Lecture 2- Innate Immune System Flashcards
PAMP-Pathogen Associated Molecular Patterns
Motifs that are entirely unique to non-self microbes, something immune system can recognize due to pattern difference
PRR-Pattern Recognition Receptor
Cellular Receptors that recognize PAMPs
Cytokine
Soluble molecules that modulate immune response
Chemokine
Soluble molecules that set up a gradient of chemoattractants to the site of infection
Type I IFN- Type I Interferon
- Cytokine made by innate immune response PAMP sensing that modulate immune response to fight.
- virus infection recognized by PRR -> cell makes IFN -> IFN Autocrine Effect: -cell shuts down normal functions/goes into antiviral state Paracrine Effect: Other cells put up their defenses
TLR- Toll Like Receptors
PRRs that primarily recognize PAMPs- signal through MyD88 and TRIF (TLR3)
IRF-Interferon Regulatory Factor
Transcription factors that control interferon production and some interferon responses
- Type I and III are innate, type II is adaptive
- All nucleated cells make and respond to Type I IFN
Levels of Innate Immunity
Barriers: physical, chemical, microbial
Molecular: Complement, Antimicrobial peptides, Antimicrobial Enzymes
Cellular: Natural Killer Cell,
Dendtritic cell, Macrophages/Monocytes, Neutrophil
Physical Barriers
Physically block pathogen from entering host,
Strong barriers: skin, hair, nails
Vulnerable barriers: mucosal membranes
Mucosal Surface Barriers
Physical and Chemical: cilia move mucous around, up and out, slows down microbes, helps body expectorate microbes
Microbial: Good flora provide resource competition for pathogenic flora, can produce toxins that inhibit other microbes
Molecular Defenses
- Antimicrobial Peptides
- Complement
- Antimicrobial Enzymes
Antimicrobial Peptides
- Defensins, Cathelicidins, Histatins
- Activated by proteolysis (cut off regulatory piece, leaves active piece)
- Amphipathic (hydrophillic and hydrophobic parts, helps insert into membrane to make pores)
- Form pores in membranes
- Made by epithelial cells
Complement
-Enzymatic cascade that leads to inflammation, neutrophil recruitment and pore formation in membranes (can’t maintain membrane integrity=death)
Antimicrobial Enzymes
- Lysozyme: in tears, saliva, phagocytes, breaks peptidoglycan (outer cell layer in bacteria), helps other molecular defenses make pores
- Phospholipase A : enters bacterial cell wall and hydrolyzes phospholipids, breaks down cell wall
Complement Pathways
Alternative: First pathway activated in body(innate) Involves interaction w surface of membrane, self-cells have off signals to end pathway
Classical: Part of adaptive response, requires prior antibody-antigen reaction
Lectin: Dependent on binding of lectin to surface mannose of pathogen, recruits proteins for enzymatic cleavage
Rest of Complement Pathway
- all complement proteins referred to as C#*
- All 3 pathways converge at C3 convertase
- C3 convertase -> C5 convertase -> MAC (Membrane Attack Complex) formation: insertion of proteins into pathogen surface= loss of membrane integrity=cell lysis
Antimicrobial Molecules
- Work directly on microbes
- Disrupt membranes
- Inhibit metabolism
- Physically slow or stop microbes (by binding to them) before they reach epithelial cell surface
- Help immune cells identify (by binding to surface) and phagocytose microbes
Innate Cellular Defenses
- Neutrophil
- Macrophages/monocytes
- Natural Killer Cell
- Dendritic Cells
Phagocytes
- Macrophages/monocytes and neutrophils
- Engulf foreign bodies via phagocytosis -> phagosome fuses with lysosome -> pathogen death in phagolysosome
- If pathogen doesn’t die via regular contact w lysosome, Macrophage receives activation signal from outside cells to use ROS and NO (bleach) and other lysosomal enzymes
Neutrophils (PMN-polymorphonuclear leaukocyte)
- Kamikaze cell -Short lived phagocyte -granules -most abundant WBC, make up pus, kill themselves to kill pathogen
- Multi-lobe nucleus allows migration through tight spaces, no need for vasodilation to access infection
- Change shape when activated to become amoeba like w pseudopods to hunt microbes
- Use chemokine/cytokine greceptors to follow gradients to site of damage
- Kill through phagocytosis, degranulation and Neutrophil Extracellular Traps (NETs)
NETs- Neutrophil Extracellular Traps
- Are condensed DNA thrown out of neutrophils to trap microbes due to negative charges
- Signals phagocytosis and other immune cells
- unique to neutrophils
Macrophages
- Garage collectors, clean up dead cells/debris -Use O2/NO to kill - Long lived phagocyte (lifetime)
- Everyday function (no pathogen/inflammation): phagocytoses apotosis cells
- Inflammation function: eliminates pathogens, antigen function
Monocytes
- Premature macrophage in blood
- After chemokine signal, migrate out of blood and mature in the tissue into primarily macrophages
- Can also become dendritic cells
Natural Killer Cells (NK Cells)
-Hold me back, bro -Induced apoptosis for altered/absence of self cells (injured cells/tumors/infected cells)
-If NK cell receives more activating signals, then induces apoptosis in target, if receives more inhibitory signals, target survives
Degranulation: pokes holes in membrane to damage cell membrane integrity
Activates Death Receptors: sends receptors to damaged cell to induce apoptosis
ADCC ( Antibody Dependent Cellular Cytotoxicity): adaptive immune response, recognizes that call has antibody bound to it, binds to back end of antibody, induces apoptosis signal
Dendritic Cells
- Messenger -Resident in tissues -Bridge between innate and adaptive, recognizes pathogen and informs adaptive via lymphatic system
- Takes up antigen -> lymphatic system -> lymph node -> presents antigent o T cell -> activate T cell =Adaptive immune response
PRR action
PRR recognizes PAMP -> Adaptor molecules -> activation of NFkB and IRF transcription factors= NFkB activate pro-inflammatory genes/addaptive immune response, IRF activates Type I interferon genes-> antiviral state
Extracellular PRRs
TLR-Toll-like Receptor: recognizes extracellular bacterial products
C type lectins: Recognize fungal polysaccharides
Cystolic PRRs
NLR-Nod-like Receptor: recognizes cytosolic bacterial cell wall products
RLR-RIG-I-like Receptor: recognizes cytosolic viral RNA
CDS- Cytosolic DNA Sensors: recognize microbial DNA in cytosol, any DNA in cytosol is bad sign
Endosomal PRRs
TLR- TLR-Toll-like Receptor: recognizes endosomal bacterial products
Getting past innate immune system
- Containment by anatomic barrier (skin, mucous, cilia, low pH)
- Recognition by preformed non-specific and broadly specific effectors (neutrophils/macrophages)
- Recognition of PAMP’s activation of effector cells and inflammation (NFkB cascade, IFN)
