Innate Immunity An Introduction - Dr Alexander Strachan (2024-25).pptx

Introduction to Innate Immunity [email protected] Literature: Cellular and Molecular Immunology- Abbas Essential Microbiology for Dentistry- Samaranayake Images and tables from Abbas unless indicated otherwise  Recommended reading: https://www.i mmunology.o rg/public...

Introduction to Innate Immunity [email protected] Literature: Cellular and Molecular Immunology- Abbas Essential Microbiology for Dentistry- Samaranayake Images and tables from Abbas unless indicated otherwise  Recommended reading: https://www.i mmunology.o rg/public-infor mation/bitesi zed-immunol ogy Introduction to Innate  Immunology in the curriculum Y1: Overview of immunology. Revisit and consolidate Key concepts Detailed and innated and Y2 introduction to innate and adaptive Immuno- pathologies immunity and : adaptive immunity interactions Introduction to Innate Why study immunology and why does it matter?  What is the main job of the immune system? To protect us from infection Maintain homeostasis Safely clear and recycle dead cells Wound healing Two main divisions of the INNATE immune system ADAPTIVE Introduction to Innate  Learning Objectives Session outline: This session aims to provide an overview of some key terms and concepts in innate immunity. From here, you can read around the topic to meet the intended learning outcomes: Students should be able to: Summarise the components of the innate immune system Explain how infection leads to inflammation Interpret the features of innate immune recognition Define the key effector mechanisms of the innate immunity Describe how the innate immune response orchestrates the adaptive immunity Discuss the components of the innate immune system present in the oral cavity Introduction to Innate  General Characteristics First line of defence against infection Phylogenetically older than adaptive The mechanisms of innate immunity exist before encounter with microbes The effector mechanisms of innate immunity are often used to eliminate microbes in adaptive immune response Innate immunity influences the nature of adaptive responses (making them optimally effective) Introduction to Innate Innate Immunity Components of the Innate Immune System Barrie Cytokin rs es Circulati Circulati ng ng effector effector cells proteins Components of the Innate Epithelial and mechanical barriers Components of the Innate  Circulating effector cells Components Dranoff, G., 2004. Cytokines in cancer pathogenesis and cancer therapy. Nature Reviews Cancer, 4, 11-22, of the Innate  Neutrophils, dendritic cells, and macrophages Neutrophils, dendritic cells, and macrophages are some of the first cells on the scene of an infection Their main jobs are to: – (1) detect an infection – (2) spread the word that there has been an infection – (3) clear up the debris from infected tissue Components of the Innate  Phagocytosis Professional Non- phagocytes professional phagocytes Macrophages Fibroblasts Neutrophils Epithelial cells Monocytes Endothelial cells Dendritic cells Components of the Innate  Natural Killer cells A subset of lymphocytes that kill infected cells and cells that have lost expression of class I MHC molecules (self molecule). Constitute 5-10% of lymphocytes in the blood and spleen. Effector functions: perforin and granzyme They secrete IFN-ϒ Components of the Innate  Natural Killer cells NK cell – Macrophage (MΦ) interaction can control intracellular infection until adaptive immune IL- 12 system takes over Cell-cell interaction (e.g. CD48 – CD244) and IL-12 secretion by MΦs induces IFN-ϒ secretion by NK cells IFN- IFN-ϒ affects MΦ activation and γ differentiation and induces killing of phagocytosed bacteria IL-12 activates and expands NK cell population Components of the Innate  Innate Lymphoid Cells ILCs are a group of cytokine producing lymphocytes which do not express the T-cell receptor Respond to cytokines rather than antigens Third largest lymphocyte population (after B- and T- cells Defined by transcription factors and cytokine profile Display similarities to T- helper cells Annunziato F, Romagnani C, Romagnani S. The 3 major types of innate and adaptive cell-mediated effector immunity. J Allergy Clin Immunol. 2015  Mast cells, eosinophils and basophils Mast cells: release histamine  increase Mast cell vascular permeability and smooth muscle contraction. Involved in allergy. Tissue resident. Basophils: also release histamine. Circulating. Important in immune Eφ Bφ response to parasites. Eosinophils: Release inflammatory molecules. Also important in response to parasites. Components of the Innate Inflammation  Inflammation A protective mechanism, consisting of recruitment of leukocytes and extravasation of several plasma proteins into a site of infection. Activation of leukocytes to eliminate the infectious agent. If not very well controlled and resolved in a timely manner can damage the host’s tissues. Unregulated/dysregulated normal defence mechanism  pathology Inflamma  Extravasation 1. Secretion of cytokines and chemokines at site of infection 2. Selectin mediated rolling of leukocytes 3. Increase in integrin affinity 4. Integrin mediated attachment to endothelium 5. Transmigration through Inflamma Circulating effector proteins  Complement Andrade, F. A.; et al. Serine proteases in the lectin pathway of the complement system. In Proteases in Physiology and Pathology. 