Week 13.1 Innate Immunity Flashcards
Primary defenses
-physical and chemical barriers:
-ciliated epithelium
-alveolar macrophages
-acid
-bile
-urine flow
-normal flora
-body temperature
-skin
-tears
-mucous
Antimicrobial secretions
-toxic to pathogens
-defensins, bactericidal/permeability increasing peptides
-lysozyme
-lactoperoxidase
Defensins
short peptides w/ broad antimicrobial activity (cell wall and membrane disruption) and/or immune signaling
Bactericidal/permeability increasing peptides (BPIs)
short peptides w/ broad antimicrobial activity and/or immune signaling
Lysozyme
breaks down peptidoglycan cell wall
Lactoperoxidase
generates reactive oxygen species
Metal ion-binding proteins sequester…
iron, zinc, or magnesium
Iron
- Why pathogens need it: TCA Cycle, electron transport, oxidative phosphorylation, aromatic biosynthesis, peroxidase, & superoxide dismutase
- Sequestered by: lactoferrin, ferritin, transferrin
Zinc
- Why pathogens need it: RNA polymerase, DNA polymerase, & alkaline phosphatase
- Sequestered by: calprotectin & metallothioneins
Magnesium
- Why pathogens need it: Superoxide dismutase
- Sequestered by: calprotectin
Internal cellular defenses (innate immunity)
monocytes
macrophages
neutrophils
NK cells
mast cells
dendritic cells
eosinophils
basophils
Monocytes
differentiates into macrophages and dendritic cells in response to inflammation
Macrophages
engulfs and kills pathogens and cancerous cells; stimulates other immune cells
Neutrophils
engulfs and kills pathogens
Natural Killer (NK) cells
kills tumor cells and virus infected cells
Mast cells
releases histamine, inflammatory response
Dendritic cells
triggers adaptive immunity (T cells)
Eosinophils
production of toxic molecules to kill pathogens and regulation of inflammation
Basophils
production of toxic molecules to kill pathogens and regulation of inflammation
Innate cellular response steps
- Detection of an infection (PAMPs and PRRs)
- Chemical signaling (cytokines, chemokines, pyrogens, interferons)
- Destruction of pathogens and damaged/infected cells
What cells detect pathogens w/ PRRs?
epithelial cells and leukocytes
Types of pathogen recognition receptors
- Toll-like receptors
- NOD-like receptors
- RIG-1-like helicases and MDA-5L
Toll-like receptors
transmembrane proteins that recognize molecules shared broadly by pathogens (broad spectrum)
NOD-like receptors
intracellular proteins that help regulate the immune response by releasing cytokines, chemokines, or apoptosis
RIG-1-like helicases and MDA-5L
intracellular proteins that detect ssRNA viruses and help regulate the immune response
What are PRRs activated by?
pathogen associated molecular patterns (PAMPs)
What are PAMPs?
molecules that are characteristic of pathogens and are not normally found inside the body
Examples of PAMPs
Lipopolysaccharides (LPS)
Lipoprotein
Peptidoglycan
Lipoteichoic acids
RNA/DNA
Flagella
Membranes
What can PRRs also recognize besides PAMPs?
damage associated molecular patterns (DAMPs)
What are DAMPs?
host signaling molecules that are produced by dying or damaged cells (regardless of infection) to activate the innate immune response
Cell signaling
When a PAMP is detected by a PRR, chemical signals (cytokines and chemokines) are secreted to tell the body an infection is starting
Cytokines
secreted molecules that cause an effect in another cell ex: interleukins, interferons, or growth factors
Chemokines
a class of cytokines that attract white blood cells (leukocytes)
ex: histamine
Proinflammatory cytokines stimulate what kind of response?
an acute inflammatory response
Acute inflammatory response
-capillary widening > increased blood flow > heat
-increased permeability > fluid release into tissues > redness and swelling
-attraction of leukocytes > extravasation of leukocytes to site of injury > tenderness
-systemic response > fever and proliferation of leukocytes > pain
Objectives of inflammation
-DESTROY the pathogen and REMOVE its by-products from the body
-CONFINE the pathogen and its products to limit the damage
-REPAIR OR REPLACE damaged tissue
What are the first cytokine signals that both stimulate an acute inflammatory response?
