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Innate immunity

Innate immunity

Presented by Nattasasi Suchamalawong, MD.

March 26, 2021

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Innate immunity

  1. 1. Innate immunity 26th March 2021 Nattasasi Suchamalawong, MD. Pediatric Allergy and Immunology Unit King Chulalongkorn Memorial Hospital
  2. 2. Outline ● Overview of innate immunity ● Recognition of microbes and damaged self ● Cell-associated pattern recognition receptors and sensors of innate immunity ● Cellular component ● Soluble recognition and effector molecule ● The inflammatory response ● The antiviral response ● Stimulation of adaptive immunity ● Homeostasis in the innate immune response
  3. 3. Abbas_Cellular and Molecular Immunology, 9th ed Bankova L.etal.middleton’s 9th edition,2020.1-19 Innate immunity - The first line of host defense against infections - Exist before exposure to microbes - React to products of microbes and injured cell - The cellular components of the innate immune system include epithelial barriers and leukocytes -Phagocytic cell : neutrophils, macrophages -Antigen presenting cell: Dendritic cell -Degranulating cell : mast cells, Eosinophils ,Basophils -NK cells
  4. 4. Turvey SE, Broide D, J Allergy Clinical imm, 2010 Components of Innate immunity 1.Anatomical barrier - Physical barriers - Chemical barriers 2.Cellular - Phagocytic cells - Dendritic cell - NK cells, ILC 3.Soluble proteins - Complement - Cytokines, Chemokines - Antimicrobial peptides (AMPs)
  5. 5. Abbas_Cellular and Molecular Immunology, 9th ed Functions & Reaction of innate immune responses 1.Initial reactions to microbes that serve to prevent, control, or eliminate infection of the host by many pathogens. Deficiencies, inhibition, or elimination of innate immunity increase susceptibility to infections, even when the adaptive immune system is intact and functional. Many pathogenic microbes have evolved strategies to resist innate immunity that are crucial for the virulence of microbes. Innate immune responses to such microbes may keep the infection in check until adaptive immune responses are activated.
  6. 6. Abbas_Cellular and Molecular Immunology, 9th ed The functions of innate immune responses 2. Innate immunity eliminates damaged cells and initiates the process of tissue repair. Innate responses may occur as a result of infection or it may be sterile cell and tissue damage in the absence of infection. 3. Stimulate adaptive immune responses and make them optimally effective against different types of microbes.
  7. 7. Abbas_Cellular and Molecular Immunology, 9th ed The Reaction of innate immune responses 2 major types of protective reactions of the innate immune system are inflammation and antiviral defense. - Inflammation - Circulating leukocytes and plasma proteins are brought into sites of infection in tissues. - Major reaction to damaged or dead cell - Antiviral defense - Mechanisms prevent virus replication - Eliminating reservoirs of viral infection without an inflammatory reaction.
  8. 8. Abbas_Cellular and Molecular Immunology, 9th ed Comparative features of innate and adaptive immunity Attribute Innate immunity Adaptive immunity Response time Immediate responses and do not require prior exposure to microbe. Several days as clones of antigen- specific lymphocytes Diversity No appreciable change in quality or magnitude of repeated exposure (exception NK cell) Repeated exposure to a microbe enhances rapidity, magnitude, and effectiveness Number & Type of receptor Recognizes only about 1000 products of microbes and damaged cells. Recognize millions of different microbial antigens, and can also recognize non microbial environmental Ag Memory response No memory cell or Trained immunity Memory cell
  9. 9. Abbas_Cellular and Molecular Immunology, 9th ed None or limited memory Memory cell
  10. 10. Trained immunity Netea G. Mihai et al. Nature review. Immunology., June 2020.375-388 • Innate immune memory : innate immune system can enhance responsiveness to subsequent triggers. Greater protection against reinfection. • Secondary response : quicker and stronger response against pathogens but less specific and shorter duration than adaptive immune memory. • Epigenetic reprogramming, alterations in gene expression and cellular function without changes to the original DNA sequence. • E.g. β-glucan, LPS or the bacillus Calmette–Guérin (BCG) vaccine.
  11. 11. Trained immunity Suratannon N et al. Asian Pac J Allergy Immunol 2020;38:170-177 long-term epigenetic reprogramming of innate immune cells (myeloid cells and NK cells) and occurs upon exposure to homeostasis perturbance by pathogens. Effect : increase immune response upon secondary stimulation ( same or even unrelated pathogens) increase production of IFN-γ, IL-1β, IL-6, and TNF-α cytokines (key cytokines in immune response to many pathogens) . Trained immunity : very important protective mechanism against (re)infection, and likely is of great importance especially in early life.
