Innate Immunity IB PDF

INNATE IMMUNITY BMV202  INNATE IMMUNITY Physical & Chemical Barriers  non-specific  present from birth  role - provide a rapid first line of defense against pathogens Skin  surface lined with dead cells  barrier to living organisms and foreign substances  dead cel...

INNATE IMMUNITY BMV202  INNATE IMMUNITY Physical & Chemical Barriers  non-specific  present from birth  role - provide a rapid first line of defense against pathogens Skin  surface lined with dead cells  barrier to living organisms and foreign substances  dead cells slough off shedding mo’s that may be attached  sweat, sebaceous secretions, fatty acids, hydrolytic enzymes (e.g. lysozymes) have antimicrobial effects BMV202  INNATE IMMUNITY Cells of the Innate Immune System R Coico and G Sunshine. (2015). Immunology: A short course. Wiley Blackwell, UK. BMV202  INNATE IMMUNITY Cells of the Innate Immune System  Polymorphonuclear Leukocytes  Granulocytes (basophils, eosinophils, neutrophils)  short-lived, phagocytes that contain enzyme rich lysosomes (enzyme filled vesicles)  produce peroxide, superoxide radicals, nitric oxide  bactericidal proteins (lactoferrin)  facilitate destruction of microorganisms  Macrophages  phagocytes that differentiate into different forms  Kupffer cells - liver  Alveolar macrophages - lung  Splenic macrophages - red pulp  Peritoneal macrophages - peritoneal fluid  Microglial cells - central nervous system  function to phagocytose mo’s & foreign substances in blood stream BMV202  INNATE IMMUNITY Cells of the Innate Immune System  Dendritic Cells  recognise and phagocytize antigens  presents antigens to T-cells  plasmacystoid dendritic cells secrete α- and β-interferons  Natural Killer Cells  large granular lymphocytes containing biologically potent mol  recognize altered features of membranes (such as those found on virus infected or cancer cells)  upon contacting cells, secretes biologically active compounds  causes pore formation in target  leading to cell lysis  other molecules enter cell and causes apoptosis  hence, able to lyse certain virus infected cells and tumour cells without stimulation BMV202  INNATE IMMUNITY Cells of the Innate Immune System  Natural Killer T-Cells  fall bet innate and adaptive immune systems  secrete interleukin-4 & interferon γ  kill target cells via Fas-Fas ligand interactions that cause apoptosis  Innate Lymphoid Cells  heterogeneous family  protective immunity at acute phase of infection  tissue remodeling  anatomical containment of commensal mo’s BMV202  INNATE IMMUNITY Pattern Recognition Receptors (PRR)  cells of innate immunity initiate host defense through pattern recognition R Coico and G Sunshine. (2015). Immunology: A short course. Wiley Blackwell, UK. BMV202  INNATE IMMUNITY Pattern Recognition Receptors (PRR)  recognize & respond to evolutionarily conserved microbial structures termed: pathogen-associated molecular patterns (PAMPs)  PAMP detection by innate cells occurs thro’ germline encoded pattern recognition receptors (PRR)  Toll-like Receptors  expressed as membrane bound or cytoplasmic receptors  recognize a large no of PAMPs expressed by many different viral, bacterial, fungal & parasitic pathogens BMV202  INNATE IMMUNITY Pattern Recognition Receptors (PRR)  Toll-like Receptors R Coico and G Sunshine. (2015). Immunology: A short course. Wiley Blackwell, UK. BMV202  INNATE IMMUNITY Pattern Recognition Receptors (PRR)  Toll-like Receptors  TLR1, TLR2, TLR4, TLR5 & TLR6 primarily expressed on plasma membrane where they sense specific molecules on microbial surfaces  TLR3, TLR7, TLR8 & TLR9 traffic from the ER to the endosome where they recognize DNA and RNA  specific TLRs interact with adaptor proteins to initiate signal transduction pathways  generates MAPK , nuclear factor kappa β, interferon BMV202  INNATE IMMUNITY Pattern Recognition Receptors (PRR)  C-Type Lectin Receptors  membrane bound  binds to carbohydrates in Ca2+ dependent manner  involved in fungal recognition  f-Met-Leu-Phe Receptors  expressed in high levels on membranes of polymorphonuclear & mononuclear phagocytes  specific for formylated peptides such as f-Met  bacterial proteins only (i.e. not eukaryotic) BMV202  INNATE IMMUNITY Pattern Recognition Receptors (PRR)  NOD-Like Receptors  intracellular PRR  recognize cytoplasmic PAMPs  some can assemble into