Lessons 1 and 2_Intro Innate Immunity, student.pdf

3/6/2024 Introduction to Immunology Goldsmith Introduction to the immune system ▪ What is immunity and the immune system? ▪ Tissues of the immune system ▪ Cells of the immune system 1 3/6/2024 Objectives ◼ After completion of this section, you will be able to: ◼ ◼ ◼ ◼ ◼ Define immunity Describe appr...

3/6/2024 Introduction to Immunology Goldsmith Introduction to the immune system ▪ What is immunity and the immune system? ▪ Tissues of the immune system ▪ Cells of the immune system 1 3/6/2024 Objectives ◼ After completion of this section, you will be able to: ◼ ◼ ◼ ◼ ◼ Define immunity Describe appropriate and inappropriate immune responses and provide examples Describe the tissues and cells of the immune system and provide examples of their roles in, and contributions to, immunity Compare and contrast innate and adaptive immunity Compare and contrast active and passive immunity Immunity = Body’s ability to resist disease ◼ ◼ Immune system is key: includes cells, tissues, and molecules Immune response: coordinated reaction of these cells and molecules ◼ Defense against infection ◼ ◼ ◼ ◼ ◼ Weakened immune system: susceptibility to lifethreatening infections Stimulating immune system: vaccination against infection Defense against tumors: immunotherapies Inappropriate immune responses: allergies, autoimmunity Recognizes and responds to grafts and new proteins 2 3/6/2024 The Goals of Immunity Appropriate: ◼ Defense against infection/disease ◼ Acquired immunity ◼ ◼ ◼ Active – induced by infection or immunization Passive – conferred upon individual by transfer of Abs of lymphocytes from actively immunized individual Defense against tumors Inappropriate: ◼ ◼ ◼ Allergy Autoimmunity Transplant rejection (+) The Immune System The body’s defense system: composed of a complex network of organs, tissues, cells, and soluble factors working together in harmony 3 3/6/2024 Comparison of innate and adaptive immunity Innate (= non- Adaptive (= specific or specific) acquired) Response time Immediate/Hours Specificity Limited and fixed; Response to repeat infection Major components Days Highly specific and not specific; does diverse; improves during not improve course of response Identical to Much more rapid than primary response primary response Barriers; B and T lymphocytes; phagocytes; antigen-specific receptors; pattern antibodies recognition molecules The Immune System: Innate and adaptive immunity First line of defense Low specificity Rapid Does not generate immunological memory Acquired response Specific Slower Memory generation 4 3/6/2024 Specificity and receptors of innate and adaptive immunity Lymphoid tissues ◼ ◼ ◼ ◼ ◼ bone marrow thymus lymph nodes spleen GALT (gut-associated lymphoid tissues) ◼ ◼ ◼ ◼ ◼ ◼ tonsils adenoids appendix Peyer’s patches: sm. int. MALT (mucosaassociated) BALT (bronchialassociated) 5 3/6/2024 Lymphocyte Generative Organs Bone Marrow Role: site of blood cell development, immune cell progenitors Spongy central cavity of bone Site of B-cell maturation 6 3/6/2024 Thymus Role: Site of T-cell development Two-lobed organ Divided by inner medulla and outer cortex Site for central tolerance; positive and negative selection Lymphatic System and Lymph Nodes Role: Lymph-borne infection filtration Lymphatic vessels: channels that connect the lymphatic system; facilitate transport between draining regions of the body and lymph nodes Lymph nodes: encapsulated nodular aggregates of lymphoid tissues located along lymphatic channels throughout the body Lymph: colorless, protein-rich, fluid that moves throughout the lymphatic system and drains back into the blood via the thoracic duct 7 3/6/2024 Spleen Role: Blood-borne infection and dead cell filtration Highly vascularized abdominal organ: serves the same role in the immune responses as the lymph nodes, but is specific to blood-borne antigens Major site of adaptive immune responses Red pulp: composed of blood-filled vascular sinusoids lined by active phagocytes that ingest opsonized antigens and damaged red blood cells White pulp: contains lymphocytes and lymphoid follicles Spleen 8 