  12. 12. Trained immunity Suratannon N et al. Asian Pac J Allergy Immunol 2020;38:170-177
  13. 13. Trained immunity and tolerance: two opposite functional programmes of innate immunity. Zhong chao et al. Front. Immunol., 21 February 2020 Netea G. Mihai et al. Nature review. Immunology., June 2020.Volume 20375-388 Found mainly monocyte/macrophage or NK cell
  14. 14. Summary of training programs induced in monocytes/macrophages. Zhong chao et al. Front. Immunol., 21 February 2020
  15. 15. Central and Peripheral trained immunity. mononuclear phagocyte lineage (monocytes and macrophages) memory NK cells undergo a secondary expansion and can more rapidly degranulate and release cytokines, resulting in a more protective immune response changes in the chromatin accessibility Netea G. Mihai et al. Nature review. Immunology., June 2020.375-388
  16. 16. Epigenetic reprogramming underlies the induction of trained immunity. Netea G. Mihai et al. Nature review. Immunology., June 2020.Volume 20.375-388 deposition of chromatin changes DNA methylation proinflammatory factors quicker & enhanced recruitment of transcription factors and gene expression
  17. 17. Bankova L.etal.middleton’s 9th edition,2019.1-19 Recognition of Microbes and Damaged self • “Pathogen associated molecular patterns (PAMPs)” : Molecular structure produce by microbial pathogens that required for survival. : not mammalian cells : Shared by entire classes of pathogens • “Damage associated molecular patterns (DMAPs) ” : recognizes endogenous molecules that are produced by or released from damaged and dying cells at both infection and sterile injury • Cellular receptors : Pattern recognition receptors (PRRs)
  18. 18. Examples recognize of PAMPs & DAMPs patterns Unmethylate CpG DNA Abbas_Cellular and Molecular Immunology, 9th ed Bankova L.etal.middleton’s 9th edition,2019.1-19
  19. 19. Bankova L.et al. middleton’s 9th edition,2019.1-19 Recognition of Microbes and Damaged self • Cell-associated recognition molecules • Phagocytes, DCs, epithelial cells, and others • Recognize both pathogen and damaged cells “Pattern Recognition Receptors (PRRs)” • Soluble recognition (effector) molecules • Facilitate clearance by enhancing uptake Abbas_Cellular and Molecular Immunology, 9th ed
  20. 20. • Principle functions of PRRs 1.) Opsonization 2.) Activation of complement 3.) Phagocytosis 4.) Activation of proinflammatory signaling pathways 5.) Induction of apoptosis Pattern Recognition Receptors (PRRs) Abbas_Cellular and Molecular Immunology, 9th ed
  21. 21. Secreted PRRs AMPs : Defensins & Cathelicidin Opsonization , chemoattractant Phagocytosis, Complement activation Mannose receptors (CD206) •C - Type Lectin Receptors • Recognized carbohydrates (Mannose) - Bacterial, Fungus, Parasite • Expressed on Macrophage • Phagocytosis, NF-kB activation Bankova L.etal.middleton’s 9th edition,2019.1-19
  22. 22. Pattern Recognition Molecules of the Innate Immune System Abbas_Cellular and Molecular Immunology, 9th ed Cytosolic DNA Sensors stimulator of IFN genes pathway RIG-like receptors C-type lectin–like receptors Toll-like receptors NOD-like receptors
  23. 23. Pattern Recognition Molecules of the Innate Immune System Abbas_Cellular and Molecular Immunology, 9th ed
  24. 24. Abbas_Cellular and Molecular Immunology, 9th ed Cellular locations of pattern recognition receptors of the innate immune system. 1 2 3 4 5 1 Anti-viral response 1.) Toll-like receptors (TLRs) 2.) NOD-like receptors (NLRs) 3.) Retinoid acid–inducible gene (RIG)-like receptors (RLRs) 4.) Cytosolic DNA sensor (CDS) 5.) C-Type Lectin Receptors (CLRs)
  25. 25. Abbas_Cellular and Molecular Immunology, 9th ed Cell-associated PRRs and sensors of innate immunity • Most cell types express PRRs and therefore are capable of participating in innate immune responses. • Phagocytes, especially macrophages, and DCs express the widest variety and greatest number of these receptors. • Role of phagocyte: detecting microbes and damaged cells and ingesting for destruction • Role of DCs: reacting to microbes in ways that elicit inflammation and subsequence adaptive immunity .
