Innate Immunity Flashcards
What are the two components of the innate immune system?
- cellular component
- humoral component
What are the two components of the adaptive immune system?
- humoral component
- cellular component
What is the difference between innate and adaptive immunity?
Innate immunity is not dependent on antigen, it is immediate, and does not leave any memory.
Adaptive immunity is antigen-specific, delayed in time, and leave memory.
What barriers does innate immunity use/provide?
- physical barriers (skin, mucus membrane)
- Humoral barriers (complement system)
- Cellular barriers (phagocytic system, NK cells)
What factors are involved in physical barriers of the innate immune system?
- Mechanical factors
- Chemical factors (fatty acids inhibit growth of bacteria, lysozyme and phospholipase in tears, saliva inhibit growth of infectious agents, low pH of sweat/gastric juices has antibacterial effects, surfactants such as opsonins in lungs enhance phagocytosis)
- Microbial factors
What are the mechanical factors of innate immunity?
- skin
- ciliary movement
- peristalic movement in GI tract washing effect of tears and saliva
- mucus layers in vagina, digestive tract and respiratory tract
What are the chemical factors of innate immunity?
- fatty acids inhibit growth of bacteria
- lysozyme and phospholipase in tears, saliva inhibit growth of infectious agents
- low pH of sweat/gastric juices has antibacterial effects
- surfactants such as opsonins in lungs enhance phagocytosis
What are microbial factors of innate immunity?
- Normal biota on skin and GI tract prevents infection by secreting inhibitory substances that prevent colonization and growth of infectious microorganisms.
What happens if the physical barriers of innate immunity are breached?
penetration of infectious agents and development of inflammation
What ar the most important humoral factors of innate immunity?
- complement system
- coagulative system
- Lactoferin and transferin
- Lysozyme
- Interferons
- Interleukin-1
What is the complement system?
a group of ~30 proteins found in serum that cooperate to prevent infection
What does activation of the coagulative system lead to?
- blood coagulation at the site of damage preventing entry to infectious agents
- some molecules of the system act as chemotactic factors, attracting other cells to the site of damage
- Beta-lysine is produced by platelets and has bactericidal effects against G+ bacteria
What does lactoferin and transferin do?
binds iron - bacteria cannot grow in the absence of iron
What does lysozyme do?
digests bacterial cell wall
What do interferons do?
inhibit infection and replication of viruses
What does interleukin-1 do?
responsible for increase in temperature during inflammation and induces acute phase proteins which are bactericidal
What are the cellular barriers of innate immunity?
- neutrophils
- Macrophages
- NK cells and LAK cells
- Eosinophils
What do neutrophils do?
belong to polymorphonuclear cells
- phagocytose microorganisms
What do macrophages do?
differentiate from monocytes and function as phagocytes
- ingest and kill microorganisms intracellularly
- may also phagocytose and kill infected cells
- may function as antigen presenting cells
- participate in wound healing
What do NK and LAK cells do?
kill infected or tumor cells
What do eosinophils do?
participate in eliminating parasites
Whata re the two vital cells of the phagocytic system?
Neutrofiles and macrophages
How are neutrofiles identified?
expression of CD66 on cell surface
What are the two types of granules stored by neutrofiles that store molecules required for the intracellular killing process?
- Azurophilic granules
- Secondary granules
What do azurophilic granules contain?
- defensins which kill bacteria
- proteolytic enzymes such as elastase, cathepsin G which degrade bacterial proteins
- Lysozyme which degrades the bacterial cell wall
- myeloperoxidase - required for the generation of bactericidal substances
What do secondary granules of neutrofiles contain?
- lysozyme
- lactoferin
- components of NADPH oxidase for production of toxic radicals
What are macrophages identified by?
the expression of CD14, CD11b, or F4/80
What are the lysosomes of macrophages used for?
they contain factors required for intracellular killing mechanisms
What do macrophages react to?
danger signals (SOS) generated at sites of pathogen entry
What are some danger signals that macrophages react to?
- N-formyl-methionine - secreted by bacteria
- Peptides of coagulative system
- complement system components
- cytokines secreted by tissue macrophages (at portals of entry)
What do danger signals do?
induce chemotaxis of macrophages towards the site of microbe entry.
