Induced Responses of Innate Immunity PDF 2024

Induced Responses of Innate Immunity Dr Allison Imrie Learning Outcomes You should understand and be able to describe: Antigen recognition by innate immune cells and the later events which occur following ligation of microbial elements How the process of inflammation is induced, and the cells that p...

Induced Responses of Innate Immunity Dr Allison Imrie Learning Outcomes You should understand and be able to describe: Antigen recognition by innate immune cells and the later events which occur following ligation of microbial elements How the process of inflammation is induced, and the cells that participate in the inflammatory response The process whereby immune cells adhere to endothelium and transition into and out of the tissue space Protective and dysfunctional cytokine responses induced by inflammation The anti-viral response Natural killer cells and their role in innate immunity Innate Immune Sensors: Innate Immune Sensors: Monocyte-derived macrophages and induction of the inflammatory response Monocyte Macrophage Neutrophil Induction of the inflammatory response Blood monocytes differentiate into tissue macrophages during process of inflammation Immune cell movement is controlled by adhesion molecules Phagocyte Vascular endothelium Neutrophils leave the blood and migrate to sites of infection in a multi-step process involving adhesive interactions that are regulated by macrophage-derived cytokines and chemokines Neutrophils leave blood and migrate to sites of infection in a multi-step process involving adhesive interactions that are regulated by macrophage-derived cytokines and chemokines Binding of a chemokine such as CXCL8 to its receptor on the neutrophil triggers activation of integrin LFA-1 Inflammatory cytokines such as TNF-⍺ are also necessary to induce expression of adhesion molecules such as ICAM-1, ligand for the integrin, on vascular endothelium Tight binding between ICAM-1 and integrin arrests rolling and allows neutrophil to squeeze between endothelial cells that form blood vessel wall Neutrophil migrates along a concentration gradient of chemokines eg. CXCL8 Important cytokines and chemokines secreted by dendritic cells and macrophages in response to bacterial products include IL-1β; IL-6; CXCL8; IL-12; and TNF-⍺ Chemokines recruit immune cells to sites of infection The cytokines TNF-⍺, IL-1β, and IL-6 have a wide range of biological activities that help coordinate the body’s response to infection The release of TNF-⍺ by macrophages induces local protective effects, but TNF-⍺ can be damaging when released systemically TNF-⍺ acts on blood vessels, especially venules, to: increase blood flow and vascular permeability to fluid, proteins and cells Increase endothelial adhesiveness for leukocytes and platelets Local release allows influx of fluids, cells and proteins into the infected tissue, where they participate in host defense Blood clots form in small vessels, preventing spread of infection via blood Accumulated fluid and cells drain to lymph nodes, to initiate adaptive immune response In a systemic infection – sepsis - TNF-⍺ is released into the blood by macrophages in the liver and spleen and acts in a similar way on small blood vessels Result is shock, disseminated intravascular coagulation with depletion of clotting factors and consequent bleeding, multiple organ failure, and frequently death The acute phase response produces molecules that bind pathogens but not host cells Acute phase proteins are produced by hepatocytes in response to cytokines produced by macrophages in the presence of bacteria The anti-viral response An infection and the response to it can be divided into a series of stages Infectious agent is delivered to lymph node inside dendritic cell to activate adaptive immune response Summary Toll-like receptors (TLRs), present on the cell surface and in endosomes, are an important family of pattern recognition receptors, recognizing a wide variety of ligands, including bacterial cell wall components and microbial nucleic acids Cytosolic pattern recognition receptors exist that recognize microbial molecules. These receptors include the retinoic acid–inducible gene (RIG)-like receptors (RLRs), which recognize viral RNA; cytosolic DNA sensors (CDSs), which recognize microbial DNA; and NOD-like receptors (NLRs), which recognize bacterial cell wall constituents and also serve as recognition components of many inflammasomes Pattern recognition receptors, including TLRs, NLRs, and RLRs, signal to activate the transcription factor NF-κB, which stimulates expression of cytokines, costimulators, and other molecules involved in inflammation, and the interferon response factor (IRF) transcription factors, which stimulate expression of the antiviral type I interferon (IFN) genes NK cells have cytotoxic functions and secrete interferon-γ (IFN-γ), similar to cytotoxic T lymphocytes (CTLs). NK cells defend against intracellular microbes by killing infected cells and providing a source of the macrophage-activating cytokine IFN-γ. NK cell recognition of infected cells is regulated by a combination of activating and inhibitory receptors. Inhibitory receptors recognize class I major histocompatibility complex (MHC) molecules, because of which NK cells do not kill normal host cells but do kill cells in which class I MHC expression is reduced, such as virus-infected cells Summary The two major effector functions of innate immunity are to induce inflammation, which involves the delivery of microbe-killing leukocytes and soluble effector molecules from blood into tissues, and to block viral infection of cells mainly by the antiviral actions of type I IFNs Several cytokines produced mainly by macrophages, dendritic cells (DCs), and other innate immune cells mediate inflammation Tumor necrosis factor (TNF) and IL-1 activate endothelial cells, stimulate chemokine production, and increase neutrophil production in the bone marrow IL-1 and TNF both induce IL-6 production, and all three cytokines mediate systemic effects, including fever and acute-phase protein synthesis by the liver IL-12 and IL-18 stimulate These cytokines function in innate immune responses to different classes of microbes, and some (IL-1, IL6, IL-12, IL-18) modify adaptive immune responses that follow the innate immune responseproduction of the macrophage-activating cytokine IFN-γ by NK cells and T cells Summary Neutrophils and monocytes (the precursors of tissue macrophages) migrate from blood into inflammatory sites during innate immune responses because of the effects of cytokines and chemokines produced by PAMP- and DAMP-stimulated tissue cells Neutrophils and macrophages phagocytose microbes and kill them by producing reactive oxygen species, nitric oxide, and enzymes in phagolysosomes. Macrophages also produce cytokines that stimulate inflammation and promote tissue repair at sites of infection. Phagocytes recognize and respond to microbial products by several different types of receptors, including TLRs, C-type lectins, scavenger receptors, and N -formyl met-leu-phe receptors Molecules produced during innate immune responses stimulate adaptive immunity and influence the nature of adaptive immune responses. DCs activated by microbes produce cytokines and costimulators that enhance T cell activation and differentiation into effector T cells Complement fragments generated by the alternative pathway provide second signals for B cell activation and antibody production