Innate Immunity PDF

INNATE IMMUNITY Dr. HÜSNİYE IŞIN General Features and Specificity of Innate Immune Responses 1. The two principal types of reactions of the innate immune system are inflammation and antiviral defense. 2. The innate immune system responds in essentially the same way to repeat e...

INNATE IMMUNITY Dr. HÜSNİYE IŞIN General Features and Specificity of Innate Immune Responses 1. The two principal types of reactions of the innate immune system are inflammation and antiviral defense. 2. The innate immune system responds in essentially the same way to repeat encounters with a microbe, whereas the adaptive immune system mounts stronger and more effective responses to each successive encounter with a microbe. 3. The innate immune system recognizes structures that are shared by various classes of microbes and are not present on normal host cells. Recognition of Microbes and Damaged Self by The Innate Immune System The specificities of innate immune recognition have evolved to combat microbes and are different from the specificities of the adaptive immune system in several respects  The microbial molecules that stimulate innate immunity are often called pathogen-associated molecular patterns (PAMPs) to indicate that they are present in infectious agents (pathogens) and shared by microbes of the same type. Different classes of microbes (e.g., viruses, gram-negative bacteria, grampositive bacteria, fungi) express different PAMPs. The innate immune system also recognizes endogenous molecules that are produced by or released from damaged and dying cells. These substances are called damage-associated molecular patterns (DAMPs) DAMPs may be produced as a result of cell damage caused by infections, but they may also indicate sterile injury to cells caused by any of myriad reasons, such as chemical toxins, burns, trauma, or decreased blood supply.  The innate immune system uses several types of cellular receptors, present in different locations in cells, and soluble molecules in the blood and mucosal secretions to recognize PAMPs and DAMPs. These cellular receptors for pathogens and damage-associated molecules are often called pattern recognition receptors. They are expressed on the plasma membrane or endosomal membranes of various cell types and also in the cytoplasm of these cells. The receptors of the innate immune system are encoded by inherited genes that are identical in all cells. Therefore, many cells of innate immunity may recognize and respond to the same microbe. This is in contrast to the antigen receptors of the adaptive immune system The components of innate immunity have evolved to recognize structures of microbes that are often essential for the survival and infectivity of these microbes. The innate immune system does not react against the normal host. Cellular Receptors for Microbes and Damaged Cells The receptors used by the innate immune system to react against microbes and damaged cells are expressed on phagocytes, dendritic cells, and many other cell types, and are expressed in different cellular compartments where microbes may be located. These receptors are present on the cell surface, where they detect extracellular microbes; in vesicles (endosomes) into which microbial products are ingested; and in the cytosol, where they function as sensors of cytoplasmic microbes. Cellular Receptors for Microbes and Damaged Cells Toll-Like Receptors (TLRs) NOD-Like Receptors and the Inflammasome (NLRs) Other Cellular Receptors of Innate Immunity The RIG-like receptor (RLR) Cytosolic DNA sensors (CDSs) Lectin (carbohydrate-recognizing) receptors A cell surface receptor Cellular locations of receptors of the innate immune system. Toll-Like Receptors (TLRs) Toll-like receptors (TLRs) are homologous to a Drosophila protein called Toll, which was discovered for its role in the development of the fly and later shown to be essential for protecting flies against infections. TLRs specific for microbial proteins, lipids, and polysaccharides (many of which are present in bacterial cell walls) are located on cell surfaces, where they recognize these products of extracellular microbes. TLRs that recognize nucleic acids are in endosomes, into which microbes are ingested and where the microbes are digested and their nucleic acids are released. Toll-like receptor (TLR) structure and binding of PAMP ligands. Structure of a TLR polypeptide chain. Each TLR polypeptide chain is made up of a ligand-binding exterior domain that contains many leucine-rich repeats. When TLRs bind their PAMP or DAMP ligands via their extracellular LRR domains, they are induced to dimerize. Toll-Like Receptors (TLRs) Different TLRs are specific for