3/6/2024 9 3/6/2024 Essential Terminology Review: Examples Adjuvant – a substance, distinct from antigen, that enhances T-cell and B-cell activation mainly by promoting the accumulation of antigen-presenting cells at the site of antigen exposure. Chemokine - a large family of structurally homologous low-molecular weight cytokines that stimulate leukocyte chemotaxis. Epitope – the specific portion of a macromolecular antigen to which an antibody binds. Hybridoma – a cell line derived by fusion between normal lymphocyte and an immortalized lymphocyte cancerous cell. Isotype – one of five types of antibodies, determined by which of five different forms of heavy chain is present. Opsonization – the process of attaching opsonins, such as IgG or complement fragments, to microbials surfaces to target them for phagocytosis. Tolerance – unresponsiveness of the adaptive immune system to antigens, as result of inaction of death of antigen-specific lymphocytes, induced by exposure to antigens. Wheal-and-flare reaction – local swelling and redness in the skin at a site of an immediate hypersensitivity reaction. Moral of the Story = The glossary will be your best friend! Immunology: Introduction to Innate Immunity Goldsmith 10 3/6/2024 Introduction to innate immunity ▪ Components of innate immune system ▪ Innate immune reactions Objectives ◼ After completion of this section, you will be able to describe, discuss the function of, and provide examples of the following components of innate immunity: ◼ ◼ ◼ Anatomic and physiologic barriers Cells Soluble and chemical mediators 11 3/6/2024 Innate Immune System = “First line of defense” Infections occur when pathogens evade/overwhelm innate defenses What is the Innate Immune System? 1 The innate immune system is: Non-specific Rapid response; immediate to less than 12 hours No memory Functional components; synergy of: 1. Physical barriers 2. Chemical barriers 3. Cellular barriers 4. Soluble mediators 2 3 4 12 3/6/2024 Components of innate immunity ◼ ◼ ◼ Anatomic and physiologic barriers ◼ Skin, mucous membranes, lysozymes (mucous secretions and tears), stomach and vaginal pH, saliva, perspiration Cellular: Cells in tissues and circulation ◼ Blood monocytes, PMNs (neutrophils), tissue macrophages (Kupffer and Langerhans cells), etc. Soluble and chemical mediators: ◼ Plasma proteins, cytokines, complement factors, collectins Innate Immunity: Physical/Anatomical Barriers ◼ ◼ Epithelial cell surfaces Epithelial barriers: ◼ ◼ ◼ ◼ ◼ Antibiotics: locally Skin made Gastrointestinal tract Respiratory tract Urogenital tract Mechanisms of protection: ◼ ◼ ◼ Continuous epithelia Intraepithelial cells Tight junctions Mucus Cilia 13 3/6/2024 Components of innate immunity ◼ ◼ ◼ Anatomic and physiologic barriers ◼ Skin, mucous membranes, lysozymes (mucous secretions and tears), stomach and vaginal pH, saliva, perspiration Cellular: Cells in tissues and circulation ◼ Blood monocytes, PMNs (neutrophils), tissue macrophages (Kupffer and Langerhans cells), etc. Soluble and chemical mediators: ◼ Plasma proteins, cytokines, complement factors, collectins Innate Immunity: Cellular Barriers Microbiome 14 3/6/2024 Phagocytes: immediate recognition of invaders ◼ ◼ Neutrophils and macrophages: recruited to, or resident in, sites of infection; recognize, ingest, and kill microbes Macrophages (Mfs, mononuclear phagocytes) ◼ ◼ ◼ ◼ Mature from circulating monocytes Resident in most tissues: unique terminology/naming scheme based on anatomical location Largest numbers: connective tissue; submucosa of g.i. tract; lung (interstitium and alveoli); liver (Kupffer cells); spleen Neutrophils (polymorphonuclear neutrophilic leukocytes, PMNs, polys): ◼ Most abundant, short-lived, circulating cells; first at site of infection from circulation PMN Monocyte Macrophage 15 3/6/2024 Macrophages (Mfs) ◼ Diverse functional potentials, depending on location and signals ◼ ◼ Two general functional classifications: ◼ M1 (inflammatory) vs. M2 macrophages (secrete growth factors and enzymes: tissue repair = “alternative macrophage activation” ) Produce cytokines: recruit & activate leukocytes, stimulate T cells ◼ Help initiate adaptive immune response ◼ Respond to T cell products ◼ Two general populations: ◼ ◼ Fcn as effector cells in cell-mediated immunity Resident: ◼ ◼ ◼ ◼ ◼ Tissue location Immunological surveillance Homeostasis Tissue Repair Inflammatory: ◼ ◼ Circulatory Respond to injury and/or infection Mononuclear phagocyte maturation 16 3/6/2024 17 3/6/2024 Application ◼ ◼ Pathogenesis of inflammatory bowel disease: Loss-of-function mutations in the IL-10 receptor linked to severe, progressive Crohn’s disease Treatment w/ allogeneic hematopoietic stem cell transplantation Components of innate immunity ◼ ◼ ◼ Anatomic and physiologic barriers ◼ Skin, mucous membranes, lysozymes (mucous secretions and tears), stomach and vaginal pH, saliva, perspiration Cellular: Cells in tissues and circulation ◼ Blood monocytes, PMNs (neutrophils), tissue macrophages (Kupffer and Langerhans cells), etc. Soluble and chemical mediators: ◼ Plasma proteins, cytokines, complement factors, collectins 18 3/6/2024 Neutrophils ◼ ◼ ◼ ◼ ◼ First responders to infection or trauma site – minutes Most abundant type of leukocyte (white blood cell = WBC) Recruited from blood to infection site driven by chemotaxis Phagocytic High local release of: ◼ ◼ Reactive oxygen/nitrogen species Cytotoxic granules Other Granulocytes Eosinophils: cytotoxic granule release Basophils: histamine release Mast cells: sentinels of the immune system; react to danger stimuli Dendritic and Mast Cells ◼ Dendritic cells: ◼ ◼ Bridge b/n innate and adaptive immunity Respond to microbes by producing cytokines ◼ ◼ ◼ Cytokines recruit leukocytes and initiate adaptive immunity “Professional” antigen presenting cells (APCs): major function Mast cells: ◼ ◼ ◼ Present in skin and mucosal epithelium Abundant cytoplasmic granules; contents (e.g., vasoactive amines) released upon activation Activated by innate and adaptive mxms 19 3/6/2024 Dendritic Cells ◼ Two general populations: ◼ Classical: ◼ ◼ ◼ ◼ ◼ ◼ Professional antigen-presenting cells “Bridge to Adaptive Immunity” High phagocytic activity High cytokine production Highly migratory Short-lived Plasmacytoid: ◼ ◼ ◼ Specialized to respond to viral infection Type I Interferon (cytokine) secretion Long-lived T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. TR Mempel, SE Henrickson, UH von Andrian. Nature 427, 154-159, January 8, 2004. T cells establish short interactions with dendritic cells 20 3/6/2024 NK cells ◼ Lymphocytes (but do NOT have Ag-specific Rs) that recognize infected and stressed cells ◼ ◼ Response triggered by invariant receptors on infected cell surfaces ◼ ◼ ◼ 10% of total lymphocyte population in circulation and peripheral lymphoid organs Release granule contents: Kill infected host cells Secrete interferon-g (IFN-g): activates macrophages Eliminate cellular reservoirs of infection by obligate intracellular microbes; remove rogue/stressed cells 21 3/6/2024 NK cells 2 ◼ Distinguish infected cells from uninfected cells, believed to involve: ◼ Inhibitory receptors specific for MHC I alleles ◼ ◼ Altered MHC I expression on cell surface: killing Activation: balance b/n activating and inhibiting receptors (motifs: ITAMs and ITIMs) NK cells and Cytotoxic T Lymphocytes (CTLs) ◼ Work in tandem: CTLs recognize MHC-displayed viral Ags ◼ If viruses prevent MHC expression, NK cells respond to their absence ◼ ◼ Tumors also targeted by NK cells b/c they often express little MHC class I 22 3/6/2024 Innate lymphoid cells (ILCs) ◼ Early defense against infection; guide later T cell responses ◼ ◼ Divided into 3 major groups based upon cytokines secreted ◼ ◼ ◼ Produce cytokines; functions similar to T lymphocytes, but with limited receptor diversity and more rapid responses Groups correspond to Th1, Th2, and Th17 subsets of CD4+ T cells Mxm of microbe recognition not defined Responses often stimulated by cytokines Innate Immune Cells Review Guide 23 3/6/2024 Bill the Cat, from the comic “Bloom County” Components of innate immunity ◼ ◼ ◼ Anatomic and physiologic barriers ◼ Skin, mucous membranes, lysozymes (mucous secretions and tears), stomach and vaginal pH, saliva, perspiration Cellular: Cells in tissues and circulation ◼ Blood monocytes, PMNs (neutrophils), tissue macrophages (Kupffer and Langerhans cells), etc. Soluble and chemical mediators: ◼ Plasma proteins, cytokines, complement factors, collectins 24 3/6/2024 Innate Immunity: Chemical Barriers ◼ ◼ Stomach acid and enzymes Antimicrobial peptides 3 mechanisms of action: 1. 