IL-1 and TNF-alpha (tumor necrosis factor)
IL-1
-induced by PAMPs
-produced by macrophages, endothelial cells, and epithelial cells
-promotes inflammation
TNF-alpha
-induced by PAMP
-produced by macrophages and T cells
-promotes inflammation, vascular permeability, chemotaxis, and apoptosis
TNF-alpha promotes inflammation
-Activates mast cells to release histamine, which causes vasodilation
-Induces fever in the hypothalamus
-Enhances production of proinflammatory cytokines (IL-1 and IL-6)
TNF-alpha helps recruit immune cells
-Stimulates endothelial cells to express adhesin molecules
-Stimulates the production of chemokines to attract leukocytes
-Loosens epithelial tight junctions to allow diapedesis
-Activates neutrophils and macrophages
How are neutrophils and macrophages recruited to infected tissue?
By chemokines that attract white blood cells; they squeeze through blood vessels aided by adhesin molecules and gaps promoted by histamine and TNF-alpha
Destruction of pathogens and damaged/infected cells
phagocytosis
Phagocytosis
ingestion of bacteria or other material by a phagocyte, stimulates the macrophage to produce more proinflammatory cytokines
Phagocytosis steps
- Attachment
- Ingestion
- Digestion
Phagocytosis Attachment step
Detect and attach to pathogens using specialized receptors
Phagocytosis Ingestion step
Engulfs pathogen by surrounding it with the phagocytes membrane
-results in membrane-bound pathogen inside the cell aka phagosome
Digestion difference in macrophages vs neutrophils
-Macrophages: phagosome is merged with lysosome
-Neutrophils: pathogens are killed by antibacterial compounds and enzymes found in primary and secondary granules
Macrophage digestion
-oxygen-dependent
-Damages DNA, RNA, and proteins
-uses reactive oxygen species (superoxides, peroxides, hydroxyl radicals), nitrous oxide, and hypochlorous ions
-long lifespan
Neutrophil digestion
-oxygen-independent
-membrane or cell wall disruption
-uses lysozyme, lactoferrin, and antimicrobial peptides
-after digestion, neutrophils self destruct and release DNA and other fibers to create a sticky antimicrobial NET (neutrophil extracellular trap)
How does the body handle large protozoan parasites?
Use neutrophils and eosinophils that can kill pathogens by excreting toxic compounds and enzymes in primary and secondary granules
Degranulation
The release of antimicrobial cytotoxic from granules from inside some cells, works via membrane or cell wall disruption
Enhanced destruction with ________________
the complement system
Complement System
- Enhance inflammation
- Help macrophages engulf pathogens (opsonization)
- Form a membrane attack complex, leading to pathogen lysis
*classical pathway or lectin pathway
Opsonization
-part of the complement system
-the coating of pathogens w/ antibodies, complement proteins, or other proteins to facilitate binding of phagocytes and NK cells
-phagocyte membrane receptors recognize and bind to C3b that activate opsonization
Lectin Complement Pathway
-grab hold of a pathogen
1. Receptor binding
2. Actin-driven protrusion
3. Coupling actin to the surface
4. Membrane delivery
5. Membrane fission
Form a membrane attack complex
-last step of complement system
-destabilizes the plasma membrane of pathogen
What two things do NK cells look for?
- Activation
- Inhibition
Activation of NK cells
proteins on surface of target cell that allow the NK cell to bind and kill
Inhibition of NK cells
protein (MHC I) on surface of infected/tumor cell that signals if a cell is healthy or not
If MHC I molecule on tumor cell matches Inhibitory KIR receptor on NK cell?
No killing
If MHC I molecule on tumor cell doesn’t match Inhibitory KIR receptor on NK cell?
Killing
Strong inhibition of NK cells
Healthy, “normal” cells express enough MHC I molecules to induce a strong inhibitory signal in NK cells and are protected from NK cell attack
Reduced inhibition of NK cells
Tumor or infected cells often downregulate MHC I molecule and can no longer deliver a strong inhibitory signal, so NK cells can overpower the signal and attack and eliminate these cells
Strong activation of NK cells
-Transformed or infected cells sometimes increase the expression of molecules that are recognized by activating NK cell receptors
-Result: NK cells receive a stronger activating signal than usual and can override inhibitory signal and attack
What two proteins do NK cells use to kill target cells?
- perforin: creates a controlled pore in the target cell to deliver granzymes
- granzymes: enzyme that activates apoptotic enzymes to induce apoptosis
