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Chapter 10 Innate Immunity. Introduction of innate immunity. Innate immunity is the first line of defense against infections. Innate immunity exist before encountering with microbes and are rapidly activated by microbes before the development of adaptive immune responses.
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Introduction of innate immunity • Innate immunity is the first line of defense against infections. • Innate immunity exist before encountering with microbes and are rapidly activated by microbes before the development of adaptive immune responses. • Innate immunity is present in all multicellular organisms, including plants and insects.
Characteristics: • Set up at birth • Non–specific and early • Heredity • Racial or species difference • No immune memory
Characteristics of Innate and Adaptive Immunity • No Immunologic memory Innate Immunity Adaptive Immunity Antigen independent Antigen dependent No time lag A lag period No antigen specific Antigen specific • Development of memory
Components of Innate and Adaptive Immunity Innate Immunity Adaptive Immunity physical barriers skin, gut Villi, lung cilia,etc none soluble factors many protein and non-protein secretions Immunoglobulins (antibody) cells phagocytes, NK cell, B1, γδT, APC T , B lymphocytes APC
Contents • PartⅠ Components of innate immune system • PartⅡ Cells participating in innate immunity • PartⅢ Recognition features of the innate immune system • PartⅣ Functions of innate immunity
PartⅠ Components of innate immune system Ⅰ.Barriers Ⅱ.Humoral factors Ⅲ. Cells
PartⅠ Components of innate immune system Ⅰ. Barriers: • Mechanical defense: skin & mucous membrane • Anatomic barrier: blood – brain barrier blood – placenta barrier blood – thymus barrier • Biotic barrier:normal flora • Chemical defense (lysozyme, acid)
PartⅠ Components of innate immune system Ⅱ.Humoral factors: Complement Cytokine---macrophage, neutrophil, NK cell Lysozyme Ⅲ. Cells: Mononuclear phagocyte, NK cell, Neutrophils, Dendritic cells,Eosinophil, Basophil, Mast cell, γδT cell, B1 cell, Microfold cell
PartⅡ Cells participating in innate immunity • Natural killer cells (NK) • Mononulear phagocytes • Neutrophils • Dendritic cells • Other cells participating in innate immunity
PartⅡ Cells participating in innate immunity Ⅰ. Natural killer(NK)cells 1. Source: Bone marrow,exist mainly in peripheral blood(5-7%) and spleen.
2. Characteristics of NK cells • Also called large granular lymphocytes (LGL) • Kill various infected and malignant cells spontaneously, without stimulation of antigen and MHC restriction • Identified by the presence of CD56,CD16 (FcRⅢ) • Activated by IL-12 and produce IFN -γ
3. Recognition mechanism of NK cells • FcγRⅢ: recognize antibody covered cell ------ADCC • Killer activating receptor and killer inhibitory receptor
Receptors associated with killer activation and killer inhibition on NK cells • NK receptors bind with class Ⅰ MHC molecules • NK receptors bind with non class Ⅰ MHC molecules
(1) NK Receptors bind with class Ⅰ molecules: -KIR(killer immunoglobin-like receptors): • Number of immunoglobin-like domain:KIR2D/KIR3D • Cytoplastic region: longer---KIR2DL/KIR3DL(ITIM), inhibitory receptor shorter---KIR2DS/KIR3DS, non-covalent combination with DAP-12(ITAM), activating receptor -KLR(killer lectin-like receptor): • Heterodimer of CD94 & NKG2 (C type lectin) CD94: short cytoplastic region, no signal transmission NKG2A: ITIM in cytoplastic region --------CD94/NKG2A, inhibitory receptor NKG2C: no signal transmission, bind with DAP-12(ITAM) --------CD94/NKG2C, activating receptor ITIM:immunoreceptor tyrosine-based Inhibitory motif ITAM:immunoreceptor tyrosine-based activation motif