an inflammasome complex  that activates caspase-1 that cleaves inactive cytokines such as IL-1 into active cytokines  increases the inflammation response BMV202  INNATE IMMUNITY Pattern Recognition Receptors (PRR)  RIG-I-Like Receptors  family of 3 cytoplasmic RNA helicases  critical for host antiviral responses  sense dsRNA (replication intermediate for RNA viruses)  leads to production of interferon-α and interferon-β BMV202  INNATE IMMUNITY Complement  major soluble element  made of 25 proteins mostly produced by liver  functions to assist (complement) action of antibodies to destroy bacteria  rids the body of antibody-coated antigens (opsonized Ag)  circulate in the body as inactive proteins  when activated, each component takes a turn in a precise chain of steps called the complement cascade  end products are molecular cylinders called membrane attack complex (MAC)  MACs inserted into bacterial membranes BMV202  INNATE IMMUNITY Complement  punches holes in bacterial membranes  causing contents to leak out  leading to bacterial death  some complement proteins bind directly to bacteria  makes bacteria more susceptible to phagocytosis by innate immune cells  can also attract other immune system cells  local mobilization of host defense mechanism BMV202  INNATE IMMUNITY Intracellular / Extracellular Killing of MO’s  certain innate immune cells sample their environment  engulfs macroparticles (endocytosis) or whole cells (phagocytosis)  foreign material fuses with lysosomes containing degradative enzymes (nucleases, lipases, proteases)  broken down into simpler products like nucleotides, sugars, peptides Phagocytosis  ingestion of whole cells (bacteria) by phagocytes  mo’s release substances that attract phagocytes BMV202  INNATE IMMUNITY Phagocytosis R Coico and G Sunshine. (2015). Immunology: A short course. Wiley Blackwell, UK. BMV202  INNATE IMMUNITY Phagocytosis  phagocytosis may be enhanced by opsonins (antibodies, complement)  foreign particle trapped in a vacuole (phagosome)  fuses with lysosome to form phagolysosome  lysosmes release enzymes like lysozymes, proteases, etc  enzymes digest particle into peptides  phagocytes can generate toxic products through respiratory burst  nitric oxide (nitric oxide synthase), hydrogen peroxide & superoxide anion (phagocyte NADPH oxidase) & hypochlorous acid (myeloperoxidase)  toxic to bacteria BMV202  INNATE IMMUNITY Inflammation  major component of the body's defense mech  initiated by tissue damage thro’ mechanical (cuts), physical (burns), chemical (exposure to corrosive chemicals), immunologic (hypersensitivity reactions;) and biological (infections by pathogenic mo’s) injuries  Hallmarks - clinical signs of pain, redness, heat - bec of increased blood flow, increased cellular metabolism, vasodilation, release of soluble mediators - mostly phagocytic cells involved BMV202  INNATE IMMUNITY Inflammation  Hallmarks - within min innate immune cells respond to microbes expressing PAMPs - release of proinflammatory cytokines (IL-1, IL-6, TNF-α) - stimulate hepatocytes to secrete acute phase proteins - polymorphonuclear leukocytes rapidly accumulate within 30 to 60 min - phagocytoze intruder or damaged tissue - release lysosomal enzymes to destroy the intruder R Coico and G Sunshine. (2015). Immunology: A short course. Wiley Blackwell, UK. BMV202  INNATE IMMUNITY Inflammation  Hallmarks - Acute Phase Proteins R Coico and G Sunshine. (2015). Immunology: A short course. Wiley Blackwell, UK. BMV202  INNATE IMMUNITY Inflammation  Hallmarks - 4 - 6 hrs, area harbouring invading mo or foreign substance is infiltrated by macrophages & lymphocytes - macrophages assist in Ag processing and presentation to T-cells BMV202  INNATE IMMUNITY Fever  can be caused by endotoxins (LPS of Gram –ve bacteria)  innate immune cells exposed to LPS releases endogenous pyrogens (IL-1, certain interferons)  IL-1 causes hypothalmus to raise body To  significance  environmental To increases above that of optimum microbial growth To - inhibits microbial growth  production of heat shock proteins - some T-cells produce inflammation inducing cytokines  increases metabolism - causes increase in enzymatic reactions, production of phagocytes, lymphocytes, Ab, cytokines, etc. BMV202  REFERENCES Coico, R. and G. Sunshine. 2015. Immunology - A Short Course. Wiley Blackwell. BMV202