  26. 26. -Type I integral membrane glycoprotein -Extracellular region : Leucine rich repeat motifs (receptors, bind directly to PAMPs) , cysteine rich flanking motif. - Transmembrane domain - Toll/IL-1 receptor (TIR) : homology domain found in their cytoplasmic tails, essential for signaling. Toll-like receptors (TLRs) Abbas_Cellular and Molecular Immunology, 9th ed Cysteine rich flanking motif 9 different functional TLRs in human • TLRs 1, 2, 4, 5 and 6 are expressed on plasma membranes. • TLRs 3, 7, 8, and 9 are mainly expressed inside cells on endoplasmic reticulum and endosomal membranes. Cell-associated PRRs and sensors of innate immunity
  27. 27. Toll-like receptors (TLRs) Abbas_Cellular and Molecular Immunology, 9th ed • TLRs 1, 2, 4, 5 and 6 - expressed on plasma membrane - recognize various PAMPs in the extracellular environment • TLRs 3, 7, 8, and 9 expressed inside cells on endoplasmic reticulum and endosomal membranes • UNC-93B is required for the endosomal localization and proper function of TLRs 3, 7, 8, and 9
  28. 28. Toll-like receptors (TLRs) • LPS-binding protein in the blood or extracellular fluid • CD14 is expressed by most cells (except endothelial cells) as a soluble protein or as a glycophosphatidylinositol-linked membrane protein. • MD2 (myeloid differentiation protein 2) binds to LPS, forming a complex that then interacts with TLR4 Abbas_Cellular and Molecular Immunology, 9th ed Bankova L.etal.middleton’s 9th edition,2020.1-19
  29. 29. • TLR 3 signal through TRIF- pathway and activates type I IFN >> antiviral state. • TLR4, induce both inflammatory and antiviral responses. (signal through both MyD88 ,TRIF- pathway ) Abbas_Cellular and Molecular Immunology, 9th ed Signaling pathways and functions of TLRs. 1. MyD88 –dependent pathway (Myeloid differentiation primary response gene 88) cell surface TLRs engage the adaptor • NF-kB (inflammation) activation. 2. TLR signaling uses the adaptor : TRIF-dependent pathway (TIR-domain-containing adaptor inducing IFN-β) • Type I IFNs (anti-viral) All TLR except TLR3 signal through MyD88 and capable of activating NF-KB >> inflammatory response • TLR 7 and TLR 9 in the endosome use MyD88 and activate both NF-κB and IRFs>> induce both inflammatory and antiviral
  30. 30. • UNC-93B : multiple-transmembrane-spanning protein in ER - required for endosomal localization & proper function of TLRs 3,7,8,9 - unknown mechanism - genetic def. in UNC-93B >> viral infections esp. Herpes simplex encephalitis Bankova L.etal.middleton’s 9th edition,2019.1-19
  31. 31. Toll-like receptors (TLRs) Bankova L.etal.middleton’s 9th edition,2020.1-19
  32. 32. Defective recognition by TLR Netea MG, new England journal med ,2011 N Engl J Med 2011; 364:60-70
  33. 33. Cytosolic Receptors for PAMPs and DAMPs Abbas_Cellular and Molecular Immunology, 9th ed • 3 major classes of these cytosolic receptors • NOD–like receptors (NLRs) • RIG (retinoic acid-inducible gene)-like receptors • Cytosolic DNA sensors (CDs) • Similar to TLRs, are linked to signal transduction pathways that promote type I IFN production.
  34. 34. NOD-Like Receptors: NOD1 and NOD2 Abbas_Cellular and Molecular Immunology, 9th ed • NOD : Nucleotide oligomerization domain • A family of more than 20 different cytosolic proteins • recognize PAMPs and DAMPs in cytosol. • Typical NLRs include : • C-terminal leucine-rich repeat domain (LRR): presence of ligand • Central NOD (NACHT) domain required for NLR proteins to bind to one another and form oligomers • N-terminal effector binding domain (NBD) : CARD, PYD, BIR
  35. 35. N-terminal effector domain C-terminal leucine-rich-repeat
  36. 36. NOD-Like Receptors: NOD1 and NOD2 Abbas_Cellular and Molecular Immunology, 9th ed • NOD1 and NOD2, members of the NLRC subfamily, : CARD domain– containing NOD subfamily • expressed in the cytosol of several cell types, including mucosal epithelial cells and phagocytes • respond to bacterial cell wall peptidoglycans. • Important in innate immune response to bacterial pathogen in GI tracts ; H.pylori , L.monocytigenes. NOD1 : • Express GI tract epithelial • Recognizes a glycosylated tripeptide called DAP (diaminopimelic acid), derived mainly from gram-negative bacterial peptidoglycan NOD2 : •expressed in intestinal Paneth cells •stimulates expression of defensins •Recognizes MDP (muramyl dipeptide), derived from both gram-negative and positive peptidoglycans.
