  The term clonal expansion refers to an increase in the number of cells that express identical receptors for the antigen and thus belong to a clone.  The increase in antigen- specific cells enables the adaptive immune response to keep pace with rapidly dividing infectious pathogens. 15 Memory  Exposure of the immune system to a foreign antigen enhances its ability to respond again to that antigen.  Responses to second and subsequent exposures to the same antigen, called secondary immune responses, are usually more rapid, larger, and often qualitatively different from the first, or primary, immune response to that antigen.  Each exposure to an antigen generates long-lived memory cells specific for the antigen. These memory cells are more efficient at responding to and eliminating the antigen than are naïve lymphocytes.  Memory B lymphocytes produce antibodies that bind antigens with higher affinities than antibodies produced in the first immune response.  Memory T cells also react much more rapidly and vigorously to antigen challenge than do naïve T cells 16 Memory 17  Properties of Antigen Presenting Cells (APC)  APC is the term used to refer to specialized cells that display antigens to lymphocytes.  APCs express class II MHC molecules and other molecules involved in stimulating T cells and are capable of activating CD4+ T lymphocytes.  Dendritic cells  Most effective APCs for activating naïve T cells and therefore for initiating T cell responses.  Macrophages and B lymphocytes; great for previously activated CD4+ helper T cells rather than for naïve T cells  Functions of APC  Antigen is the first signal for the activation of naïve T cells, the additional stimuli that also activate naïve T cells are called second signals  Co-stimulators are membrane bound molecules of APCs that function together with antigens to stimulate T cells  Adjuvants are products of microbes, that enhance the expression of co- stimulators and cytokines and also stimulate the antigen-presenting functions of APCs. Properties and Functions of APCs  Role of Dendritic Cells Common routes of antigens entry  Some antigens are transported in the lymph by APCs (primarily DCs) that capture the antigen and enter lymphatic vessels.  Antigens that enter the bloodstream may be sampled by DCs that are in the spleen, or captured by circulating DCs and taken to the spleen.  Resting tissue-resident DCs use receptors to capture, such as C-type lectins, that bind and endocytose microbes or microbial proteins and then process the ingested proteins into peptides capable of binding to MHC molecules.  DCs can ingest antigens by pinocytosis, a process that does not involve specific recognition receptors but serves to internalize whatever molecules might be in the fluid phase in the vicinity of the DCs.  The DCs are activated by cytokines, such as tumor necrosis factor (TNF), produced in response to the microbes. The activated DCs (also called mature DCs) lose their adhesiveness for epithelia or tissues and begin to express a chemokine receptor called CCR7 that is specific for two chemokines, CCL19 and CCL21, that are produced in lymphatic vessels and in the T cell zones of lymph nodes. Nature of T Cell Responses  Cytosolic antigens are presented by nucleated cells to CD8+ CTLs, which kill (lyse) the antigen-expressing cells.  Extracellular antigens are presented by macrophages or B lymphocytes to CD4+ helper T lymphocytes, which activate the macrophages or B cells and eliminate the extracellular antigens.  Sequential Events for Lymphocyte Development 1 2 3 4 5  The process by which lymphocyte progenitors in the thymus and bone marrow differentiate into mature lymphocytes that populate peripheral lymphoid tissues is called lymphocyte development or lymphocyte maturation  The greatest proliferative expansion of lymphocyte precursors occurs after successfully rearranged the Ig heavy chain gene (B cell) or the TCR β chain gene (T cell). Multipotent stem cells give rise to distinct B and T lineages  The EBF, E2A, and Pax-5 transcription factors induce the expression of genes required for B cell development:  Rag-1 and Rag-2 proteins  Pre-B and the B cell receptor  Down stream signaling proteins  The Notch 1 and GATA3, signaling proteins induce the expression of genes required for T cell development: IgM Rag-1 and Rag-2 proteins IgD  IL-7 is required for the proliferation of T cell progenitors: Mutations in the IL-7 gene rise to an immunodeficiency disorder in called X-linked severe combined immunodeficiency disease (X-SCID)  Checkpoints in Lymphocyte Maturation Apoptosis Apoptosis  Positive selection preserves receptor-expressing cells and is coupled to the generation of different B cell subsets  Negative selection is the process that eliminates developing lymphocytes whose antigen receptors bind strongly to self-antigens present in the generative lymphoid organs.  