(2) NK receptors bind with non class Ⅰ MHC molecules --NKG2D:Express mainly on the surface of NK and γδT No signal transmission Non-covalent binding with DAP-10(ITAM) MHC class Ⅰ chain-related molecules A/B(MIC A/B) --Natural cytotoxic receptor(NCR): NKp46,NKp30,NKp44 IgSF Express on the surface of NK cells Bind with other molecules(ITAM) Kill target cells when KIR/KLR lose their function
Receptors associated with killer activation and killer inhibition on NK cells Killer activatory receptor Killer inhibitory receptor Function KIR: KIR2DS,KIR3DS KLR: CD94/NKG2C NKG2D NKp46 NKp30 NKp44 KIR2DL,KIR3DL CD94/NKG2A Bind class I HLA molecules Bind non-class I HLA molecules NCR
Figure 3-23 These are important NK inhibitory ligands( CD94/NKG2A/B/C) These are important molecules for presentation of peptides to CD8 T cells
Normal condition(Class Ⅰ HLA molecules are expressed normally): Effect of Inhibitory recepter > Activatory recepter------Killing effect of NK cell is inhibited • Abnormal condition(Class Ⅰ HLA molecules are expressed abnormally) : NK cells lose ability of distinguishing self from non-self------NK cells kill target cells(NKG2D and NCR)
NK cells is tolerant to self-antigen: • Only virus infected cells and tumor cells could be killed by NK cells, not the normal tissue cells. • Virus infected cells or tumor cells MHC-I inhibitory signal Killed by NK cells。
4. Effector of NK cells • Secretion of cytokines,e.g. IFN-γ, to a activates macrophages • Cytotoxicity: -ADCC-mediated by FcγRⅢ(CD16) -Granules like CTLs: Perforin: creates pores in target cell membranes Granzymes : enzymes which enter through perforin pores and induce apoptosis of target cells. -FasL/Fas pathway -TNF-α/TNFR-Ⅰ pathway
TNFR-I TNF- α Target cell Contact tightly NK cell ADCC
5. Functions of NK cells • Participate in anti-tumor and anti-virus immunity • Participate in immunological regulation
PartⅡ Cells participating in innate immunity Ⅱ. Mononuclear phagocytes
George Bernard Shaw wrote: “There is at bottom only one genuine treatment for all diseases,…to stimulate the phagocytes. Drugs are a delusion. …(when) the phagocytes are stimulated; they devour the disease…” Phagocytes are the Most Important Cells
Tissues macrophage Blood
Macrophages • Phagocytose & kill intracellularly • Characteristic nucleus and identified by CD14 • Act as APC • Activated by cytokines • Kill malignant and altered self targets • Adherent of plastic and glass surfaces
Macrophages phagocytose and degrade foreign particles, bacteria and dead (and dying) host cells. Receptors on Macrophages: Fcγ receptors Complement receptors IFN-g receptor Chemokine receptors Mannose receptor Toll-like receptors(TLRs) Scavenger receptors(SRs) LPS receptor(CD14)
1. Recognizing and excluding pathogens Recognizing Ingestion Digestion Exclusion recognizing ingestion exclusion digestion
(1) Recognition Mechanism Pattern recognition receptor(PRR): The receptor on macrophage which can recognize and bind specific molecular structure on some pathogens , injured or apoptotic cells.
The receptor associated with antigen-recognition of macrophage • Pattern recognition receptor (PRR) or non-opsonic receptor ------Mannose receptor(MR) Scavenger receptor(SR) Toll like receptor(TLR) • Opsonic receptor ------FcγR and C3bR/C4bR
ScavengerR IgG FcR CR Initiation of Phagocytosis
(2) Ingesting and digesting the pathogen • Oxygen-dependent system: ---Reactive oxygen intermediates, ROIs: O2-, OH-, H2O2, 1O2 ---Reactive nitrogen intermediates, RNIs: NO • Oxygen-independent system: ---Low pH(3.5-4) , Lysozyme,Defensin
2. Functions of macrophage • Recognizing and excluding pathogens and died cells; Killing target cells(tumor cells and virus-infected cells) • Participating in and stimulating inflammation • Participating in immunological regulation • Processing and presenting antigen, initiating adaptive immune response