  37. 37. NOD-Like Receptors: NOD1 and NOD2 Abbas_Cellular and Molecular Immunology, 9th ed • Oligomers of NODs recognize their peptide ligands, including bacterial toxins, • A conformational change occurs that allows the CARD effector domains of NOD proteins to recruit multiple copies of kinase RIP2, forming a signaling complex that has been called NOD signalosome. • The RIP2 kinases in these complexes activate NF-κB, which stimulates production of cytokines and other molecules involved in inflammation (similar to TLRs that signal through MyD88)
  38. 38. NLR (NOD-like receptor) and Inflammasome Abbas_Cellular and Molecular Immunology, 9th ed • nucleotide oligomerization domain-containing protein • Expressed on several cell types : Mucosal epithelial cells, Phagocytes • Response to bacterial cell wall peptidoglycans 2 Groups • NOD1 (CARD4), NOD2 (CARD15) : similarly to TLRs • NLRP3: Intracellular microbes and danger signals – Caspase-1 – Inflammasome Deficiency/defect • Autoimmune diseases; DM, IBD, MS • Crystal-induced arthritis
  39. 39. Defective in NOD2 gene Abbas_Cellular and Molecular Immunology, 9th ed • NOD2 gene polymorphisms increase the risk for an inflammatory disease of the bowel “ Crohn’s disease”. • Gain-of-function mutations of NOD2 that cause increased NOD signaling and NF-κB activation lead to a systemic inflammatory disease called “Blau syndrome”. • Early onset sarcoidosis • Triad : granulomatous arthritis , uveitis , dermatitis
  40. 40. 2.RIG-Like Receptors (RLRs) Abbas_Cellular and Molecular Immunology, 9th ed • Cytosolic sensors of viral RNA that respond to viral nucleic acid by inducing the production of antiviral type I IFN. • Recognize ds RNA and RNA-DNA heteroduplexes, (RNA viruses and RNA transcripts of RNA and DNA viruses). • RIG-I (retinoic acid–inducible gene 1) >> 5′ triphosphate moiety, which is NOT present in mammalian host cell. • MDA5 (melanoma differentiation-associated gene 5)>> long ds RNA • Binding viral dsRNA, the RLRs are recruited to the outer mitochondrial membrane. • Formation of filaments by a prion-like mechanism • Initiates signaling events that lead to phosphorylation and activation of IRF3 and IRF7 → type I IFN
  41. 41. Abbas_Cellular and Molecular Immunology, 9th ed RIG-Like Receptors (RLRs) formation of filament by prion- like mechanism
  42. 42. • CDSs (Cytosolic DNA sensors) are molecules that detect microbial dsDNA in cytosol and activate signaling pathways that initiate antimicrobial responses, including type 1 IFN production and autophagy. • The STING (stimulator of IFN genes) pathway is major mechanism of dsDNA induced activation of type 1 IFN responses . 3.Cytosolic DNA Sensors and the STING Pathway Abbas_Cellular and Molecular Immunology, 9th ed
  43. 43. The STING cytosolic DNA sensing pathway. - Important mechanism of dsDNA induced activation of type 1 IFN responses 1 2 3 4 1
  44. 44. • Inflammasomes are multiprotein complexes form in the cytosol response to cytosolic PAMPs and DAMPs, • function is to generate active forms of cytokines IL1β and IL18. • Inflammasomes can form with different sensor protein include NLRB, NLRC4, and at least six NLRP proteins • Proteolytically cleaved by the enzyme caspase-1 to become active cytokines Inflammasome Abbas_Cellular and Molecular Immunology, 9th ed
  45. 45. Abbas_Cellular and Molecular Immunology, 9th ed • After binding of a ligand, multiple identical NLRP3 proteins interact to form oligomer • Each NLRP3 protein in oligomer binds ASC adaptor protein • Triggers conformational changes of other ASC molecules in the cytosol by a prion-like • The filaments of ASC that can cluster and recruit inactive caspase-1 • The recruitment and consequent clustering of pro- caspase-1 proteins result in the generation of active caspase-1. Inflammasome Sensors respond to PAMPs, DAMPs, induce pro IL-1B. 1 Caspase-1 cleaves cytosol pro–IL-1β , pro IL-18, pro IL-33 → IL-1β, IL-18, IL-33 (active form) → inflammation 2 3
  46. 46. • Associated with infections and cell stress, including microbial products, environmentally or endogenously derived crystals, and reduction in cytosolic K+. • NLRC4 recognizes cytosolic flagellin • NLRP1 recognizes anthrax lethal toxin. • NLRP3 senses many DAMPS and PAMPS, including uric acid crystals, aluminum hydroxide crystals used in vaccine adjuvants, ATP released from mitochondria, silica, bacterial products, bacterial toxins, bacterial DNA-RNA hybrids, and influenza virus. • NLRP12 senses PAMPS from Yersinia species and is required for control of Yersinia. Inflammasomes Abbas_Cellular and Molecular Immunology, 9th ed
  47. 47. • Programmed cell death of macrophages and DCs : called pyroptosis. • Pyroptosis, characterized swelling of cells, loss of plasma membrane integrity, and release of mediators including IL1β, IL-18, TNF, IL-6, and IL-8. • A key feature is caspase-mediated cleavage of a protein called gasdermin D, which leads to formation of membrane pores. • The amplification of inflammation provided by pyropotosis enhances bacterial clearance but also may contribute to septic shock. Inflammasomes Abbas_Cellular and Molecular Immunology, 9th ed
  48. 48. Gout • Painful ,Inflammatory condition of the joints caused by deposition of monosodium urate crystals in joint. • urate crystals activate the inflammasome • Treatment : IL-1 antagonists (effectively for severe cases ,resistant to conventional therapy) Inflammasome activation of caspase-1 Abbas_Cellular and Molecular Immunology, 9th ed