T Lymphocyte Maturation in the Thymus  Thymic stromal cells, secrete IL-7, a critical lymphopoietic Double + growth factor.  The movement of cells into and through the thymus is driven by chemokines. Double - Cortex: CCR9:CCL25 Medulla: CCR7:CCL19/21 The cell death (Apoptosis) is due to a combination of factors, including: Failure to productively rearrange the TCR β chain gene and thus to fail the pre-TCR/β, Failure to be positively selected by self MHC molecules in the thymus, Self antigen–induced negative selection. Activation of naive and effector T cells by antigen Sequence of events in T cell responses Cytokines  CD4 Lymphocytes Functions CD8  Role of Costimulation in T Cell Activation The proliferation and differentiation of naive T cells require signals provided by molecules on APCs, called costimulators, in addition to antigen-induced signals  Costimulatory Pathways The interaction of CD40L on T cells with CD40 on APCs enhances T cell responses by activating the APCs. Mechanisms of T cell costimulation by CD28. Costimulation molecules of the CD28 family  Therapeutic Costimulatory Blockade  CTLA-4-Ig is an approved therapy for rheumatoid arthritis and transplant rejection.  Inhibitors of the CD40L:CD40 pathway are in clinical trials for transplant rejection and autoimmune diseases  Antibodies that block the CTLA-4 and PD-1 inhibitory receptors are approved for the immunotherapy of tumors. They work by preventing CTLA-4 or PD-1 from binding their ligands, reducing inhibition and enhancing T cell activation and enabling the cancer- bearing individual to mount more effective antitumor immune responses. Immunoglobulin Expression during B Lymphocyte Maturation  Role of T cells in eradicating infections CD4+ T cells recognize antigens of phagocytosed and extracellular microbes and produce cytokines that recruit and activate the phagocytes to kill the microbes. CD8+ T cells can also secrete some cytokines and participate in similar reactions. B, CD8 + cytotoxic T lymphocytes (CTLs) recognize antigens of microbes residing in the cytoplasm of infected cells and kill the cells. Subsets of CD4+ Effector T Cells CXCR3 / CCR5 P, E Selectins Tissues of innate Immunity CCR3-4-8 Mucosal Tissues CCR6 Tissues cells, Macrophages Th1/Th2 Germinal centers Development of Subsets of CD4+ Effector T Cells Th1 Cells Th2 Cells Th17 Cells Functions of Th1 cells  IFN-γ activates macrophages to kill phagocytosed microbes.  FN-γ promotes the differentiation of CD4+ T cells to the Th1 subset and inhibits the development of Th2 and Th17 cells.  IFN-γ stimulates expression of several different proteins that contribute to enhanced antigen presentation and T cell activation  IFN-γ acts on B cells to promote switching to certain IgG subclasses, and to inhibit switching to IL-4– dependent isotypes, such as IgE.  Th1 cells produce tumor necrosis factor (TNF) and various chemokines, which contribute to the recruitment of leukocytes and enhanced inflammation.  Th1 cells are also produce IL-10, which functions mainly to inhibit dendritic cells and macrophages and thus to suppress Th1 activation. Macrophage activation by Th1 cells Functions of Th2 Cells Classical and alternative macrophage activation Functions of Th17 Cells Role of helper T cells in the differentiation of CD8+ T lymphocytes IL-2 Paracrine Inhibition of CD8+ T Cell Responses: T Cell Exhaustion Steps in CTL-mediated lysis of target cells Mechanisms of CTL-mediated killing of target cells Adaptive defenses Humoral immunity Antigen-binding site Immunoglobulin H ea vy ch ai n Li gh tc ha n i Hinge region Stem region Heavy chain Light chain variable region variable region Heavy chain Light chain constant region constant region Disulfide bond Pre-T Cell Receptor  the TCR β chain is expressed on the cell surface in association with an invariant protein called pre-Tα, along with CD3 and ζ proteins to form the pre-TCR complex.  TCR α gene expression in the double-positive stage leads to the formation of the complete αβ TCR.  