Innate Immunity - 2.1 PDF

**[Innate Immunity - 2.1]** Innate is phylogenetically older than adaptive - - - - **Mechanical barriers** - - - **Circulating effector cells**  Neutrophil = dendritic Macrophages = first cell **Phagocytosis**  Professional AG pr...

**[Innate Immunity - 2.1]** Innate is phylogenetically older than adaptive - - - - **Mechanical barriers** - - - **Circulating effector cells**  Neutrophil = dendritic Macrophages = first cell **Phagocytosis**  Professional AG presenting cells present MHC-II to CD4 T lymphocytes All cells present MHC-I **Professional phagocytes** **Non-professional phagocytes** ----------------------------- --------------------------------- Macrophages Fibroblasts Neutrophils Epithelial cells Monocytes Endothelial cells Dendritic cells Osteoclasts **Natural killer cells** Subset of lymphocytes that kill infected cells and cells that have lost expression of class I MHC mols (self mols) Make up 5-10% of lymphocytes in blood and spleen Release perforin and granzyme Secrete IFN-y  - - - - Kills cells: - - -  **Innate lymphoid cells** - - - - -  **Granulocytes** Mast cells = release histamine - - - Basophils = release histamine - -  Eosinophils = release inflammatory mols - **Inflammation** - - Extravasation 1. 2. 3. 4. 5. 6.  **Complement** A = smaller portion B = larger portion   - - - - - In lectin p/w - lectin binding mannose binds to bacteria's mannose carb Then C4 binds to mannose binding lectin  **Cytokines** Red = learn +-----------------+-----------------+-----------------+-----------------+ | Cytokine | Size | Principal cell | Principal | | | | source | cellular | | | | | targets and | | | | | biological | | | | | effects | +=================+=================+=================+=================+ | **TNF** | 15 kD; 51 kD | Macrophages, T | Endothelial | | | homotrimer | cells | cells : | | | | | activation | | | | | (inflammation, | | | | | | | | | | coagulation) | | | | | | | | | | Neutrophils: | | | | | activation | | | | | | | | | | Hypothalamus: | | | | | fever | | | | | | | | | | Liver: | | | | | synthesis of | | | | | acute-phase | | | | | proteins | | | | | | | | | | Muscle, fat: | | | | | catabolism | | | | | (cachexia) | | | | | | | | | | Many cell | | | | | types: | | | | | apoptosis | +-----------------+-----------------+-----------------+-----------------+ | **IL-1** | 17 kD mature | Macrophages, | Endothelial | | | form; 33 kD | endothelial | cells : | | | precursors | cells and some | activation | | | | epithelial | (inflammation, | | | | cells | coagulation) | | | | | | | | | | Hypothalamus: | | | | | fever | | | | | | | | | | Liver: | | | | | synthesis of | | | | | acute-phase | | | | | proteins | | | | | | | | | | T cells: Th17 | | | | | differentiation | +-----------------+-----------------+-----------------+-----------------+ | **IL-12** | Heterodimer of | Macrophages, | T cells: Th1 | | | 35 kD (p35) and | dendritic cells | differentiation | | | 40 kD (p40) | | | | | subunits | | NK cells and T | | | | | cells: IFN-y | | | | | synthesis, | | | | | increased | | | | | cytolytic | | | | | activity | +-----------------+-----------------+-----------------+-----------------+ | **Type I | IFN-α: 15 -- 21 | IFN-α: | All cells: | | interferons** | kD | macrophages, | antiviral | | | | plasmacytoid | state, | | | IFN-β: 20 -- 25 | DCs | increased class | | | kD | | I MHC | | | | IFN-β: | expression | | | | fibroblasts | | | | | | NK cells: | | | | | activation | | | | | | | | | | Causes cells to | | | | | release protein | | | | | kinase R | +-----------------+-----------------+-----------------+-----------------+ | **IL-10** | Homodimer of 34 | Macrophages, T | Macrophages, | | | -- 40 kD and 18 | cells (mainly | dendritic cells | | | kD subunits | Tregs) | : Inhibition of | | | | | IL-12, | | | | | co-stimulators | | | | | and class II | | | | | MHC molecules | | | | | | | | | | Anti | | | | | inflammatory | +-----------------+-----------------+-----------------+-----------------+ | IL-6 | 19 -- 26 kD | Macrophages, | Liver: | | | | endothelial | synthesis of | | | | cells, T cells | acute-phase | | | | | proteins | | | | | | | | | | B cells: | | | | | proliferation | | | | | of antibody | | | | | producing cells | | | | | | | | | | T cells: Th17 | | | | | differentiation | +-----------------+-----------------+-----------------+-----------------+ | IL-15 | 13 kD | Macrophages, | NK cells: | | | | others | proliferation | | | | | | | | | | T cells: | | | | | proliferation | | | | | (memory CD8^+^ | | | | | cells) | +-----------------+-----------------+-----------------+-----------------+ | IL-18 | 17 kD | Macrophages | NK and T cells: | | | | | IFN-γ synthesis | +-----------------+-----------------+-----------------+-----------------+ | IL-23 | Heterodimer of | Macrophages and | T cells: | | | a 19 kD (p19) | dendritic cells | development and | | | and 40 kD (p40) | | maintenance of | | | subunits | | IL-17 producing | | | | | T cells (Th17) | +-----------------+-----------------+-----------------+-----------------+ | IL-27 | Heterodimer of | Macrophages and | T cells : Th1 | | | 28 kD and 13 kD | Dcs | differentiation | | | subunits | | ; | | | | | inhibition of | | | | | Th17 cells | | | | | | | | | | NK cells: IFN-γ | | | | | synthesis | +-----------------+-----------------+-----------------+-----------------+ **Chemokines** Chemokine Original name Chemokine receptor Major Function ----------- --------------- -------------------- ------------------------------------------------------------------ CCL2 MCP-1 CCR2 Mixed leucocyte recruitment CCL3 MIP-1α CCR1, CCR5 Mixed leucocyte recruitment CCL4 MIP-1β CCR5 T cell, DC, monocyte and NK recruitment; HIV coreceptor **CCL5** RANTES CCR1, CCR3, CCR5 Mixed leucocyte recruitment, causes osteo degregation CCL11 EOTAXIN CCR3 Eosinophil, basophil and Th2 recruitment CCL19 MIP-β CCR7 T cell and DC migration into parafollicular zones of lymph nodes CCL21 SLC CCR7 T cell and DC migration into parafollicular zones of lymph nodes CCL22 MDC CCR4 Lymphocyte recruitment into intestine CXCL1 GROα CXCR2 Neutrophil recruitment CXCL8 IL-8 CXCR1, CXCR-2 Neutrophil recruitment XCL1 LYMPHOACTIN XCR1 T cell and NK cell recruitment CX3CL1 FRACTALINE CX3CR1 T cell, NK cell and monocyte recruitment **Innate immune recognition** - - - - Also CDS - DNA sensors Receptors are encoded in germline **PAMPS/DAMPS and PRRs** +-----------------+-----------------+-----------------+-----------------+ | Molecular | Source | Pattern | Principal | | pattern of | | recognition | innate immune | | microbe | | receptor of | response | | | | innate immunity | | +=================+=================+=================+=================+ | Double stranded | Replicating | Toll like | Type I | | RNA (dsRNA) | viruses | receptor (TLR) | interferon | | | | 3 | production | +-----------------+-----------------+-----------------+-----------------+ | Lipopolysacchar | Gram negative | TLR2/4\*/CD14 | Macrophage | | ide | bacterial cell | | activation | | (LPS) | wall | | | +-----------------+-----------------+-----------------+-----------------+ | Unmethylated | Bacterial DNA | TLR9 | Macrophage | | CpG nucleotides | | | activation | +-----------------+-----------------+-----------------+-----------------+ | N-formylmethion | Bacterial | N-formylmethion | Neutrophil and | | yl | proteins | yl | macrophage | | peptides | | peptide | activation | | | | receptors | | +-----------------+-----------------+-----------------+-----------------+ | Mannose rich | Microbial | 1\. Macrophage | 1. 2. | | glycans | glycoproteins | mannose | | | | or glycolipids | receptor | | | | | | | | | | 2\. Plasma | | | | | mannose | | | | | binding | | | | | lectin | | +-----------------+-----------------+-----------------+-----------------+ | Phosphorylcholi | Microbial | Plasma | Opsonisation, | | ne | membranes | C-reactive | complement | | and related | | protein | activation | | molecules | | | | +-----------------+-----------------+-----------------+-----------------+ **Interferons** Inhibits viral replication in neighbouring cells Virus infected cell releases IFNa and IFNb which makes nearby healthy cell release protein kinase R IFNy binds to macrophage IFNy receptor → macrophage proliferation +-----------------------+-----------------------+-----------------------+ | | **Released from** | **Causes** | +=======================+=======================+=======================+ | **IFN-y** | Macrophage | Binds to gamma | | | | interferon receptors | | | NK cell | | | | | causes macrophage | | | | activation and | | | | proliferation | | | | | | | | Causes killing of | | | | phagocytosed bacteria | | | | | | | | Antiviral and tumour | | | | response | | | | | | | | Activates Mos, NK | | | | cells | | | | | | | | Cell mediated imm | +-----------------------+-----------------------+-----------------------+ | **IFN-b** | Platelets | | +-----------------------+-----------------------+-----------------------+ | **IFNa and IFNb** | Virus infected cell | Makes nearby healthy | | | | cell release protein | | | | kinase R t protect | | | | against virus | | | | | | | | Activate NK cell | +-----------------------+-----------------------+-----------------------+ **Toll-like receptors** - - - - Functions - - - - - On cell membrane - - - - - Inside cell - - - - Toll like receptor Exogenous ligand -------------------- ------------------------------ TLR1\* Lipoproteins Lipopeptides TLR2\* Lipoglycans Modified Lipopolysaccharide Lipoteichocic Acid Peptidoglycan Zymosan Phospholipomannan Protozoan GPI anchor Viral envelope proteins dsRNA TLR4 Lipopolysaccharide Lipid-A Glycoinositolphospholipids Mannan Viral envelope proteins RSV F-protein TLR5 Flagellin TLR6\* Multiple diacyl lipopeptides TLR7 ssRNA TLR8 ssRNA TLR9 CpG DNA dsDNA TLR10 ?????????????????????? **TLR LPS signalling** 2 main signalling mechanisms of TLR4 signalling: 1. 2. - Components Principal functions ------------------------------- ---------------------------------------------------------------------------------------------------- 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, opsonisation of microbes, activation of leukocytes Mannose binding lectin Opsonisation of microbes, activation of complement (lectin pathway) C-reactive protein Opsonisation of microbes, activation of complement Coagulation factors Walling of infected tissues Cytokines TNF, IL-1 Inflammation Type I interferons Resistance to viral infection Type II interferon Macrophage activation IL-12, IL-18, IL-23 Type II interferon production by NK and T cells IL-15 Proliferation of NK cells IL-10, TGF-β Control of inflammation