  49. 49. Cryopyrin Associated Periodic Syndromes (CAPS) >> NLRP3 GOF • Subset of a larger group of periodic fever syndrome • Fever, rash, joint pain ,eye redness/pain and fatigue • Dysregulated activation of the inflammasome due to autosomal gain-of-function mutations of the NLRP3 gene • Leads to inappropriately excess IL-1 production. • Treatment : IL-1 antagonists (Anakinra) Familial Mediterranean Fever (mutation of the MEFV gene which encodes pyrin) Autoinflammatory syndromes Abbas_Cellular and Molecular Immunology, 9th ed
  50. 50. Characteristics of Immunodeficiency Due to Defective Recognition by Pattern- Recognition Receptors (PRRs) Netea MG, new England journal med ,2011 N Engl J Med 2011; 364:60-70
  51. 51. 1. C-type lectin receptors for microbial Carbohydrates • Mannose receptors • Dectins • Other dendritic cell carbohydrate receptors include langerin (CD207) 2. Scavenger Receptors 3. Formyl-Peptide Receptors Other Cell-Associated Pattern Recognition Receptors Abbas_Cellular and Molecular Immunology, 9th ed
  52. 52. • Cellular receptors recognize carbohydrates on the surface of microbes facilitate the phagocytosis of the microbes → secretion of cytokines promote inflammation and subsequent adaptive immune responses • C-type lectins with specificities for different carbohydrates, including mannose, glucose, N-acetylglucosamine, and β-glucans. • Found on surfaces of macrophages, DCs, and some tissue cells. • Other Lectins are soluble proteins in the blood and ECFs → complement 1.Receptors for Carbohydrates ( C-type lectin receptors) Abbas_Cellular and Molecular Immunology, 9th ed
  53. 53. Mannose receptor (CD206) • Involved in phagocytosis of microbes • first step : ingestion microbes by macrophages • Recognizes certain terminal sugars on microbial surface carbohydrates; including d-mannose, l-fucose, and N-acetyl-glucosamine [ These terminal sugars are often present on the surface of microorganisms ] Receptors for Carbohydrates ( C-type lectin receptors) Abbas_Cellular and Molecular Immunology, 9th ed
  54. 54. Dectins = dendritic cell–associated C-type lectin • Dectins are expressed on DCs and macrophages play important roles in antifungal immunity • Dectin-1 (CD369): binds β-glucan, which is a major cell wall component of many fungal species→ immunity to various pathogenic fungal species, including candida, aspergillus, and pneumocystis. • Dectin-2: recognize high-mannose oligosaccharides on the hyphal form of some fungi and bacteria • Tail: ITAM-> signal to NF-kB • In response to ligand binding to dectin-1, dectin-2→ promote the development of Th17 Receptors for Carbohydrates ( C-type lectin receptors) Abbas_Cellular and Molecular Immunology, 9th ed
  55. 55. • Langerin (CD207): mainly expressed by epidermal Langerhans cells • DC-SIGN (CD209): expressed on the majority of dendritic cells associated hepatitis C virus and HIV-1. Receptors for Carbohydrates ( C-type lectin receptors) Abbas_Cellular and Molecular Immunology, 9th ed
  56. 56. Receptors for Carbohydrates ( C-type lectin receptors) Abbas_Cellular and Molecular Immunology, 9th ed
  57. 57. • Structurally and functionally diverse collection of cell surface proteins • Some of these scavenger receptors, including SR-A and CD36, are expressed on macrophages and mediate the phagocytosis of microorganisms • CD36 functions as a coreceptor in TLR2/6 recognition and response to bacteria • Wide range of molecular structures bind to each scavenger receptor, including LPS, lipoteichoic acid, nucleic acids, β-glucan, and proteins. 2.Scavenger Receptors Abbas_Cellular and Molecular Immunology, 9th ed
  58. 58. • Formyl peptide receptor-1 (FPR1), expressed on leukocytes, recognizes bacterial peptides containing N-formylmethionyl residues . • The bacterial peptide ligands are the most potent known chemoattractant for leukocytes. • FPR1 and all other chemoattractant receptors belong to GTP –binding protein–coupled receptor superfamily that are responsible for the increased cell motility. 3.Formyl-Peptide Receptors Abbas_Cellular and Molecular Immunology, 9th ed
  59. 59. Turvey SE, Broide D, J Allergy Clinical imm, 2010 Components of Innate immunity 1.Anatomical barrier - Physical barriers - Chemical barriers 2.Cellular - Phagocytic cells - Dendritic cell - NK cells, ILC - Mast cell 3.Soluble proteins - Complement - Cytokines, Chemokines - Antimicrobial peptides (AMPs)
  60. 60. Abbas_Cellular and Molecular Immunology, 9th ed 1.Epithelial Barriers ▪ Skin and the mucosal surfaces of the GI, respiratory, and GU tracts. ▪ Loss of the integrity of these epithelial layers by trauma → risk of infection ▪ Tight junctions and outer layer of keratin (block microbial penetration) ▪ Mucins is produced by respiratory, gastrointestinal, and urogenital epithelial (physically impairs microbial invasion). ▪ Ciliary action in bronchial tree and peristalsis in gut (elimination of microbes) physical and chemical defenses at epithelial barriers which block microbial entry.
  61. 61. Abbas_Cellular and Molecular Immunology, 9th ed 2 structurally distinct families of antimicrobial peptides are defensins and cathelicidins. 1. Defensins (α and β) - produced by epithelial cells of mucosal surfaces ,neutrophils, NK cells and cytotoxic T cell. - Direct toxicity to microbes(bacteria, fungi ,enveloped viruses) and activation of cells. Epithelial Barriers : antimicrobial peptides 2. Cathelicidin - Produced by neutrophils and barrier epithelial cells in skin, Gl tract (colon), and respiratory tract, - direct toxicity and activation cells. - Can bind and neutralize LPS, the toxic component of the outer wall of gram-negative bacteria - e.g. C-terminal fragment (LL-37)
  62. 62. Summary of human antimicrobial peptides Gallo et al. J Allergy Clin Immunol 2002;110:823-31.
