Innate immunity and Antigen presenting cells

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1 Innate immunity and Antigen presenting cells Sanipa Suradhat, D.V.M., Ph.D. Dept. of Veterinary Microbiology Faculty of Veterinary Science Chulalongkorn University Innate & specific immune responses Innate Immunity Response is antigenindependent There is immediate maximal response Not antigen-specific Exposure results in no immunologic memory Specific Immunity Response is antigen-dependent There is a lag time between exposure and maximal response Antigen-specific Exposure results in immunologic memory 1

2 Here s how we fight the intruders Pathogen attacks Security breached Sentinel cells sending SOS Inflammation Phagocytic cell entering the site APC migration (APC leave the crime scene) Killing and clearing of invaders Pathogen clearance & Tissue repair Effector cells entering the site Activation of adaptive immunity In the lymphoid tissues Immediate action Back up plan Innate immunity and inflammation Adaptive immunity 2

3 Innate immunity Previously believed to be nonspecific, weak, and non effective Now: Innate immunity specifically target microbes and is a powerful early defense mechanism. Not only provide the early defense against infection, innate immunity instructs the adaptive immune system to respond to different microbes properly. Conversely, adaptive immune response often uses mechanisms of innate immunity to eradicate infection. Thus, there is a constant bidirectional cross-talk between innate and adaptive immunity Pathogen associated molecular patterns (PAMPs) Pattern recognition receptor (PRRs) Abbas & Lichtman,

4 Component of the innate immunity Epithelial barrier Epithelial lining Antimicrobial substances Lymphocytes Phagocytes Neutrophils Monocytes/Macrophages Natural killer cells Plasma proteins The complement system Cytokine and other proteins Epithelial barriers Physical barrier Antimicrobial substances Peptide antibiotics Normal flora Innate-like lymphocytes Mostly recognize lipid antigens B-1 cells (in epthelia of the peritoneal cavity), producing natural antibodies Intraepithelial γδ T-lymphocytes NK T cells 4

5 How inflammation is triggered? Pathogen attacks/ Abnornal cell damages Sentinel cells sending SOS Inflammation Mast cells Dendritic cells Macrophages Phagocytic cell entering the site Killing and clearing of invaders Pathogen clearance & Tissue repair 5

6 Recognition of microbes by the innate immune system The components of innate immunity recognize structures (highly conserved molecular patterns) that are shared by various classes of microbes and are not present in the host cells. The microbial molecule that are the target of innate immunity is called pathogen associated molecular pattern (PAMP). The receptor of the innate cells that recognize the shares structures are pattern recognition receptors (PRRs). Example: Toll like receptor (TLR), scavenger receptors, Macrophage mannose receptors, c-type lectin receptors The protein of the complement system (alternative and mannose-binding lectin (MBL) pathways) also recognize microbe surface molecules. Pattern recognition receptors (PRRs) Pattern recognition receptors TLR1 a TLR2 TLR3 TLR4 TLR5 TLR6 TLR7 TLR8 TLR9 TLR10 TLR11 NOD1 b, NOD2 Scavenger receptors Macrophage mannose receptors and other c-type lectin receptors Type 3 complement receptors and dectin type receptors a Toll-like receptors b Nucleotide oligomerizing domain protein Bacterial lipoproteins from Mycobacteria, Neisseria Zymosan yeast particles, peptidoglycan, lipoproteins, glycolipids, lipopolysaccharide (LPS) Viral double stranded RNA, poly I:C Bacterial LPS, plant product taxol Bacterial flagellins Yeast zymosan particles, lipotechoic acid, lipopeptides from Mycoplasma Single-stranded RNA Single-stranded RNA CpG oligonucleotides Unknown Bacterial components from uropathogenic bacteria Peptidoglycans Acetylated/malelylated proteins, modified low-density lipoproteins and other polyanionic ligands Sulfated sugars, mannose-, fucose-, and galactose-modified polysaccharides and proteins Zymosan particles, β-glucan Ligands Adapted from Pashine et al., Nature Medicine (Suppl.) : S63-S68 6