different components of microbes TLR-2 recognizes several bacterial and parasitic glycolipids and peptidoglycans; TLR-3, -7, and -8 are specific for viral single-stranded and double- stranded RNAs; TLR-4 is specific for bacterial LPS (endotoxin); TLR-5 is specific for a bacterial flagellar protein called flagellin; and TLR-9 recognizes unmethylated CpG DNA, which is more abundant in microbial genomes than in mammalian DNA. Different TLRs respond to many different, structurally diverse products of microbes. Endosomal TLRs respond only to nucleic acids. All TLRs contain a ligand-binding domain composed of leucine-rich motifs and a cytoplasmic signaling, Toll-like interleukin-1 (IL- 1) receptor (TIR) domain. Toll-Like Receptors (TLRs) Signals generated by engagement of TLRs activate transcription factors that stimulate expression of genes encoding cytokines, enzymes, and other proteins involved in the antimicrobial functions of activated phagocytes and other cells. NOD-Like Receptors and the Inflammasome (NLRs) The NOD-like receptors (NLRs) are a large family of cytosolic receptors that sense DAMPs and PAMPs in the cytoplasm. They play major roles in activating beneficial innate immune and inflammatory responses, but, as we will see, some NLRs also trigger inflammation that causes extensive tissue damage and disease. The human genome contains approximately 23 NLR genes All NLRs contain a central NOD (nucleotide oligomerization domain) but have different N-terminal domains. NOD-Like Receptors and the Inflammasome (NLRs) Three important NLRs are NOD-1, NOD-2, and NLRP-3. NOD-1 and NOD-2 are cytosolic proteins containing N-terminal CARD (caspase related) domains. They are specific for bacterial peptidoglycans, which are common components of bacterial cell walls. They both activate the NF-κB transcription factor. Important PAMPs recognized by NOD1 and NOD2 are breakdown products produced during the synthesis or degradation of cell Wall peptidoglycans of either intracellular or extracellular bacteria—peptides from the latter must enter the cell to activate NODs. NLRP-3 (NOD-like receptor family, pyrin domain containing 3) is a cytosolic NLR that responds to many unrelated microbial structures or pathologic changes in the cytosol and reacts by enhancing production mainly of the inflammatory cytokine IL-1β. NLR families The Inflammasome NLRP-3 oligomerizes with an adaptor protein and an inactive (pro) form of the enzyme caspase-1, resulting in generation of the active form of the enzyme This cytosolic complex of NLRP-3 (the sensor), an adaptor protein, and caspase-1 is known as the inflammasome. The inflammasome is important not only for host defense but also because of its role in several diseases. Gain-of-function mutations in NLRP-3 are the cause of rare autoinflammatory syndromes, characterized by uncontrolled and spontaneous inflammation. IL-1 antagonists are effective treatments for these diseases. The common joint disease gout is caused by deposition of urate crystals, and subsequent inflammation mediated by inflammasome recognition of the crystals and IL-1β production. The inflammasome Other Cellular Receptors of Innate Immunity The RIG-like receptor (RLR) family recognizes RNA produced by viruses in the cytosol and activates signaling pathways that lead to the production of type I interferon (IFN). Cytosolic DNA sensors (CDSs) include several structurally related proteins that recognize cytosolic viral DNA and also induce type I IFN production. Lectin (carbohydrate-recognizing) receptors in the plasma membrane are specific for fungal glycans (these receptors are called dectins) and for terminal mannose residues (called mannose receptors) phagocytosis of fungi and bacteria and in inflammatory responses to these pathogens. A cell surface receptor expressed mainly on phagocytes recognizes peptides that begin with N-formylmethionine, which is specific to bacterial proteins, and promotes the migration as well as the antimicrobial activities of the phagocytes. Components Of Innate Immunıty The components of the innate immune system include epithelial cells; sentinel cells in tissues (macrophages, dendritic cells, mast cells, and others); innate lymphoid cells, including NK cells; and a number of plasma proteins. Epithelial Barriers The major interfaces between the body and the external environment - the skin, - gastrointestinal tract, - respiratory tract, and - genitourinary tract are protected by continuous epithelia that provide physical and chemical barriers against infection Functions of epithelia in innate immunity. Epithelia present at the portals of entry of microbes provide physical barriers formed by keratin (in the