  63. 63. • Atopic dermatitis • reduction cathelicidin , β- defensins 2,3 • IL-4 and IL-13 production: suppress production of cathelicidin, β- defensins 2,3 • More susceptible to herpes viruses and Staphylococcus aureus • Vitamin D: promote production of cathelicidin via TLR-2-dependent manner Clinical implication Abbas_Cellular and Molecular Immunology, 9th ed
  64. 64. • Intraepithelial T lymphocytes are present in the epidermis of the skin and in mucosal epithelial. • Several subsets: • αβ form of TCR : lymphoid tissue, circulation • γδ form of TCR : epithelial • Common characteristic of intraepithelial T cells is limited diversity of their antigen receptors • Recognize a small number of commonly encountered microbial structures • Activated NOT by antigen recognition but by cytokines and other molecules produced by epithelial cells Intraepithelial T lymphocytes Abbas_Cellular and Molecular Immunology, 9th ed
  65. 65. • Primarily macrophages and neutrophils, are the first line of defense against microbes that breach epithelial barrier • The essential role that phagocytes is demonstrated by the high rate of lethal bacterial and fungal infections in patients with low blood neutrophil counts • Function – Phagocytosis , Cytokine production 1.Phagocytes (phagocytic cell) Abbas_Cellular and Molecular Immunology, 9th ed CELLULAR COMPONENTS OF THE INNATE IMMUNE SYSTEM • Neutrophils: – Short lifespan (2-3days) • Monocytes/Macrophages: – Longer lifespan (several months) – Main source of inflammatory cytokines: initiates inflammation
  66. 66. 1.Phagocytes (phagocytic cell) Abbas_Cellular and Molecular Immunology, 9th ed CELLULAR COMPONENTS OF THE INNATE IMMUNE SYSTEM Cytokine production NETosis (NET formation) – Another form of programmed cell death by releasing of decondensed chromatin bound to cytosolic contents . • The fibrous structure contains: – Histone, chromatin and DNA structure – Antimicrobial substances: neutrophil elastase, cathepsin G, lactoferrin, myeloperoxidase
  67. 67. • Dendritic cells (DCs) rapidly and efficiently detect invading microbes because of their location in tissues • Expression of numerous pattern recognition receptors for PAMPs and DAMPs • The plasmacytoid subset of DCs is a major source of the antiviral cytokines, type I interferons produced in response to viral infections • Express abundant amounts of the endosomal TLRs (TLRs 3, 7, 8, 9) • Direct naïve T cell differentiation (adaptive immunity) 2.Dendritic Cells : Antigen presenting cell Abbas_Cellular and Molecular Immunology, 9th ed CELLULAR COMPONENTS OF THE INNATE IMMUNE SYSTEM
  68. 68. • Mast cells are sentinel cells present in the skin, mucosal epithelium, and connective tissues • Rapidly secrete proinflammatory cytokines and lipid mediators in response to infections and other stimuli • Contain abundant cytoplasmic granules (histamine) filled with various inflammatory mediators (prostaglandins) and cytokines (such as TNF) 3.Mast cells Abbas_Cellular and Molecular Immunology, 9th ed CELLULAR COMPONENTS OF THE INNATE IMMUNE SYSTEM
  69. 69. • Innate lymphoid cells (ILCs): bone marrow–derived cells with lymphocyte morphology that serve diverse antimicrobial functions • Produced cytokines similar to those made by T cells but lacked TCRs • There are different subsets of ILCs that arise from the same common lymphoid precursor T cells 4.Innate Lymphoid Cells Abbas_Cellular and Molecular Immunology, 9th ed CELLULAR COMPONENTS OF THE INNATE IMMUNE SYSTEM
  70. 70. Abbas_Cellular and Molecular Immunology, 9th ed Cytokine producing innate lymphoid cell subsets
  71. 71. • LC1s are likely important for defense against intracellular microbes. • LC2s are important for defense against parasites, allergic diseases. • ILC3s are found at mucosal sites and in defense against extracellular fungi and bacteria, as well as in maintaining the integrity of epithelial barriers. • Early host defense is that they are always resident in epithelial barrier tissues Cytokine-Producing Innate Lymphoid Cells (ILCs) Abbas_Cellular and Molecular Immunology, 9th ed
  72. 72. • Important roles in innate immune responses, mainly against viruses and intracellular bacteria • 5-15% of the mononuclear cells in blood and spleen. • Major function is killing infected cells, similar cytotoxic T lymphocytes (CTLs), also secrete IFN-γ • Expression of CD56 , CD16 (involved in recognition of antibody-coated cells) and absence CD3. 5.Natural Killer Cells Abbas_Cellular and Molecular Immunology, 9th ed CELLULAR COMPONENTS OF THE INNATE IMMUNE SYSTEM
  73. 73. • Kill infected cells and to produce IFNγ → activates macrophages to destroy phagocytosed microbes • NK cells are activated, granule exocytosis releases these proteins adjacent to the target cells (Perforin, Granzymes (proteolytic enzymes ). • Early in the course of a viral infection (few days in CTL) • Killing infected cells that have escaped by reducing expression of class I MHC Natural Killer Cells Abbas_Cellular and Molecular Immunology, 9th ed
  74. 74. Functions of NK cells Abbas_Cellular and Molecular Immunology, 9th ed NK cells recognize ligands on infected cells Activates the macrophages to kill phagocytosed microbes.