7 Toll-like receptors Trends in Immunology 2004, 25 (7):345. DAMPs Damage associated molecular patterns Ex. uric acid, heat shock proteins, defensins, Hyaluronic acid, fibronectin etc. Kono and Rock Nat. Rev. Immunol. 8:

8 Janeway s Matzinger s Kono and Rock Nat. Rev. Immunol. 8: 279. The role of sentinel cells in acute inflammation Microbial invasion Tissue damage PRRs Lysed cells Neurons Mast cells Macrophages Vasoactive molecules Proinflammatory cytokines Chemokines Sticky endothelium Acute inflammation Activated neutrophils adherence & emigration degranulation 8

9 Vasoactive molecules Histamine Serotonin Inflammatory lipids (eicosanoids) Arachidonic acid Leukotrienes Prostaglandins Protease enzymes tryptase chymase Vasoactive polypeptides Anaphylatoxin (C3a, C5a) Bradykinin Proteoglycans Platelet activating factors Pain Increased vascular permeability Vasodilation Neutrophil chemotaxis/activation Platelet activation Proinflammatory cytokines Tumor necrosis factor-alpha (TNF-α) Interleukin-1 (IL-1) Interleukin-6 (IL-6) Produced mainly by activated neutrophil macrophages and mast cells An essential mediator of inflammation Activate vascular endothelial cells Activate mast cells, neutrophils, macrophages and lymphocytes 9

10 Chemokines (Chemoattractant cytokines) A family of chemotactic cytokines (at least 50 chemokines) Small proteins (8-10 kda) produced by various cell types Stimulate leukocyte movement and regulate the migration of leukocytes (chemotaxis) from the blood to tissues. Some chemokines (CXCL4, CCL20, CCL5) also have antimicrobial activities. Classified to 4 families according to the spacing of the cysteine residues Example of chemokines and their receptors New Name α family CCL2 CCL3 CCL4 CCL5 CCL7 CCL8 CCL11 b family CXCL1 CXCL8 γ family XCL1 δ family CX3CL1 Old Name MCP-1 MIP-1α MIP-1β RANTES MCP-3 MCP-2 Eotaxin GRO-1 IL-8 Lymphotacin Fractalkine Receptor CCR2 CCR1, CCR5 CCR5 CCR1, CCR3, CCR5 CCR3 CCR3 CCR3 CXCR2 CXCR1, CXCR2 XCR1 CX3CR1 CXCL = CXCR (ligand) (receptor) Attract and activate neutrophils MIP: macrophage inflammatory protein MCP: monocyte chemotactic protein Adapted from Tizards,

11 The cardinal signs of acute inflammation Tissue damage Vasoactive factors Neutrophil margination Vasodilation Increased vascular permeability Emigration Redness Heat Pain Swelling 11

12 12

13 Phagocytosis Phagocytic enzymes 1) Phagocyte oxidase O 2 >> reactive oxygen intermediates (ROIs) (superoxide anion, free radicals) 2) Inducible nitric oxide syntase (inos) Arginine >> nitric oxide 3) Lysosomal proteases >> break down microbial proteins Abbas and Lichtman,

14 Functions of activated macrophages Abbas and Lichtman,

15 The role of APC in induction of adaptive immunity Pathogen attacks Security breached Sentinel cells sending SOS Inflammation Phagocytic cell entering the site APC migration (APC leave the crime scene) Killing and clearing of invaders Pathogen clearance & Tissue repair Effector cells entering the site Activation of adaptive immunity In the lymphoid tissues Immediate action Back up plan How does the immune system work? Secondary lymphoid tissue within hrs Periphery: effector site Abbas & Lichtman,

16 Abbas & Lichtman, 2004 The capture and display of microbial antigens. Microbes enter through an epithelium and are captured by antigen presenting cells resident in the epithelium, or they enter lymphatic vessels or blood vessels. The microbes and their antigens are transported to peripheral lymphoid organs, the lymph nodes, and the spleen, where protein antigens are displayed for recognition by T lymphocytes. 16

