Chapter 2-3: Innate Immunity Flashcards
What does innate immunity do?
acts immediately to effect removal of pathogen without development of disease in the host
When are adaptive immune responses required?
if innate immune responses are overwhelmed, bypassed, or evaded by the pathogen
Recognizing Pathogens
What are pattern recognition receptors (PRRs)?
receptors that recognize parts of the most common pathogens we’re likely to encounter
Recognizing Pathogens
What are pathogen-associated molecular patterns (PAMPs) not produced by?
multicellular host organism
Recognizing Pathogens
What are PAMPs shared by?
large groups of pathogens
Recognizing Pathogens
Do PAMPs undergo frequent mutation?
no
Recognizing Pathogens
What are PAMPs essential for?
pathogen’s survival
Recognizing Pathogens
What are PAMPs recognized by in the innate response?
pattern recognition receptors (PRRs)
Recognizing Pathogens
What are 2 examples of PAMPs?
- peptidoglycan in Gram-positive bacteria
- lipopolysaccharide (LPS) in outer membrane of Gram-negative bacteria
Recognizing Pathogens
What are the 2 main groups of cell-associated PRRs?
- phagocytosis receptors
- toll-like receptors (TLRs)
Recognizing Pathogens
What do phagocytosis receptors do?
used to bring particle inside phagocyte
Recognizing Pathogens
What do toll-like receptors (TLRs) do?
allow phagocyte to determine if particle is dangerous (ie. a pathogen)
Toll-like Receptors (TLRs)
What are the 3 critical components of the conserved structural features of TLRs?
- extracellular leucine-rich repeat (LRR) motif
(or domain) - transmembrane helix
(or domain) - intracellular Toll/Interleukin-1 receptor (TIR) domain
(cytoplasmic domain)
Toll-like Receptors (TLRs)
What does the extracellular leucine-rich repeat (LRR) motif (or domain) do?
recognizes PAMP
Toll-like Receptors (TLRs)
What is the cytoplasmic domain homologous to?
IL-1 receptor
Toll-like Receptors (TLRs)
What is the IL-1 receptor?
receptor that binds the cytokine, interleukin-1 (IL-1)
Toll-like Receptors (TLRs)
How many different TLRs have been described in mammals so far?
13 in mice
11 in humans
Toll-like Receptors (TLRs)
What does each different TLR do?
recognizes a distinct set of molecular patterns that are not found in the host
Toll-like Receptors (TLRs)
What do TLRs function as?
homodimers OR heterodimers
Toll-like Receptors (TLRs)
What does the ability of TLRs to form heterodimers do?
extends the range of PAMPs that can be recognized
Toll-like Receptors (TLRs)
What does binding of mammalian TLRs do?
leads to activation of NF-κB
Toll-like Receptors (TLRs)
What is NF-κB?
important family of transcription activators that bind to promoters of genes that code for antimicrobial peptides
Complement (C’) System
What is the complement system?
set of plasma proteins that act together to attack extracellular pathogens
Complement (C’) System
What does the activation of the complement component usually involve?
cleavage of protein to make two smaller proteins
Complement (C’) System
How is the complement system activated?
in a series of reactions, where product of one reaction catalyzes the next, etc.
Complement (C’) System
In what order do the components of the complement system work?
in a set order (ie. some act early in cascade, others act at a much later stage)
Complement (C’) System
When are complement proteins activated?
when antibodies made during a previous adaptive immune response bind to pathogen surface (ie. classical pathway – Chapter 6)
Complement (C’) System
What are antibodies?
type of plasma protein produced by B cells
Complement (C’) System - Alternative Pathway
What do complement proteins do in the alternative pathway?
bind directly to bacteria and initiate complement activation cascade directly
(eliminates need for antibody recognition to start the cascade)
Complement (C’) System - Alternative Pathway
Where are complement C3 proteins?
lots in the blood
Complement (C’) System - Alternative Pathway
Describe the steps of the pathway.
- C3 (in blood) spontaneously breaks down to form C3a + C3b
- C3b binds to pathogen surface and recruits other complement proteins to form C3 convertase (enzyme complex)
- results in formation of additional C3b protein - some C3b is used to form additional C3 convertase, some is used as opsonin, and some is used to form C5 convertase
- C5 convertase cleaves C5 into C5a and C5b
- C5b is used to form membrane attack complex (MAC)
Complement (C’) System - Alternative Pathway
What are the 3 important consequences of the formation of C3 convertase?