Double-positive cells that successfully undergo selection processes go on to mature into CD4+ or CD8+ T cells T Cell Receptor (TCR) Domains of Immunoglobulin Proteins variable domains constant domains CDRs : Complementary Determining regions International Nonproprietary Names (INNs) for Monoclonal Antibodies  INN system begun in 1950 by the World Health Organization (WHO) to provide a unique (generic) name to identify each pharmaceutical substance  INN system has important goals and benefits: Clear identification, safe prescription and dispensing of medicines to patients. Communication and exchange of information among health professionals and scientists worldwide.  Limitations of monoclonal antibodies Not orally bioavailable: delivery by injection usually needed Optimal for extracellular targets; difficult intracellular delivery. Cannot penetrate the blood-brain barrier. Chemistry, Manufacturing and Controls (CMC) Issues: – Complex molecules produced by living cells; hard to characterize and to control batch-to-batch variation and stability Potential for immunogenicity: If recognized as foreign by the immune system, will trigger the formation of anti-drug antibodies (ADA). – A mouse antibody injected into a human will elicit a Human Anti-Mouse Antibody (HAMA) response; – Even human antibodies can trigger antibody responses in humans; HAHA responses. Anti-Drug Antibodies (ADA) in Patients  Recombinant Antibodies Re-engineered to reduce immunogenicity in humans Paul Carter Nat. Rev. Cancer, Nov, 2001. 118-129. WHAT IS IMMUNOGENICITY? FDA Definition: Host immune response against a therapeutic protein  Typically studied in the context of the formation of Anti-Drug Antibodies (ADA)  All biotherapeutics include a section on immunogenicity in their FDA-approved label (Section 6.2)  This is within the Adverse Reactions section of the label Factors That Determine the Immunogenicity and Tolerogenicity of Protein Antigens  Tolerogenic antigens are expressed in generative lymphoid organs, where they are recognized by immature lymphocytes. In peripheral tissues, self antigens engage antigen receptors of specific lymphocytes for prolonged periods and without inflammation or innate immunity.  The nature of the dendritic cell that displays antigens to T lymphocytes is an important determinant of the subsequent response. 56  TYPES OF ANTI-DRUG ANTIBODIES Know the two main classes of ADA: 1. Binding: Interacts with the drug molecule but does not inhibit its binding to the pharmacologic target a) May impact pharmacokinetics b) May impact safety 2. Neutralizing: Directly blocks interaction of drug with its pharmacologic target a) Loss of efficacy b) May impact pharmacokinetics c) May impact safety GR Gunn, DCF Sealey et al. Clin Exp Immunol. 184(2);137-146 (2016).  PHYSIOLOGIC DRIVERS OF Immunogenicity is largely thought to be a T-cell dependent IMMUNOGENICITY phenomenon  The context of presentation to T- cells is likely a driver of ultimate response  Presentation to Thelper cells leads to ADA generation  Presentation to Treg cells limits ADA generation  Amino acid sequences in proteins known as ‘T cell epitopes’ and ‘Tregitopes’ are thought to drive whether an immunogenic response occurs V Jawa, F Terry et al. Front Immunol. 11;1301 (2020).  ‘HUMAN-NESS’ DRIVES Increasing the human content of the primary (amino acid) sequence decreases IMMUNOGENICITY immunogenicity  Non-human IgG sequences are more readily recognized as ‘non- self’ by the immune system  All mAbs being developed now are either humanized or fully human  mAbs with mouse Fc are eliminated more rapidly and need more frequent dosing  Dosing frequency seems to correlate with immunogenicity as well M Sauerborn. Handbook of Therapeutic Antibodies, 2e. (2014).  ROUTE OF ADMINISTRATION IMPACTS Subcutaneous and intramuscular injections are often more immunogenic than IMMUNOGENICITY intravenous dosing.  Injection into these spaces puts the drug near antigen- presenting cells, namely dendritic cells  Proteins must travel through lymph nodes to reach the systemic circulation following SC/IM dosing  Injections may lead to local inflammation, which further primes the immune system for response N Jarvi, SV Balu-Iyer. BioDrugs. 