What receptors do phagocytes posess which are used to bind microorganisms?
- Fc receptors
- Complement component receptors
- Scavenger receptors
- Toll-like receptors
Where are Fc receptors found and how do they work?
- found on macrophages
- antibodies bound to antigens expose their Fc ends
- Fc regions of an antibody are used to bind the Fc receptors on phagocytes
- Phagocyte binding of the Fc end of an antibody that is bound to a microorganisms surface enhances the metabolic activity of the phagocyte
Which complement component do phagocytes have receptors for?
C3b
How do complement components initiate phagocytosis?
C3b binds to the antigen, then binds to its receptor on the phagocyte - this signal leads to activation of phagocytosis
What are scavenger receptors and where are they found? What do they do?
they are SRA, CD68, Lox-1 or CD36 on macrophages.
- directly bind various polyamines found on bacterial surfaces initiating phagocytosis
What do toll-like receptors recognize?
Pathogen Associated Molecular Patterns (PAMPs)
What does macrophage binding to antigen through the Toll-like receptors do?
macrophages become activated and secrete cytokines such as IL-1, TNF and IL-6 in preparation for an inflammatory reaction
What is phagocytosis?
- it is an active process of capturing and ingesting foreign objects/microorganisms by phagocytes
What is the purpose of phagocytosis?
- to detect and destroy microorganisms, to remove damaged cells and foreign objects
- to produce cytokines required for development of an inflammatory reaction
- to process and present anitgens required to induce an immune response by lymphocytes
What are the steps of phagocytosis?
- Chemotaxis- first, phagocytes move towards objects to be phagocytosed
- Phagocytes detect and bind their target/object through appropriate receptors
- They surround the captured object with pseudopodia and engulf the object through endocytosis
- The endocytosed object becomes enclosed in the phagosome
- Later, the phagosome fuses with the lysosome to form a phagolysosome
- contents of the lysosome are released into the phagosome and the digestion of endocytosed objects begins
What are the two killing pathways of intracellular killing in neutrophils, monocytes and macrophages?
- Oxidative pathway
- Non-oxidative pathway
What does the oxidative pathway depend on?
on generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS)
What does the non-oxidative pathway depend on?
lysosomal toxic substances
What is a respiratory burst?
a process during phagocytosis (oxidative pathway) in which the use of oxygen and glucose increase several fold which leads to formation of reactive oxygen species which are toxic to microorganisms
- oxygen dependent intracellular killing
How are reactive oxygen species (ROSs) generated?
- glucose is metabolised through the pentose-phosphate pathway - leading to production of NADPH
- Cytochrome oxidase activates NADPH
- Activated NADPH+ uses O2, leading to production of superoxide anion (O2-)
- The superoxide anion may be reduced to H2O2 and 1O2 by the superoxide dismutase
- Or the superoxide anion may react with H2O2, leading to production of hydroxyl radicals (OH-)
When is myeloperoxidase released?
during the fusion of azurophilic granules with phagosome
- myeloperoxidase uses H2O2 and Cl- to produce hypochlorous acid
How is a reactive oxygen species (RNS) generated?
- the superoxide anion can interact with a reactive nitrogen species nitric oxide to produce peroxynitrite, another RNS
- nitric oxide can also undergo oxidation to generate the RNS nitrogen dioxide
What does the main killing mechanism of the non-oxidative intracellular killing pathway depend on?
the action of the toxic substances (peptides, proteins, enzymes) present in lysosomes
What toxic substances are found in lysosomes that aid in the non-oxidative intracellular killing pathway? What do they do?
- Cationic proteins - damage the bacterial cell wall
- Lysozyme - damages the mucopeptides in the bacterial cell wall
- Lactoferrin - sequestrates iron thus inhibiting bacterial growth
- Proteolytic and hydrolytic enzymes - digest killed bacteria
How is TNFalpha secreted and what does it do?
phagocytes bind bacteria through TLR which causes the secretion on TNFalpha, among other cytokines, which later induces the expression of inducible nitric oxide synthetase (iNOS)
What does (iNOS) inducible nitric oxide synthetase do?