skin) or secreted mucus (in the gastrointestinal, bronchopulmonary and genitourinary systems) and by tight junctions between epithelial cells. Epithelial Barriers Keratin on the surface of the skin and mucus secreted by mucosal epithelial cells prevent microbes from coming in contact with and infecting the epithelia. Epithelial cells also produce peptide antibiotics, called defensins and cathelicidins, which kill bacteria and thus provide a chemical barrier against infection. In addition, epithelia contain lymphocytes called intraepithelial T lymphocytes that belong to the T cell lineage but express antigen receptors of limited diversity. Some of these T cells express receptors composed of two chains, γ and δ, that are similar but not identical to the αβ T cell receptors expressed on the majority of T lymphocytes Phagocytes: Neutrophils and Monocytes/ Macrophages The two types of circulating phagocytes, Neutrophils Monocytes, are blood cells that are recruited to sites of infection, where they recognize and ingest microbes for intracellular killing Phagocytes: Neutrophils and Monocytes/ Macrophages Neutrophils, also called polymorphonuclear leukocytes (PMNs), are the most abundant leukocytes in the blood, numbering 4000 to 10,000 per μL In response to infections, the production of neutrophils from the bone marrow increases rapidly, and their number may rise to as high as 20,000 per μL of blood. The production of neutrophils is stimulated by cytokines, known as colony-stimulating factors (CSFs), which are secreted by many cell types in response to infections and act on hematopoietic stem cells to stimulate proliferation and maturation of neutrophil precursors. Phagocytes: Neutrophils and Monocytes/ Macrophages Neutrophils are the first cell type to respond to most infections, particularly bacterial and fungal infections, and thus are the dominant cells of acute inflammation Neutrophils ingest microbes in the circulation, and they rapidly enter extravascular tissues at sites of infection, where they also phagocytose (ingest) and destroy microbes. Neutrophils express receptors for products of complement activation and for antibodies that coat microbes. These receptors enhance phagocytosis, and also transduce activating signals that enhance the ability of the neutrophils to kill ingested microbes. Neutrophils live for only a few hours in tissues, so they are the early responders, but they do not provide prolonged defense. Phagocytes: Neutrophils and Monocytes/ Macrophages Monocytes, are less abundant in the blood than neutrophils, numbering 500 to 1000 per μL They also ingest microbes in the blood and in tissues. During inflammatory reactions, monocytes enter extravascular tissues and differentiate into cells called macrophages, which, unlike neutrophils, survive in these sites for long periods. Thus, blood monocytes and tissue macrophages are two stages of the same cell lineage, which often is called the mononuclear phagocyte system Some macrophages that are resident in different tissues, such as the brain, liver, and lungs, are derived not from circulating monocytes but from progenitors in the yolk sac or fetal liver early during the development of the organism. Phagocytes: Neutrophils and Monocytes/ Macrophages Macrophages serve several important roles in host defense: they produce cytokines that induce and regulate inflammation, they ingest and destroy microbes, and they clear dead tissues and initiate the process of tissue repair A number of receptor families are expressed in macrophages and involved in the activation and functions of these cells. Pattern recognition receptors discussed earlier, including TLRs and NLRs, recognize products of microbes and damaged cells and activate the macrophages Phagocytosis is mediated by cell surface receptors, such as mannose receptors and scavenger receptors, which directly bind microbes (and other particles), and receptors for products of complement activation and antibodies that are also expressed by neutrophils. Some of these phagocytic receptors activate the microbial killing functions of macrophages,  Macrophages may be activated by two different pathways that serve distinct functions 1. Classical macrophage activation, is induced by innate immune signals, such as from TLRs, and by the cytokine IFN-γ, which may be produced in both innate and adaptive immune responses Classically activated macrophages, also called M1, are involved in destroying microbes and in triggering inflammation. 