(I) Lecture 3: Innate Immunity Part II Flashcards
Innate Immune Cell Differentiation
all start hematopoietic stem cell and then differentiate into myeloid and lymphoid progenitors which differentiate into phagocytes and lymphocytes respectively
Myeloid Origin Immune Cells
Neutrophils
Monocytes/Macrophages
Dendritic Cells
destroy EXTRACELLULAR pathogens by PHAGOCYTOSIS
Lymphoid Immune Cells
Natural Killer Cells
destroy INTRACELLULAR viruses by APOPTOSIS
How are pathogens detected?
Compromise of barrier = pathogens inside tissue = release of chemical signals sensed by cells in blood that swarm to site infection
Pathogen detections is needed to recruit and activate immune cells
PRRs
Pattern Recognition Receptors
- expressed at the surface and within many cell types
- recognize conserved, invariant regions of pathogens (don’t change and recognize broad patterns)
- can also recognize damage/infection signals
- specificity is germ-line encoded (doesn’t change from, birth)
- triggers IMMEDIATE response
PAMPs
Pathogen Associated Molecular Patterns
- what PRRs recognize
- usually from extracellular pathogens
- include sugars, lipids, proteins, viral nucleic acids
- only expressed by pathogens (not self molecules)
- highly conserved (low mutation rate). critical for microbial survival and pathogenesis
- detection of PAMPs is critical to initiation of immune responses
Examples of PAMPs
Some are critical for microbe’s structure (integrity)
- ex. peptidoglycan in cell wall of gram + bacteria
Some are critical for microbe’s pathogenicity (ability to infect)
- ex. bacterial flagellin
Some are viral PAMPs
- ex. viral nucleic acids
PRRs and PAMPs
- each TLR has distinct range of specificities
- surface TLRs recognize components on the OUTSIDE of the pathogens (ex. peptidoglycan, flagellin)
- endosomal TLRs recognize components released during DEGRADATION (ex. bacterial + viral nucleic acids)
- one type of PRR can bind many different PAMPs (redundancy increases the range of pathogens that can be detected)
- we only have limited # of PRRs (< 100)
Families of PRRs
4 families:
- Toll-like receptors (TLR)
- C-type lectin receptors (CLR)
- Nucleotide oligomerization receptors (NLR)
- RIG-I like receptors (RLR)
Candida albicans
opportunistic pathogen yeast in the human gut microbiome
How do PRRs bind PAMPs?
- Recognition: PRRs bind to PAMPs
- Pseudopods engulf pathogen: actin forms pseudopods which eat the pathogen
- Phagosome formation
Phagocytosis
Cell eating
Killing happens in the phagolysosome b/c the phagosome is not toxic w/o the lysosome
- Bacterium binds to PRRs on pseudopodia (membrane evaginations)
- Bacterium is ingested into phagosome
- Phagosome fuses w/ lysosome
- Bacterium is killed and digested by low pH-activated lysosomal enzymes
- Digestion products are released from cell
The Phagolysosome
Phagosome is innocuous but phagosome-lysosome fusion makes it highly bacteriocidal
- phagocytes engulf microbes and they are broken down in phagolysosomes
Antimicrobial Properties of Phagolysosome
- low pH
- NADPH oxidase = Reactive Oxygen Species (toxic)
- Myeloperoxidase (MPO) transforms H2O2 into bleach
- Lactoferrin captures Fe2+ needed for bacterial growth
- Defensins form pores
- Lysozyme degrades peptidoglycan
Most abundant leukocyte
Neutrophils
Neutrophils
- majority (50-70%) of blood circulating leukocytes (WBCs)
- exit blood and rapidly enter infected tissues
- swarm in large numbers to site of infection to respond to inflammatory molecules
- main component of PUS
- life span is only a few days
Neutropenia
Abnormally low levels of neutrophils
- highly susceptible to deadly infections
- can restore neutrophil levels via blood transfusion (of neutrophil rich blood)
- if untreated, innate immune response can’t control infection so pathogen can spread rapidly, even into blood = septic shoc/neutropenic sepsis
Macrophages
Professional phagocytes
- remove pathogens and damaged host cells
- differentiate from monocytes (when there is infection signal)
- also works in adaptive immunity
- have SPECIALIZED functions based on location
- long life span (months to years)
Dendritic Cells
- bridge btwn innate and adaptive immunity
- role and function depend on MATURATION STATE
Maturation of Dendritic cells
Immature DC:
- circulate in blood AND reside in tissue below/among epithelial cells
- role in innate immunity (PHAGOCYTE)
Mature DC:
- initiates adaptive immunity
- antigen presentation
Phagocytes Process of Action
- Tissue damage and bacteria cause chemoattractants and vasoactive factors to trigger a local increase in blood flow and capillary permeability
- Permeable capillaries allow influx of fluid and cells
- Neutrophils and other phagocytes migrate to site of inflammation (chemotaxis)
- Phagocytes and antibacterial substances destroy bacteria
Natural Killer Cells
Cytotoxic cell killers that circulate in the blood
Kill INTRACELLULAR VIRUSES (virus-infected and cancer cells)
- have granules that contain cytotoxic enzymes (perforin and granzyme) that cause cell death in target cells
- early component of the response of viral infection
- after cytokine release, a wave of NKC follows
Perforin
In NKC
forms a pore in the cell membrane
- allows granzyme to enter the virus-infected cell
Granzyme
In NKC
degrades nucleic acids and triggers APOPTOSIS
- also degrades viral nucleic acids to PREVENT VIRAL REPLICATION
NKC deficiency
Ppl w/ NKC deficiency are susceptible to frequent herpesvirus infections
Destroying extracellular microbes
via PHAGOCYTOSIS
- macrophages
- neutrophils
-dendritic cells
Destroying intracellular viruses
via APOPTOSIS
Natural Killer Cells target virus-infected cells
Destroying intracellular bacteria
NO innate mechanism to deal with them
good at avoiding phagocytosis
control of these bugs may require T-cell help from adaptive immune system
Survival to phagocytosis
Intracellular bacteria can survive phagocytosis to live/replicate inside a phagocytes
- bacteria can live in phagosome: inhibit lysosome-phagosome fusion
- bacteria live in phagolysosome: resistant to lysosomal acids/enzymes
control of these bugs may require T cell help from adaptive immune system
L. monocytogenes
Listeria (can survive in cytoplasm and spread cell to cell)
- InIA: internalization
- lets it directly affect the cell - LLO: Listeriolysin, degrades the phagolysosome
- can escape to cytoplasm where it can survive - ActA: Actin assembly-inducing protein
- uses cell’s actin filaments to propel themselves to the next cell
- big problem for pregnant ladies
True or False
Innate immunity involves receptors formed prior to pathogen exposure
True
because they are germline-encoded from birth
True or False
NK cells effectively kill intracellular bacteria
False
NO good innate response against intracellular bacteria