35(2):125-146 (2021). Effector Functions of Antibodies 61 Vaccine-Induced Humoral Immunity 62 Functions of Antibody Isotypes 63 Subunit composition of Fcγ receptors 64 Antibody-mediated opsonization and phagocytosis of microbes 65 Antibody-dependent cell-mediated cytotoxicity 66 Complement Activation 67 Complement Activation Regulatory Mechanisms 68  Complement Activation Regulatory Mechanisms Complement activation needs to be regulated because:  Low-level complement activation goes on spontaneously, and if such activation is allowed to proceed, the result can be damage to normal cells and tissues.  Even when complement is activated where needed, such as on microbial cells or antigen-antibody complexes, it needs to be controlled because degradation products of complement proteins can diffuse to adjacent cells and injure them.  Different regulatory mechanisms include:  Inhibition of the formation of C3 convertases in the early steps of complement activation.  Break down and inactivate C3 and C5 convertases.  Inhibition of the formation of the MAC in the late steps of the complement pathway. 69 Functions of complement 70 Immunologic Tolerance and Autoimmunity Central and peripheral tolerance to self antigens  In central tolerance, immature lymphocytes specific for self antigens may encounter these antigens in the generative lymphoid organs (referred to as central organs in the context of tolerance induction) and are deleted, change their specificity (B cells only), or (in the case of CD4+ T cells) develop into regulatory lymphocytes (Tregs).  In peripheral tolerance, some self-reactive lymphocytes may mature and enter peripheral tissues and may be inactivated or deleted by an encounter with self antigens in these tissues or are suppressed by the regulatory T cells (Tregs, peripheral tolerance). 71 Regulatory T cells 72 Role of interleukin-2 in the maintenance of regulatory T cells Tregs appear to suppress immune responses at multiple Steps:  Production of the immunosuppressive cytokines IL-10 and TGF-β.  Reduced ability of APCs to stimulate T cells.  Consumption of IL-2 73  Effector and regulatory T cells in the intestinal mucosa  In the gastrointestinal tract, different subsets of effector CD4+ T cells are induced by and protect against different microbial species.  Th17 effector T cells and regulatory T cells are abundant in the intestinal mucosa. Bacterial antigen– specific Th17 cells differentiate from naive CD4+ T cells in gut-associated lymphoid tissues in response to antigens presented by dendritic cells (DCs) and cytokines they secrete, including interleukin-6 (IL-6) and IL-23.  Differentiation of bacterial antigen–specific regulatory T cells (Tregs) is promoted by transforming growth factor-β (TGF-β) and retinoic acid produced by intestinal epithelial cells. Thymic Tregs that migrate to the intestine expand in number under the influence of bacterial metabolites. Regulatory T cells require antigen presentation by DCs; the nature of these antigens is unknown. 74 EVOLUTION OF THERAPIES FOR AUTOIMMUNE DISORDERS Characterized by a loss or failure of self- tolerance  More than 80 known autoimmune disorders  May affect a wide range of organ systems  Both cellular and humoral components of the immune system may be implicated  COMMON AUTOIMMUNE MECHANISMS  Each autoimmune disease likely has specific triggers and pathogenesis  Common mechanisms include development of autoantibodies and aberrant cytokine signaling  Therapeutic strategies focus on dampening the aberrant immune response JM Anaya. Autoimmunity Rev. 11(11);781-784 (2012). Postulated mechanisms of autoimmunity  The factors that contribute to the development of autoimmunity are genetic susceptibility and environmental  triggers, such as infections and local tissue injury.  Autoimmune diseases may be systemic or organ specific, depending on the distribution of the autoantigens that are recognized.  Various effector mechanisms are responsible for tissue injury in different autoimmune diseases including: immune complexes, circulating autoantibodies, and autoreactive T lymphocytes  Autoimmune diseases tend to be chronic, progressive, and self-perpetuating. 77  Immunologic Abnormalities Leading to Autoimmunity  Defective self-tolerance. Inadequate elimination or regulation of T or B cells, leading to an imbalance between lymphocyte activation and control, is the underlying cause of all autoimmune diseases.  Defects in deletion (negative selection) of T or B cells or receptor editing in B cells during the maturation of these cells in the generative lymphoid organs.  Defective numbers or functions of regulatory T lymphocytes.  Defective apoptosis of mature self-reactive lymphocytes.  