2. Alternative macrophage activation occurs in the absence of strong TLR signals and is induced by the cytokines IL-4 and IL-13; these macrophages, called M2, appear to be more important for tissue repair and to terminate inflammation. Macrophages are also important effector cells in both the cell- mediated arm and the humoral arm of adaptive immunity. Initiation of a local inflammatory response. Dendritic Cells Dendritic cells respond to microbes by producing numerous cytokines that serve two main functions: they initiate inflammation and they stimulate adaptive immune responses. By sensing microbes and interacting with lymphocytes, especially T cells, dendritic cells constitute an important bridge between innate and adaptive immunity. Mast Cells Mast cells are bone marrow–derived cells with abundant cytoplasmic granules that are present in the skin and mucosal epithelium. Mast cells can be activated by microbial products binding to TLRs, as part of innate immunity, or by a special antibody-dependent mechanism. Mast cell granules contain vasoactive amines such as histamine that cause vasodilation and increased capillary permeability, as well as proteolytic enzymes that can kill bacteria or inactivate microbial toxins. Mast cells also synthesize and secrete lipid mediators (e.g., prostaglandins) and cytokines (e.g., tumor necrosis factor [TNF]), which stimulate inflammation. Mast cell products provide defense against helminths and other pathogens and are responsible for symptoms of allergic diseases Innate Lymphoid Cells (ILCs) Innate lymphoid cells (ILCs) are lymphocyte-like cells that produce cytokines and perform functions similar to those of T lymphocytes but do not express T cell antigen receptors (TCRs). ILCs have been divided into three major groups based on their secreted cytokines; these groups correspond to the Th1, Th2, and Th17 subsets of CD4+ T cells ILCs provide early defense against infections and also guide the subsequent T cell response. Natural Killer Cells Natural killer (NK) cells constitute a third branch of lymphoid cells, along with B and T lymphocytes of the adaptive immune system, all differentiating from the common lymphoid progenitor into three separate lineages Natural killer (NK) cells recognize infected and stressed cells and respond by killing these cells and by secreting the macrophage- activating cytokine IFN-γ NK cells make up approximately 10% of the lymphocytes in the blood and peripheral lymphoid organs. NK cells contain abundant cytoplasmic granules and express some unique surface proteins but do not express immunoglobulins or T cell receptors, the antigen receptors of B and T lymphocytes, respectively. Natural Killer Cells Functions of natural killer (NK) cells. A, NK cells kill host cells infected by intracellular microbes, thus eliminating reservoirs of infection. B, NK cells respond to interleukin- 12 (IL-12) produced by macrophages and secrete interferon-γ (IFN-γ), which activates the macrophages to kill phagocytosed microbes. Natural Killer Cells On activation by infected cells, NK cells empty the contents of their cytoplasmic granules into the extracellular space at the point of contact with the infected cell. The granule proteins then enter infected cells and activate enzymes that induce apoptosis. The cytotoxic mechanisms of NK cells, which are the same as the mechanisms used by cytotoxic T lymphocytes Thus, as with CTLs, NK cells function to eliminate cellular reservoirs of infection and eradicate infections by obligate intracellular microbes, such as viruses  Natural Killer Cells Activated NK cells also synthesize and secrete the cytokine interferon-γ. IFN-γ activates macrophages to become more effective at killing phagocytosed microbes. Cytokines secreted by macrophages and dendritic cells that have encountered microbes enhance the ability of NK cells to protect against infections. Three of these NK cell–activating cytokines are interleukin-15 (IL-15), type I interferons (type I IFNs), and interleukin-12 (IL-12). IL-15 is important for the development and maturation of NK cells, and type I IFNs and IL-12 enhance the killing functions of NK cells. Macrophages ingest microbes and produce IL-12, IL-12 activates NK cells to secrete IFN-γ, and IFN-γ in turn activates the macrophages to kill the ingested microbes. Natural Killer Cells The activation of NK cells is determined by a balance between engagement of activating and inhibitory receptors The activating receptors recognize cell surface molecules typically expressed on cells infected with viruses and intracellular bacteria, as well as cells stressed by DNA damage and malignant transformation. NKG2D; it recognizes molecules that resemble class I major histocompatibility complex (MHC) proteins and are expressed in response to many types of cellular stress. CD16, is specific for immunoglobulin G (IgG) antibodies bound to