17 Essential feature of adaptive immunity Foreign material (antigen) Antigen presenting cells Antigen-specific B cells Antigen-specific T cells Memory cell Antibody producing cell Effector T cell Memory cell Humoral Immunity Cell-mediated immunity Antigen elimination T cell antigen recognition T-cell The majority of T lymphocytes recognize peptide antigens that are bound and displayed by the major histocompatibility complex (MHC) molecules of the antigen presenting cells APC 17

18 Antigen presenting cells (APC) Antigen Presenting Cells (APC): A special cells that capture microbial antigens and display them for recognition by T lymphocytes As naïve T cells required both antigen and co-stimulatory signals to become activated. The APC that can provide both signals to T lymphocytes is called professional APC. Professional antigen presenting cells DC is considered the best professional APC. 18

19 The 2-signal hypothesis Activation of naïve T cells requires 2 independent signals. 1) The binding of peptide:mhc complex by the TCR 2) The co-stimulatory signal T cell stimulation Danger signal Abbas & Lichtman,

20 Role of innate immunity on T cell activation Co-stimulatory (2 nd ) signal Antigen (1 st ) signal The APCs: Dendritic cells (DC), Macrophage, B cells DC maturation Abbas & Lichtman,

21 Professional APCs DENDRITIC CELLS MACROPHAGE B CELLS Antigen Uptake Macropinocytosis Phagocytosis Viral infection Phagocytosis Ag-specific receptor (Ig) MHC expression Low on tissue DC High on Lymphoid DC Inducible by bacteria and cytokines (- to +++) Constitutive, Increase on activation (+++ to ++++) Costimulatory delivery Antigen expressed Constitutive by mature nonphagocytic lymphoid DC (++++) Peptides, Viral Ag, Allergens Inducible (- to +++) Particulate Ag, Intracellular and extracellular Ag Inducible (- to +++) Soluble Ag, toxins, viruses Location Lymphoid tissue, Connective tissue, Epithelia Lymphoid tissue, Connective tissue, Body cavities Lymphoid tissue, Peripheral blood 21

22 Test yourself! Veterinary Immunology 2008: Self-evaluation Topics: Innate immunity and antigen presenting cells 1. W hich of the following serves as a sentinel cell a. Neuron b. Enterocyte c. M ast cell d. Neutrophil e. Eosinophil 2. W hat is a chemokine? a. A type of cell b. A small chemotactic protein c. A cell adherence molecule d. A neurotransm itter m olecule e. A vasoactive protein 3. W hich of the follow ing is not one of the cardinal signs of inflammation? a. Heat b. Redness c. Pain d. Sw elling e. Granuloma 4. Prostaglandins are a. A type of cell b. V asoactive lipids c. Adherence molecules d. Chemokines e. Cytokines 5. W hich of the following is not a type of macrophage? a. Basophil b. H istiocyte c. K upffer cell d. M icroglia e. M onocyte Pre-test Post-test 6. Inflammation leads to the expression of which molecules on blood vessel endothelial cells? a. Lectins b. Cadherins c. Fc receptors d. Selectins e. Acute-phase proteins 7. The migration of neutrophils under the influence of external chemical gradients is called a. Endocytosis b. Chemotaxis c. Phagocytosis d. Chemolysis e. Exotaxis 8. A ctivated m acrophages can kill intracellular organisms by producing a. N itric oxide b. Antibodies c. Chemokines d. Interferons e. Interleukins 9. W hich of the follow ing is not undertaken by macrophages? a. Promotion of wound healing b. Production of antibodies c. Production of cytokines d. Capture of invading organisms e. Processing of antigens 10. W hich of the follow ing is not an antigen presenting cell? a. M acrophages b. T cells c. Langerhans cells d. B cells e. D endritic cells Score 22

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