- activation of inflammatory response
- opsonization and enhancement of phagocytosis
- formation of membrane attack complex and bacterial lysis
Complement (C’) System - Alternative Pathway
Inflammatory Response
What do C3a and C5a do? (2)
bind to specific receptors on blood vessels
bind to receptors on resident mast cells and resident macrophages
Complement (C’) System - Alternative Pathway
Inflammatory Response
What happens when C3a and C5 bind to blood vessels? (2)
- increases permeability of blood vessels
- induces expression of adhesion molecules that allow leukocytes (such as neutrophils and monocytes) to attach to blood vessels
Complement (C’) System - Alternative Pathway
Inflammatory Response
What happens when C3a and C5 bind to mast cells?
releases additional histamine - this increases permeability of blood vessels
Complement (C’) System - Alternative Pathway
Inflammatory Response
What happens when C3a and C5 bind to macrophages?
releases additional TNF-α
Complement (C’) System - Alternative Pathway
Inflammatory Response
What does C5a attract?
C5a is a powerful chemoattractant for neutrophils and monocytes
Complement (C’) System - Alternative Pathway
Inflammatory Response
What happens when C3a and C5a are produced in large amounts?
effect of C3a and C5a on blood vessel permeability can induce a generalized circulatory collapse, producing anaphylactic shock (a shock-like syndrome)
Complement (C’) System - Alternative Pathway
Inflammatory Response
What are anaphylatoxins?
C3a and C5a (small complement fragments)
because large amounts of these fragments can produce anaphylactic shock
Complement (C’) System - Alternative Pathway
Opsonization and Enhancement of Phagocytosis
Which fragment can function as an opsonin?
C3b bound to pathogen surface
Complement (C’) System - Alternative Pathway
Opsonization and Enhancement of Phagocytosis
What is opsonization?
alteration of pathogen surface or particle surface so that phagocytic cells can engulf it more efficiently
Complement (C’) System - Alternative Pathway
Opsonization and Enhancement of Phagocytosis
What does coating a pathogen with C3b do?
enhances phagocytosis by neutrophils and macrophages
Complement (C’) System - Alternative Pathway
Opsonization and Enhancement of Phagocytosis
What occurs during opsonization?
C3b binds to a receptor on surface of phagocytic cell
results in increased number of contact points between phagocytic cell and pathogen
Complement (C’) System - Alternative Pathway
Formation of MAC
How is a membrane attack complex (MAC) formed?
C5b is deposited on (binds to) the pathogen surface, and late/terminal complement components (other proteins) are recruited is initiated to form the complex
Complement (C’) System - Alternative Pathway
Formation of MAC
What does the MAC do?
forms pores in pathogen surface (cytoplasmic membrane), causing pathogen cell lysis and death of pathogen
Recognizing a Pathogen
What happens when PAMPs bind to PRRs on innate immune cells? (2)
- phagocytosis of the pathogen
- cytokine production by the immune cell
Inflammatory Response
When does inflammation begin?
after damage to tissue
Inflammatory Response
What causes swelling?
cells, proteins, and fluid leak into tissues
Inflammatory Response
Describe the steps of the response.
- mast cells release histamine that increases permeability of blood vessels
- cells, proteins, and fluid leak into tissues, causing swelling
- pathogens activate macrophages, which release alarm cytokines and recruit more cells from the blood
- macrophages and neutrophils phagocytose and destroy pathogens
- coagulation proteins seal off inflamed area, and complement activation increases recruitment, phagocytosis, and pathogen destruction
Complement (C’) System
What can be used to activate the complement system?
classical pathway OR alternate pathway
Complement (C’) System
How does the classical pathway work?
uses antibodies generated by a previous adaptive immune response to the pathogen
Complement (C’) System
How does the alternate pathway work?
spontaneous, and requires no previous exposure
What initiates the adaptive response?
activation of dendritic cells (which link innate and adaptive immune systems)
Inflammatory Response
What causes inflammation?
physical or chemical insult, or by infection with microorganisms
Inflammatory Response
What is acute inflammation?
initial response to an infectious agent
- typically short duration
- causes very little tissue damage to the host
Inflammatory Response
What is chronic inflammation?
presence of a persistent infectious agent
- longer duration (months to years)
- often causes considerable tissue destruction
Inflammatory Response
Why does chronic inflammation often cause a lot of tissue damage?
due to persistent release of oxygen metabolites, nitric oxide (NO), and proteases by inflammatory cells (Chapter 12)
Inflammatory Response
What cells are involved in chronic inflammation?
activated macrophages and T cells
Inflammatory Response
Brief overview of the inflammatory response.
bacterial infection initiates a series of responses through:
- activation of alternative complement pathway
- stimulation of tissue-resident macrophages that detect bacterial-derived PAMPs
results in recruitment of additional innate cells and proteins that work together to eliminate the infection
Inflammatory Response
Brief overview of phagocytosis and killing of pathogens.