  75. 75. Abbas_Cellular and Molecular Immunology, 9th ed Functions of NK cells Inhibitory receptors of NK cells recognize class I MHC molecules protein tyrosine kinases (PTKs), protein tyrosine phosphatases (PTP).
  76. 76. NK cells induce target cell apoptosis by the release of toxic granules containing granzymes and perforins : disrupt cell membranes. Express apoptosis-inducing FAS ligand (FASLG) &TRAIL that interact with their counterparts on target cells. IFN γ augment cytotoxic T lymphocyte and Th1 immune Natural killer (NK) cells recognize and target infected or malignant cells in an antigen-independent manner. Bankova L.etal.middleton’s 9th edition,2020.1-19
  77. 77. Structure and ligands of activating and inhibitory receptors of NK cells Abbas_Cellular and Molecular Immunology, 9th ed Activating receptors:ITAMs Inhibitory receptors:ITIMs Ab-dependent cell-mediated cytotoxicity (ADCC) • CD16 (FcγIII): bind Fc region of Ab (IgG1,IgG3: produce during infection) >> cell apoptosis • Perforin , Granzyme B NKG2D: • C-type lectin • Bind class 1 MHC like protein (MIC-A, MIC-B) on viral infected cell, tumor cells FcγIII
  78. 78. • Cytokines can enhance the functional responses of NK cells. • The major cytokines of the innate immune system that stimulate NK function are IL-12, IL-15, IL-18, and type I interferons. • IL-15 are important growth factors for NK cells Cytokines & Functional responses of NK cells Abbas_Cellular and Molecular Immunology, 9th ed
  79. 79. • Small populations of lymphocytes express antigen receptors that are structurally the same as those of T and B cells, but these receptors have very little diversity. • T cell : Invariant NK T cells (iNKT), γδ T cells, MAIT cells, and intraepithelial T cells with αβ TCRs • B cell : B-1 cells and marginal-zone B cells 6.T and B Lymphocytes with Limited Antigen Receptor Diversity Abbas_Cellular and Molecular Immunology, 9th ed
  80. 80. Soluble effect molecules of the innate immunity
  81. 81. • Recognize microbes and promote innate responses exist in soluble form in the blood and extracellular fluids. • 2 major function • Opsonins: binding to microbes, enhance the ability of macrophages and neutrophils to phagocytose microbes • Promote inflammatory responses : bring more phagocytes to sites of infections, directly kill microbes Soluble effect molecules of the innate immunity Abbas_Cellular and Molecular Immunology, 9th ed The major components: • Complement system • Collectins • Ficolins • Pentraxins
  82. 82. Pathways of complement activation. Abbas_Cellular and Molecular Immunology, 9th ed C3 convertase
  83. 83. • Plasma protein prominent members: Short pentraxins, C-reactive protein (CRP) and serum amyloid P (SAP), and the long pentraxin PTX3. • All activate complement by binding C1q and initiating the classical pathway • Increased levels of CRP are result of increased synthesis by liver induced the cytokines IL-6 and IL-1 → “acute phase reactants” Pentraxins Abbas_Cellular and Molecular Immunology, 9th ed
  84. 84. • Collectin: • The collectins are a family of trimeric or hexameric proteins, contains a collagen-like tail • There are mannose-binding lectin (MBL) and pulmonary surfactant proteins SP-A and SP-D • Ficolin: • The molecular ligands of the ficolins include N-acetylglucosamine and the lipoteichoic acid component of the cell walls of gram-positive bacteria Collectins and Ficolins Abbas_Cellular and Molecular Immunology, 9th ed Ficolin
  85. 85. Pattern Recognition Molecules of the Innate Immune System Abbas_Cellular and Molecular Immunology, 9th ed Bacterial phospholipids (phosphorylcholine) Functions Opsonization, complement activation, microbial cell lysis, chemoattraction, phagocytosis Opsonization, complement activation Opsonization, complement activation, microbial cell lysis, chemoattraction, phagocytosis Opsonization,killing,phagocytosis, proinflammatory and Anti-inflammatory mediator release Microbial mannan Bacterial cell wall lipids; viral coat proteins
  86. 86. Inflammatory response
  87. 87. • The major proinflammatory cytokines • Recruitment of Leukocytes to infection sites → Activated phagocytes Inflammatory response Abbas_Cellular and Molecular Immunology, 9th ed • Innate immune system deals with infections and tissue injury to stimulate acute inflammation -> accumulation of leukocytes, plasma proteins, and fluid derived from the blood • Chronic inflammation : takes over from acute inflammation if the infection is not eliminated or the tissue injury is prolonged
  88. 88. • Mainly by tissue macrophages and dendritic cells • Three of the most important proinflammatory cytokines of the innate immune system are TNF, IL-1 and IL-6 • TNF,IL-17, IL-5, IFN-ɣ -> from both innate and adaptive The Major Proinflammatory Cytokines Abbas_Cellular and Molecular Immunology, 9th ed