2017: 397-420  Cytokines Cytokine Size Principal cell source Principal cellular targets and biological effects TNF 15 kD; 51 kD homotrimer Macrophages, T cells Endothelial 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 form; 33 kD Macrophages, endothelial Endothelial cells : activation (inflammation, precursors cells and some epithelial coagulation) cells Hypothalamus: fever Liver: synthesis of acute-phase proteins T cells: Th17 differentiation IL-12 Heterodimer of 35 kD Macrophages, dendritic T cells: Th1 differentiation (p35) and 40 kD (p40) cells NK cells and T cells: IFN-y synthesis, subunits increased cytolytic activity Type I IFN-α: 15 – 21 kD IFN-α: macrophages, All cells: antiviral state, increased class I interferons IFN-β: 20 – 25 kD plasmacytoid DCs MHC expression IFN-β: fibroblasts NK cells: activation IL-10 Homodimer of 34 – 40 kD Macrophages, T cells Macrophages, dendritic cells : Inhibition of and 18 kD subunits (mainly Tregs) IL-12, co-stimulators and class II MHC molecules IL-6 19 – 26 kD Macrophages, endothelial Liver: synthesis of acute-phase proteins cells, T cells B cells: proliferation of antibody producing cells T cells: Th17 differentiation IL-15 13 kD Macrophages, others NK cells: proliferation T cells: proliferation (memory CD8+ cells) IL-18 17 kD Macrophages NK and T cells: IFN-γ synthesis IL-23 Heterodimer of a 19 kD Macrophages and dendritic T cells: development and maintenance of IL-  Chemokines Chemoki Original Chemokine Major Function ne name receptor 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 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 Features of innate immunity Features of Innate Immune Recognition Bacterial Microbial Recognizes structures that are cell wall lipid Toll like polysacchari characteristic of microbial receptor de (TLR) C-type lectin pathogens and are not present on mammalian cells 4 major classes: TLRs – bacteria and viruses CLRs – fungi NLRs – bacteria and cell damage RLRs – viruses (also CDS – DNA sensors) The receptors of the innate immune system are encoded in the germline Features of innate  Examples of PAMPS/DAMPS and PRRs Molecular pattern of Source Pattern recognition Principal innate microbe receptor of innate immune response immunity Double stranded RNA Replicating viruses Toll like receptor Type I interferon (dsRNA) (TLR) 3 production Lipopolysaccharide Gram negative TLR2/4*/CD14 Macrophage activation (LPS) bacterial cell wall Unmethylated CpG Bacterial DNA TLR9 Macrophage activation nucleotides N-formylmethionyl Bacterial proteins N-formylmethionyl Neutrophil and peptides peptide receptors macrophage activation Mannose rich glycans Microbial 1. Macrophage 1. Phagocytosis glycoproteins or mannose receptor 2. Opsonisation, glycolipids 2. Plasma mannose complement activation binding lectin Phosphorylcholine and Microbial Plasma C-reactive Opsonisation, complement related molecules membranes protein activation Features of innate  Toll-like Receptors Toll like Exogenous ligand Reference receptor TLRs recognise TLR1* Lipoproteins (Takeuchi et al., 2002) Lipopeptides (Takeuchi et al., 2002) conserved molecular TLR2* Lipoglycans (Quesniaux 2004) et al., patterns derived from Modified Lipopolysaccharide (Darveau et al., 2004) potentially Lipoteichocic Acid (Schroder et al., 2003) pathogenic sources Peptidoglycan (Takeuchi et al., 1999) Zymosan (Ozinsky et al., 2000) i.e. of bacterial, viral, Phospholipomannan Protozoan GPI anchor (Li et al., 2009) (Campos et al., 2001) protozoan and fungal TLR3 Viral envelope proteins dsRNA (Boehme et al., 2006) (Alexopoulou et al., origin. 2001) TLRs 2 and 1 or 6 TLR4 Lipopolysaccharide (Shimazu et al., 1999) Lipid-A (Qureshi et al., 1985) dimerize to recognise Glycoinositolphospholip (Medeiros et al., 2007) ids increase specificity Mannan (Tada et al., 2002) To date, no specific Viral envelope proteins (Madeira et al., 2016) RSV F-protein (Rallabhandi et al., ligand has been 2012) Features of innate TLR LPS signalling ST2 Two primary signalling mechanisms have been identified in TLR4 signalling; MyD88-dependant TLR TLR SIGIRR CD36 which is shared with TLR2 signalling and MyD88- 4 2 independent MyD88 mediated signalling is associated with the MyD88s SARM PTPB1 SOCS1 RIP2 production of pro-inflammatory cytokines and SARM SOCS3 IRAK1 IRAK4 PTP1B IRAKM TOLLIP chemokines through the NFκB transcription factor IRF5 ENDOSOME SHIP-1 TRAF6 TANK A20 or via MAP kinases. CYLD SHP TRAF3 TAB1 MyD88-independent signalling recruits the RIP1 TAK1 TAB2 TRAF6 TANK A20 adaptors, TRIF and TRAM which upon LPS NEMO MKKs binding relocate the LPS/TLR/TRIF/TRAM TBK1 IKKε IKKα IKKβ complex to internal endosomes and is associated with type I interferon responses. IκBα ERK JNK1/2 P38 P50 P65 Both signalling mechanisms are tightly regulated at phases throughout the signalling cascade to IRFs NFκB AP-1 CREB prevent unwarranted or excessive inflammation Features of innate The Innate Immune System and the Oral Cavity Features of innate Recap: Components of the innate immune Components system Principal functions summary Barriers Epithelial layers Prevent microbial entry Defensins Microbial killing Intraepithelial Microbial killing lymphocytes 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  Role of Innate Immunity in Stimulating Adaptive Immune Responses  Any questions to Alexander.strachan@plymout h.ac.uk