- macrophages and neutrophils express many surface receptors that may bind microbes for subsequent phagocytosis
- microbes are ingested into phagosomes that fuse with lysosomes to from phagolysosomes
- microbes are killed by enzymes and several toxic substances produced in phagolysosomes
Inflammatory Response
What are the 5 main steps?
- bacteria in wound are immediately recognized by tissue resident macrophages
- inflammatory response at site of infection is initiated by tissue-resident macrophages and tissue-resident mast cells
- large numbers of neutrophils and monocytes are recruited to site of infection within a few hours after infection has been detected
- clotting mechanisms and skin repair mechanisms are activated – helps wall off site of wound/infection and immobilize bacteria
- pus is formed
Inflammatory Response
Step 1: bacteria in wound are immediately recognized by tissue resident macrophages
- PRR binds to structure on bacterium to trigger phagocytosis
- TLR binds to PAMP interaction – initiates a signalling cascade that results in activation of NF-κB
- NF-κB activation results in transcription of 3 pro-inflammatory cytokines (TNF-α, IL-1, and IL-6)
- CXCL8 acts as chemoattractant to guide recruited phagocytic cells to site of infection
Inflammatory Response
What is TNF-α?
genes encoding tumor necrosis factor alpha
Inflammatory Response
What do pro-inflammatory cytokines do?
promote inflammatory response
Inflammatory Response
What is CXCL8?
chemokine that acts as chemoattractant to guide recruited phagocytic cells to site of infection
Inflammatory Response
Step 2: inflammatory response at site of infection is initiated by tissue-resident macrophages and tissue-resident mast cells
- upon injury to tissue, mast cells release histamine and other inflammatory molecules
- cytokines released by macrophages also act on blood vessel walls, increasing permeability of blood vessel and inducing expression of particular adhesion molecules on surface of endothelial cells lining the blood vessel
- increased vascular permeability allows components of blood to leak into tissue – fluid, complement proteins, coagulation proteins and antibodies, and cells such as neutrophils and monocyte
- accumulation of fluid in tissues causes swelling and pain associated with inflammation
- extravasation
- gradient of CXCL8 guides neutrophils, monocytes and dendritic cells to location of bacteria in tissues
- neutrophils immediately begin to phagocytose bacteria
- monocytes must mature into macrophages before they become effective phagocytic cells
Inflammatory Response
What does histamine do?
causes blood vessels to dilate, increasing blood flow to the area and resulting in redness and heat association with inflammation
Inflammatory Response
What is extravasation?
process in which adhesion molecules allow leukocytes (ie. neutrophils and monocytes) to stick to endothelial cells of blood vessel, then squeeze through spaces between endothelial cells of blood vessel and into tissue
Inflammatory Response
Step 3: large numbers of neutrophils and monocytes are recruited to site of infection within a few hours after infection has been detected
- when neutrophil or macrophage phagocytoses bacteria, bacteria are brought into the cell in a phagosome
- phagosome is then acidified, and lysosomes fuse with phagosome to form phagolysosome
- in phagolysosome, nitric oxide (NO), superoxide anion (O2-), hydrogen peroxide (H2O2), cationic peptides (defensins) and proteases work together to kill bacteria and degrade it into smaller fragments
Inflammatory Response
What is a phagosome?
special membrane-bound vesicle
Inflammatory Response
What is a lysosome?
membrane-bound granule
Inflammatory Response
What is a phagolysosome?
formed by fusion of acidified phagosome and a lysosome
Inflammatory Response
What happens in phagolysosomes?
nitric oxide (NO), superoxide anion (O2-), hydrogen peroxide (H2O2), cationic peptides (defensins) and proteases work together to kill bacteria and degrade it into smaller fragments
Inflammatory Response
What is pus?
aggregation of macrophages, neutrophils, live and dead skin cells, dead and dying bacteria, and plasma (blood fluid)