  89. 89. Abbas_Cellular and Molecular Immunology, 9th ed Cytokine of innate immunity
  90. 90. Abbas_Cellular and Molecular Immunology, 9th ed Dendritic cell
  91. 91. Abbas_Cellular and Molecular Immunology, 9th ed Cytokine of innate immunity Homologous to IL-2
  92. 92. 2.Recruitment of Leukocytes to sites of infection Abbas_Cellular and Molecular Immunology, 9th ed express E-selectin secrete chemokines (CXCL8 and CCL2)
  93. 93. • Neutrophils and macrophages that are recruited into sites of infections ingest microbes into vesicles by the process of phagocytosis and destroy these microbes • Signals from various receptors, including PRR :such as TLRs Opsonin receptors : Fc and C3 receptors Receptors for cytokines :mainly IFN-γ and CD40, function cooperatively to activate phagocytes to kill ingested microbes. • Fusion of phagocytic vacuoles (phagosomes) Ingestion and Killing of Microbes by Activated Phagocytes Abbas_Cellular and Molecular Immunology, 9th ed
  94. 94. Ingestion and Killing of Microbes by Activated Phagocytes Abbas_Cellular and Molecular Immunology, 9th ed 1 Activated neutrophils and macrophages kill phagocytosed microbes by the action of microbicidal molecules in phagolysosomes
  95. 95. • Neutrophils also kill microbes by extruding their DNA and granule contents, which form extracellular threads on which bacteria and fungi are trapped and killed. • The extruded contents, which are called neutrophil extracellular traps (NETs) • NETs: composed of strands of DNA and histones to and of antimicrobial granule contents, including lysozyme, elastase, and defensins. • NET formation leads to neutrophil cell death NETosis Abbas_Cellular and Molecular Immunology, 9th ed
  96. 96. Functions of macrophages. Abbas_Cellular and Molecular Immunology, 9th ed Promote tissue repair and fibrosis
  97. 97. Abbas_Cellular and Molecular Immunology, 9th ed Local and systemic actions of cytokines in inflammation. Septic shock
  98. 98. • The major way by innate immune system blocks viral infections is to induce the expression of type I interferon → action to inhibit viral replication • The most important type I interferons in viral defense are IFN-α and IFN-β • Signaling through the type I interferon receptor → confer on cells a resistance to viral infection called “an antiviral state” The Antiviral Response Abbas_Cellular and Molecular Immunology, 9th ed
  99. 99. Biologic action of type I interferons Abbas_Cellular and Molecular Immunology, 9th ed paracrine action
  100. 100. Stimulation of adaptive immunity by innate immune responses Abbas_Cellular and Molecular Immunology, 9th ed Two-signal hypothesis - Antigen recognition by lymphocytes provides signal 1 - innate immune responses to microbes provide signal 2. - DCs activated by microbes produce cytokines and costimulators : enhance T cell activation and differentiation into effector T cells. - Complement fragments generated by the alternative pathway : provide second signals for B cell activation and antibody production.
  101. 101. Innate immune instruction of adaptive immunity Bankova L.etal.middleton’s 9th edition,2020.1-19
  102. 102. HOMEOSTASIS IN THE INNATE IMMUNE SYSTEM ▪ Innate immune responses are regulated by negative feedback mechanisms ▪ Macrophages have an essential role in maintaining immune homeostasis ▪ Classic activation of macrophages - Proinflammatory : TNF-α - Anti-inflammatory mediators : IL-10, TGF-β, and PGE2 (downregulate macrophage and DC functions) Bankova L.etal.middleton’s 9th edition,2020.1-19 anti-inflammatory mediators 1 2 3 IL-10 : inhibits activation of macrophages and DCs.
  103. 103. Examination
  104. 104. 1.Which of the following statements is accurate? a. MyD88/TRAM pathway is required for all TLR signaling. b. The TRIF/TRAM pathway leads to activation of NF-κB. c. Inflammasome activation and the generation of mature IL-1B is elicited by TLR signaling. d. Viral nucleic acid is recognized by both NLRs and RIG-I. e. Endocytosis is the primary function of C-type lectin receptors.
  105. 105. 2. Which neutrophil granule product exploits a structural difference in the cellular membrane organization between bacterial and mammalian cells for its microbicidal activity? a. Myeloperoxidase b. Human α-defensins c. Neutrophil elastase d. Cathepsin G
  106. 106. 3. Which cytokine is released by necrotic epithelial cells but has also been shown to play a role in restoration of epithelial integrity and thermogenesis? a. IL-33 b. IL-25 c. Thymic stromal lymphopoietin (TSLP) d. IL-8
  107. 107. 4. Which is a bacterial metabolic by-product with anti-inflammatory properties linked to dietary fiber breakdown in the intestine? a. Long chain fatty acids b. Butyrate c. Alpha ketoglutarate d. Citric acid
  108. 108. Thank you For your attention

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