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Transcript
Innate Immunity Rui He [email protected] Department of Immunology Shanghai Medical School Fudan University Components of Immunity Innate Immunity: non-specific, also called natural or native immunity Adaptive Immunity: specific, also called acquired immunity Features of Innate and Adaptive Immunity Innate Adaptive Characteristics Specificity For structures shared by groups of related microbes For antigens of microbes and for nonmicrobial antigens Diversity Limited; germline-encoded Very large; receptors are produced by somatic recombination of gene segments Memory None Yes Nonreactivity to self Yes Yes Components Cellular and chemical barriers Skin, mucosal epithelia; antimicrobial chemicals Lymphocytes in epithelia; antibodies secreted at epithelial surfaces Blood proteins Complement, others Antibodies Cells Phagocytes (macrophages, neutrophils), natural killer cells Lymphocytes The physiologic function of immune system Defense against infectious microbes Innate Immunity: the early reactions Adaptive Immunity: the later responses Innate Immunity FUNCTIONS COMPONENTS Innate immunity recognition The influence on adaptive immunity OVERVIEW The first line of defense against infection An evolutionarily older defense strategy, found in all classes of plants and animals Preexist infection or exposure to foreign antigen Respond immediately after recognition of microbes Respond in essentially the same way to repeated infection FUNCTIONS Initial response to microbes to prevent infection with elimination of danger Innate components also important in adaptive immunity Stimulates adaptive responses Components of innate immune system Components Principal Functions Epithelial barriers Epithelial layers Prevent microbial entry Defensins Microbial killing Intraepithelial lymphocytes Microbial killing Circulating effector cells Neutrophils Early phagocytosis and killing of microbes Macrophages Efficient phagocytosis and killing of microbes, secretion of cytokines that stimulate inflammation NK cells Lysis of infected cells, activation of macrophages Circulating effector proteins Complement Killing of microbes, opsonization of microbes, activation of leukocytes Mannose-binding lectin (collectin) Opsonization of microbes, activation of complement (lectin pathway) C-reactive protein (pentraxin) Opsonization of microbes, activation of complement Cytokines Epithelial barriers Physical barriers Skin Mucosal surfaces of the gastrointestinal tracts (GI) Mucosal surfaces of the respiratory tracts Antimicrobial Peptides Defensins Cystein-rich peptides with 29-34 amino acids Present in the skin and abundant in neutrophil granules Broad-spectrum antibiotics Upregulated by inflammatory cytokines Cryptocidines Secreted by the epithelium of the intestine Locally sterilize the lumen of intestine Intraepithelial lymphocytes Intraepithelial T cells Present in the epidermis of the skin and in mucosal epithelia cells and NKT cells Serve as sentinels at common sites of microbial invasion B-1 cells Present in peritoneal cavity Produce NATURAL antibodies Components of innate immune system Components Principal Functions Epithelial barriers Epithelial layers Prevent microbial entry Defensins Microbial killing Intraepithelial lymphocytes Microbial killing Circulating effector cells Neutrophils Early phagocytosis and killing of microbes Macrophages Efficient phagocytosis and killing of microbes, secretion of cytokines that stimulate inflammation NK cells Lysis of infected cells, activation of macrophages Circulating effector proteins Complement Killing of microbes, opsonization of microbes, activation of leukocytes Mannose-binding lectin (collectin) Opsonization of microbes, activation of complement (lectin pathway) C-reactive protein (pentraxin) Opsonization of microbes, activation of complement Cytokines Phagocytes Cell types Neutrophils and Macrophages Primary functions Identify, ingest, and destroy microbes Neutrophils Polymorphonuclear neutrophils (PMNs) Neutrophils The most abundant population of circulating leukocytes Mediate the earliest phases of inflammatory responses Macrophages Name of cell Alveolar macrophages Histiocytes Kupffer cells Microglia Epithelioid cells Osteoclasts Sinusoidal lining cells Location pulmonary alveolus of lungs connective tissue liver neural tissue granulomas bone spleen Macrophages Dominant effector cells of the later stages of innate immune responses Play central role in both innate and adaptive immune responses The steps of functional responses of phagocytes 1. Active recruitment of the cells to sites of infection 2. Recognition of microbes 3. Phagocytosis 4. Destruction of ingested microbes Recruitment of leukocytes © 2005 Elsevier Phagocytosis A cytoskeleton-dependent cellular process of phagocytes of engulfing large particles Bound microbes are ingested into vesicles called phagosome Destruction of phagocytosed microbes Where Phagolysosome Killing Mechanisms 1. Reactive oxygen intermediates (ROIs) 2. Reactive nitrogen intermediates: mainly NO 3. Preformed antimicrobials BUT, these mechanisms also can cause host tissue injury Effector functions of macrophage Natural Killer cells (NK cells) A type of cytotoxic lymphocytes The principal physiologic role 1. Defense against infections by viruses and some other intracelluar microbes 2. Rejection of tumors The mechanism of effector function Perforin Granzyme Components of innate immune system Components Principal Functions Epithelial barriers Epithelial layers Prevent microbial entry Defensins Microbial killing Intraepithelial lymphocytes Microbial killing Circulating effector cells Neutrophils Early phagocytosis and killing of microbes Macrophages Efficient phagocytosis and killing of microbes, secretion of cytokines that stimulate inflammation NK cells Lysis of infected cells, activation of macrophages Circulating effector proteins Complement Killing of microbes, opsonization of microbes, activation of leukocytes Mannose-binding lectin (collectin) Opsonization of microbes, activation of complement (lectin pathway) C-reactive protein (pentraxin) Opsonization of microbes, activation of complement Cytokines The complement system A complex series of some plasma proteins Pathways of complement activation 1. Classical Pathway 2. Alternative Pathway 3. The lectin Pathway Pathways of complement activation. The activation of the complement system may be initiated by three distinct pathways, all of which lead to the production of C3b (the early steps). C3b initiates the late steps of complement activation, culminating in the production of peptides that stimulate inflammation (C5a) and polymerized C9, which forms the membrane attack complex, so called because it creates holes in plasma membranes. The principal functions of major proteins produced at different steps are shown. The activation, functions, and regulation of the complement system are discussed in much more detail in Chapter 14. The effect of complement activation Opsonization of pathogen Recruitment of leukocytes Killing of pathogens Cytokines Proteins secreted by the cells of innate and adaptive immunity that mediate many of the functions of these cells. Cell source: macrophages, neutrophils, and NK cells, endothelial cells, some epithelial cells Functions 1. Recruit and activate leukocytes 2. Produce systemic alterations that contribute to potentiate antimicrobial responses Cytokines TNF, IL-1 Inflammation IFN-γ Macrophage activation IL-12 IFN-γ production by NK cells and T cells IL-15 Proliferation of NK cells IL-10, TGF-β Control of inflammation In severe infection, excess systemic cytokine production is harmful and may even cause death of the host Summary The first line of host defense against microbes The mechanisms of innate immunity exist before exposure to microbes The components of the innate immune system include epithelial barriers,leukocytes, circulating effector proteins and cytokines Neutrophils and macrophages are phagocytes that kill ingested microbesby producing ROIs, nitric oxide, and enzymes in phagolysosomes NK cells are lymphocytes that defend against intracelluar microbes by killing infected cells and providing a source of the macrophage-activatingcytokine IFN-γ The complement system is activated by microbes, and products of complement activation promote phagocytosis and killing of microbes and stimulate inflammation Different cytokines of innate immunity recruit and activate leukocytes, enhance the microbicidal activities of phagocytes, and stimulate NK cells and T cell responses To be continued