2. 3. ◼ 1 2 Membrane disruption Nutrient sequestration Enzymatic degradation Reactive oxygen/nitrogen species 3 Innate Immunity: Soluble Mediators ◼ ◼ Cytokines/Chemokines The Complement System 25 3/6/2024 Cytokines ◼ ◼ ◼ ◼ Small peptides (25 kDa) Released by variety of cells, mediate many cellular rxns of innate (& adaptive) immunity Induce responses by binding specific receptors Communication b/n leukocytes and b/n leukocytes and other cells ◼ ◼ Autocrine, paracrine, endocrine Structurally diverse, grouped by structure, as are receptors 26 3/6/2024 Complement system ◼ First discovery: Augments opsonization and bacterial killing by antibodies ◼ ◼ ◼ i.e., it “complements” antibacterial activity BUT: has role in innate immunity Consists of MANY distinct plasma proteins ◼ Produced by liver; inactive in plasma and tissue until activated locally by exposure to: ◼ ◼ Specific carbohydrate chains on microbial surface; Ag-Abs complexes; lectin binding to pathogen surface These proteins react with one another in a cascade (many are proteases themselves) Complement system: Functions and Nomenclature ◼ ◼ ◼ ◼ Lyse cells, bacteria, and viruses Coat microbes: Opsonins; promote phagocytosis Inflammatory mediators Nomenclature: designated by numerals and by letters, some with more arcane names ◼ Peptide fragments denoted by small letters (a, b) 27 3/6/2024 Complement cascade: 3 pathways for activation ◼ Alternative pathway: ◼ ◼ Classical pathway: ◼ ◼ Triggered by certain complement proteins being activated on microbial surfaces = innate immunity Triggered after Abs bind to microbes or other Ags = humoral arm of adaptive immunity Lectin pathway: ◼ Triggered after plasma protein, mannose-binding protein, binds to terminal mannose residues on surface of microbe glycoproteins = innate Complement activation ◼ Regardless of initial stimulus, activated complement proteins fcn as proteolytic enzymes, cleave other complement proteins ◼ ◼ ◼ Cascade is amplified Late steps converge, perform same effector fcns Central component: C3 ◼ One fragment, C3b, attaches to microbes activating downstream complement proteins 28 3/6/2024 Effector fcns Complement activation http://www.studentconsult.com Application: Complement block ◼ ◼ Eculizumab: monoclonal Ab against complement factor, C5 Reduces hemolysis in paroxysmal nocturnal hemoglobinuria: ◼ ◼ Acquired genetic mutation: membrane defect in stem cells and progeny (RBCs, WBCs, platelets) Unusual sensitivity to normal C3 in the plasma: causes ongoing intravascular hemolysis of RBCs and diminished WBC and platelet production 29 3/6/2024 Application of Innate Immunity: Inflammation Purposes of Inflammation: 1. Delivery of additional effector molecules and cells to site of infection (augmenting local macrophages) 2. Microvascular coagulation helps prevent pathogen spread into bloodstream (physical barrier) 3. Promote tissue repair following injury Accumulation and activation of leukocytes and plasma protein at site of infection or injury Clinical symptoms of inflammation: pain, redness, heat, swelling Innate immunity stimulates adaptive immunity ◼ ◼ ◼ Innate responses generate molecules (2nd signals), act w/ Ags to activate T and B cells Full activation of Ag-specific T and B lymphocytes requires 2 signals: ◼ Ag = signal 1; ◼ Microbes, innate response to microbes, damaged host cells = signal 2 Protective: lymphocytes respond only to infectious agents/damage, not harmless things 30 3/6/2024 Innate immunity: Second signals ◼ ◼ Stimulate adaptive immunity AND guide the nature of adaptive immune response ◼ Intracellular and phagocytosed microbes: cellmediated immunity = T cell mediated ◼ ◼ Dendritic cells and macrophages provide second signals Blood-borne microbes: humoral immunity = B cell mediated ◼ Complement activated, provides second signal 31