- oxidises L-arginine to yield L-citrulline and nitric oxide (NO)
- NO is highly toxic to microorganisms in the vicinity of phagocytes
Macrophages, dendritic cells, and mast cells use PRRs (pattern recognition receptors) to sense the presence of what?
- PAMPs (pathogen-associated molecular patterns)
- DAMPs Damage-associated molecular patterns)
What are pattern recognition receptors (PRRs)?
natural or innate immune system receptors that recognize molecular patterns produced by microorganisms
What are Pathogen-associated molecular patterns (PAMPs)?
repetitive motifs of molecules such as lipopolysaccharide, peptidoglycan, lipoteichoic acids, mannan, broadly expressed by microbial pathogens and not found on host tissues
What are DAMPs (damage-associated molecular patterns)?
endogenous molecules released from damaged cells
What are the 5 classes of PRRs?
- toll-like receptors (TLRs)
- NOD-like receptors (NLRs)
- RIG-like receptors (RLRs)
- C-type lectin receptors (CLRs)
- Peptidogylcan-recognition proteins (PRGPs)
What are toll-like receptors?
major PRRs located on host cell membranes or within the host cells that signal the presence of invaders in innate immune response
How do toll-like receptors signal?
signal through MyD88 is central to all TLRs except TLR3 which signals through TRIF
What is the end point of TLR signalling?
production of proinflammatory cytokines
What are NOD-like receptors?
nucleotide-binding oligomerization domain-like receptors
- receptors that are found inside the cells and can detect pathogens in the cytoplasm
- they sense intracellular bacteria
What are the types of NOD-like receptors and what do they do?
- NOD1 recognizes bacterial peptidoglycans
- NOD2 recognizes muramyl dipeptides
What happens when a NOD-like receptor detects PAMPs?
- leads to activation of the transcription factor NF-KB. this leads to transcription of genes responsible for expression of pro-inflammatory cytokines
- signalling through IRF3/7 leads to production of type I interferons (IFNs)
True or False? NOD-like receptors can be activated by DAMPs.
True
What are RIG-like receptors?
retinoic acid inducible gene-like receptor
- expressed in the cytoplasm of cells and detects viral RNA
- induce production of antiviral cytokines such as IFNs and inflammatory cytokines
What are C-type lectin receptors (CLRs)?
large family of receptors that bind to carbohydrates in calcium-dependant manner
- expressed by most cell types including macrophages and dendritic cells
What are C-type lectin receptors (CLRs) involved in?
fungal recognition and modulation of the innate immune response
What are Peptidoglycan-recognition proteins (PGRPs)?
polymers of alternating N-acetylglucosamine and N-acetyl muraminic acid found on the surface of both G- and G+ bacteria.
PGRPs detect microbial peptidoglycan and induce production of antimicrobial peptides such as defensins.
Where can Peptidoglycan-recognition proteins (PGRPs) be found?
localized in the large granules of neutrophils
- in pigs they are expressed constitutively in the skin, bone marrow, and intestines
What are some antimicrobial peptides? Where are they found?
- alpha-defensin ( paneth cells of intestines and cytoplasmic granules of neutrophils)
- beta-defensin (epithelia and other tissues)
- Cathelicidins (humans, bovines)
What is an acute phase response?
change ins erum proteins during infection
What are acute phase response proteins? (APR proteins)
proteins whose concentrtions increase or decrease during infection
- most synthesized in the liver
What are some acute phase response proteins (APR proteins)?
- complement system proteins
- C-reactive proteins (CRP)
What are acute phase response proteins (APR proteins) induced by?
signals that travel through blood from the site of injury or infection
What induces the synthesis of acute phase response proteins?
pro-inflammatory cytokines which are produced by phagocytes
What are C-reactive proteins?
proteins that belong to pentraxins (pentameric proteins)
- CRPs bound to the surface of microbes promote uptake by phagocytes and activates complement-mediated attack
What is Mannose-binding lectin?
an acute phase response protein that recognizes mannose on microbes and not vertebrate cells