Inadequate function of inhibitory receptors.  Abnormal display of self antigens. Abnormalities may include increased expression and persistence of self antigens that are normally cleared, or structural changes in these antigens resulting from enzymatic modifications or from cellular stress or injury, “neoantigens”.  Inflammation or an initial innate immune response may contribute to the development of autoimmune disease, perhaps by activating APCs, which overcome regulatory mechanisms and result in excessive T cell activation 78 Role of infections in the development of autoimmunity 79  THERAPEUTIC TARGETS IN AUTOIMMUNITY  Many potential therapeutic targets for autoimmune disorders  Targets include cell surface markers, cytokines, and autoantibodies  Selection of optimal target will depend on the disease pathology IB McInnes, EM Gravallese. Nat Rev Immunol. 21;680-686 (2021). DISEASE MODIFYING AGENTS  Frequently referred to as ‘disease modifying anti-rheumatic drugs’  Synthetic agents (sDMARD)  Conventional: Methotrexate, Sulfasalazine, Leflunomide, etc.  Targeted: Tofacitinib, etc.  Biological (bDMARD)  Original: Anti-TNF mAbs, anti-CD20 mAbs, anti-IL-6R mAbs, IL-1 inhibitor, etc.  Biosimilars: Generic versions of original bDMARD  These act to slow disease progression (hence the name!)  Drugs such as NSAIDs and steroids treat symptoms but do not slow disease progression  Wide range of therapies give providers many options to treat patients if they relapse or are refractory to a given therapy  HOW DO B CELL DEPLETING MABS WORK?  Rituximab leads to death of CD20-expressing B cells by 3 mechanisms  Direct lysis  Antibody-dependent cellular cytotoxicity  Complement-dependent cytotoxicity  This significantly reduces circulating B cells and therefore reduces B cell-dependent autoimmunity RP Taylor, MA Lindorfer. Nat Rev Rheumatol. 3;86-95 (2007). JCW Edwards, L Szczepanski et al. N Engl J Med. 350;2572-2581 (2004).  HOW DOES IVIG WORK IN AUTOIMMUNITY?  IVIG has many likely mechanisms by which it acts in autoimmune conditions  Direct neutralization of autoantibodies and cytokines is possible  Altered function of effector mechanisms (FcR) – biased towards anti-inflammatory  Accelerated elimination of pathogenic antibodies N Nikolov, J Reisinger et al. Immunotherapy. 8(8);923-940 (2016). Hypersensitivity Disorders The Coombs and Gell classification of the four types of hypersensitivity reaction Hypersensitivity refers to harmful immune responses against foreign antigens:  Environmental antigens,  Drugs,  Microbes. 84  Classification of Hypersensitivity Diseases  Hypersensitivity diseases are commonly classified according to the type of immune response and the effector mechanism responsible for cell and tissue.  These mechanisms include some that are predominantly dependent on antibodies and others predominantly dependent on T cells, although humoral and cell-mediated immunities often coexist, and both contribute to tissue injury in many hypersensitivity diseases. 85  Effector mechanisms of antibody-mediated disease  Auto Abs that are receptor agonists mimic the natural ligand of the receptor and cause the receptor to transduce activating signals in the absence of its ligand.  In contrast, autoAbs that are receptor antagonists do not activate signaling on binding to the receptor and they block the natural ligand from binding to the receptor and activating its signaling function. 86 Diseases Caused by Cell- or Tissue-Specific Antibodies Antibodies that cause cell- or tissue-specific diseases are usually autoantibodies produced as part of an autoimmune reaction, but sometimes the antibodies are specific for microbes. 87 Mechanisms of T cell–mediated diseases  T lymphocytes injure tissues by either producing cytokines that induce inflammation or directly killing target cells.  Inflammatory reactions are elicited mainly by CD4+ T cells of the Th1 and Th17 subsets. In some T cell–mediated disorders, the principal mechanism of tissue injury is killing of cells by CD8+ CTLs.  The T cells that cause tissue injury may be autoreactive, or they may be specific for foreign protein antigens that are present in or bound to cells or tissues.  T lymphocyte–mediated tissue injury may also accompany strong protective immune responses against persistent microbes, especially intracellular microbes that resist eradication by phagocytes and antibodies. 