cells. Natural Killer Cells The inhibitory receptors of NK cells, which block signaling by activating receptors, are specific for self class I MHC molecules, which are expressed on all healthy nucleated cells. Therefore, class I MHC expression protects healthy cells from destruction by NK cells. Two major families of NK cell inhibitory receptors in humans are the killer cell immunoglobulin-like receptors (KIRs), so called because they share structural homology with Ig molecules and receptors consisting of a protein called CD94 and a lectin subunit called NKG2. Natural Killer Cells when the inhibitory receptors of NK cells encounter self MHC molecules on normal host cells, the NK cells are shut off Many viruses have developed mechanisms to block expression of class I molecules in infected cells, which allows them to evade killing by virus-specific CD8+ CTLs. When this happens, the NK cell inhibitory receptors are not engaged, and if the virus induces expression of activating ligands at the same time, the NK cells become activated and eliminate the virus-infected cells. Functions of natural killer (NK) cells. A, NK cells kill host cells infected by intracellular microbes, thus eliminating reservoirs of infection. B, NK cells respond to interleukin-12 (IL-12) produced by macrophages and secrete interferon-γ (IFN-γ), which activates the macrophages to kill phagocytosed Complement System The complement system is a collection of circulating and membrane- associated proteins that are important in defense against microbes. The complement cascade may be activated by any of three pathways 1. The alternative pathway 2. The classical pathway 3. The lectin pathway Complement System The alternative pathway is triggered when some complement proteins are activated on microbial surfaces and cannot be controlled, because complement regulatory proteins are not present on microbes The classical pathway is most often triggered by antibodies that bind to microbes or other antigens and is thus a component of the humoral arm of adaptive immunity. The lectin pathway is activated when a carbohydrate-binding plasma protein, mannose-binding lectin (MBL), binds to terminal mannose residues on the surface glycoproteins of microbes. This lectin activates proteins of the classical pathway, but because it is initiated by a microbial product in the absence of antibody, it is a component of innate immunity. Complement System Activated complement proteins function as proteolytic enzymes to cleave other complement proteins. Such an enzymatic cascade can be rapidly amplified. The central component of complement is a plasma protein called C3, which is cleaved by enzymes generated in the early steps. The major proteolytic fragment of C3, called C3b, becomes covalently attached to microbes and is able to recruit and activate downstream complement proteins on the microbial surface. Complement System The complement system serves three main functions in host defense: 1. Opsonization and phagocytosis. C3b coats microbes and promotes the binding of these microbes to phagocytes, by virtue of receptors for C3b that are expressed on the phagocytes. This process of coating a microbe with molecules that are recognized by receptors on phagocytes is called opsonization. 2. Inflammation. 3. Cell lysis. Other Plasma Proteins of Innate Immunity Plasma mannan-binding lectin (MBL), recognizes microbial carbohydrates and can coat microbes for phagocytosis or activate the complement cascade by the lectin pathway, as discussed earlier. C-reactive protein (CRP) is a pentraxin (five-headed molecule) that binds to phosphorylcholine on microbes and opsonizes the microbes for phagocytosis by macrophages, which express a receptor for CRP. The circulating levels of many of these plasma proteins increase rapidly after infection. This protective response is called the acute- phase response to infection. Cytokines of Innate Immunity In response to microbes, dendritic cells, macrophages, mast cells, and other cells secrete cytokines that mediate many of the cellular reactions of innate immunity Most of the molecularly defined cytokines are called interleukins, by convention, implying that these molecules are produced by leukocytes and act on leukocytes. Tumor necrosis factor (TNF), interleukin-1 (IL-1), and chemokines (chemoattractant cytokines) are the principal cytokines involved in recruiting blood neutrophils and monocytes to sites of infection Dendritic cells, macrophages, and other cells respond to microbes by producing cytokines that stimulate inflammation (leukocyte recruitment) and activate natural killer (NK) cells to produce the macrophage-activating cytokine interferon-γ (IFN-γ).