88 T Cell–Mediated Diseases  Many organ-specific autoimmune diseases are caused by activation of autoreactive T cells by self antigens, leading to cytokine release and inflammation.  This is thought to be the major mechanism underlying rheumatoid arthritis, multiple sclerosis (MS), type 1 diabetes, psoriasis, and other autoimmune diseases  Type 1 diabetes, also called insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes, is caused by the selective autoimmune destruction of the insulin-producing cells of the pancreas. 89 Cytokines  Cytokines are responsible for many of the cellular responses of innate and adaptive immunity and thus function as the “messenger molecules” of the immune system.  Cytokines secreted by helper T lymphocytes stimulate the proliferation and differentiation of the T cells themselves and activate other cells, including B cells, macrophages, and other leukocytes. Biologic actions of IL-2 A, Interleukin-2 (IL-2) stimulates the survival, proliferation, and differentiation of T lymphocytes, acting as an autocrine growth factor, leading to the generation of effector and memory cells. B, IL-2 also promotes the survival of regulatory T cells and maintains their functional capability, and thus controls immune responses (e.g., against self antigens). TCR, T cell receptor.  Autocrine  Paracrine  Endocrine 92 The Immune Synapse 93  The Immune Synapse  The synapse forms a stable contact between an antigen- T Cell specific T cell and an APC displaying that antigen and becomes the site for assembly of the signaling machinery of the T cell, including the TCR complex, coreceptors, costimulatory receptors, and adaptors.  The immune synapse provides a unique interface for TCR triggering, thus facilitating prolonged and effective T cell signaling.  The synapse ensures the specific delivery of secretory granule contents and cytokines from a T cell to APCs or to targets that are in contact with the T cell.  The synapse, may also be an important site for the turnover of signaling molecules. This degradation of signaling proteins contributes to the termination of T cell activation. APC 94 T cell signaling 95 Cytokine Antagonists in Clinical Use or Trials 96 Therapeutic Approaches for Immunologic Diseases 97 Mechanisms of action of immunosuppressive drugs 98 Mechanisms of action of immunosuppressive drugs 99 Mechanisms of action of immunosuppressive drugs 100  Corticosteroids switch on anti-inflammatory gene expression Corticosteroid activation of anti-inflammatory gene expression. Corticosteroids bind to cytoplasmic glucocorticoid receptors (GRs) that translocate to the nucleus, where they bind to glucocorticoid response elements (GREs) in the promoter region of steroid- sensitive genes and also directly or indirectly to coactivator molecules such as cAMP-response-element-binding-protein-binding protein (CBP), p300/CBP-associated factor (pCAF) or steroid receptor coactivator (SRC)-2, which have intrinsic histone acetyltransferase (HAT) activity, causing acetylation of lysines on histone H4, which leads to activation of genes encoding anti- inflammatory proteins, such as secretory leukoprotease inhibitor (SLPI), mitogen-activated protein kinase phosphatase (MKP)-1, inhibitor of nuclear factor-κB (IκB-α) and glucocorticoid-induced leucine zipper protein (GILZ). ↑: increase. European Respiratory Journal 2006 101  Corticosteroids switch off inflammatory genes  Corticosteroid suppression of activated inflammatory genes. Inflammatory genes are activated by inflammatory stimuli, such as interleukin (IL)-1β or tumour necrosis factor (TNF)-α, resulting in activation of inhibitor of I-κB kinase (IKK)2, which activates the transcription factor nuclear factor (NF)-κB.  A dimer of p50 and p65 NF-κB translocates to the nucleus and binds to specific κB recognition sites and also to coactivators, such as cAMP-response-element-binding-protein-binding protein (CBP) or p300/CBP-associated factor (pCAF), which have intrinsic histone acetyltransferase (HAT) activity.  This results in acetylation of core histone H4, resulting in increased expression of genes encoding multiple inflammatory proteins. Glucocorticoid receptors (GRs), after activation by corticosteroids, translocate to the nucleus and bind to coactivators in order to inhibit HAT activity directly and recruiting histone deacetylase (HDAC)2, which reverses histone acetylation, leading to suppression of these activated European Respiratory Journal 2006 inflammatory genes. ↑: increase; -: suppression. 102 Immunosuppressive drugs 103