6 - Innate 4: Effector Flashcards
What is an example of a small extracellular threat?
Bacteria
What is an example of a large extracellular threat?
Multicellular parasites
What are some intracellular infections?
Virus, some bacteria, some parasites
What are 3 effector functions?
- Phagocytosis and killing of microbes within phagosome
- Release of antimicrobial products to kill extracellular microbes and parasites
- Targeted destruction of infected/transformed host cells by NK-mediated cytotoxicity
Which immune cells are “professional” phagocytes?
Neutrophils (granulocyte) and Macrophages (monocytic-phagocytic lineage)
What are 3 specialized lineages of phagocytic leukocytes?
- Kupffer cells (liver)
- Langerhans cells (epithelium)
- Microglia (CNS)
What are the 3 basic steps of phagocytosis?
- Recognition and adhesion plasma membrane
- Membrane/cytoskeleton reorganization; engulfment; phagosome
- Maturation to microbicidal and degradative phagolysosome
Is there collateral damage with phagocytosis?
No
What are PRRs?
Phagocytic-pattern Recognition Receptors
What do PRRs do?
They recognize PAMPs on pathogens and recognize apoptotic host cells
Why is it important for macrophages to recognize apoptotic host cells?
Because they “clean up” after inflammation, which assists in the healing process
What do C-type lectin receptors recognize?
Terminal mannose/fucose residues
What do scavenger receptors recognize?
Mostly lipoproteins on bacteria
What occurs inside the cell during phagocytic engulfment?
The cytoskeleton is remodelled to allow involution of the plasma membrane and the creation of a new intracellular vacuole (phagosome)
What are the 2 opsonin receptors macrophages have?
- Complement receptors
- Immunoglobulin Fc receptors
What is the ligand that gets deposited on the surface of a pathogen that can be recognized by a complement receptor?
C3b (or its cleavage products)
What is the ligand that gets deposited on the surface of a pathogen that can be recognized by an immunoglobulin Fc receptor?
Antibody
What is the purpose of having opsonin ligands/receptors?
They tag fast-moving blood-borne pathogens and make them easier to recognize by other immune cells for more effective immunity
What events follow phagocytosis?
- Proton pumps insert into phagosomal membrane to acidify interior
- Endosomal/lysosomal compartments (containing hydrolytic and antimicrobial enzymes) fuse with the phagosome
- The phagosome now becomes an acidic, digestive, antimicrobial phagolysosome
What is the main way pathogens avoid destruction once in a phagosome?
They prevent the fusion of the endosome/lysosome so that the phagosome does not become an ouchy phagolysosome
What is the intraphagosomal environment like?
-Acidic
-Has antimicrobial peptides
-Has hydrolases
-Low availability of essential nutrients
-Oxidative radicals (ROS)
What is formed from the reaction of ROS (reactive oxygen species) and RNI (reactive nitrogen intermediates)?
Unstable free radicals
Why must the ROS stay within the phagolysosome?
Because they can cause damage to any cells, including the host cells
What are 4 ROS (from weakest to strongest if u can)?
Free radical superoxide (O2-)
Hydroxyl radical (OH)
Hydrogen peroxide (H2O2)
Hypochlorous acid (HClO)
Which enzyme do only neutrophils have that allow them to produce hypochlorous acid?
Myeloperoxidase (MPO)
Which ROS does NADPH Oxidase produce?
Free radical superoxide
Hydroxyl radical
Hydrogen peroxide
What is ClO- similar to?
Bleach!
Where is myeloperoxidase stored in a neutrophil?
In azurophilic granules
What reaction does myeloperoxidase catalyze?
Hydrogen peroxide + Cl- —-> hypochlorous acid
When is hypochlorous acid synthesized?
During neutrophil’s respiratory burst
What cofactor does MPO require?
Heme peroxidase (iron)
If pus has a green tinge to it, what does that mean?
Lots of neutrophils are present with lots of MPO
What allows for more efficient bacterial recognition by phagocytic cells?
The addition of complement and immunoglobulin-based opsonins
What are 4 proteins that stimulate eosinophil degranulation?
-Major basic protein
-Eosinophil cationic protein
-Eosinophil peroxidase
-Eosinophil-derived neurotoxin
What is a major side effect of eosinophil degranulation?
Hypersensitivity triggered by IgE
What does major basic protein stimulate?
-Cytotoxin and helmithotoxin
-Mast cell degranulation
What does Eosinophil cationic protein stimulate?
Cationic ribonuclease and pore forming
What does Eosinophil peroxidase stimulate?
Oxidizes a variety of substrates in the presence of hydrogen peroxide
What does Eosinophil-derived neurotoxin stimulate?
Ribonuclease (anti-viral activity)
What is degranulation by neutrophils?
The release of hydrolases that cause a respiratory burst into the extracellular space
Which hydrolases are released during neutrophil degranulation?
-Proteases
-MPO
-NADPH oxidase
What is the issue with neutrophil degranulation?
Collateral damage to host
What does NETs stand for?
Neutrophil Extracellular Traps
What are NETs?
Large extracellular fibers that contain strands of chromatin and globular proteins with antimicrobial proteins
What is the release of NETs stimulated by?
PAMPs and cytokines
What is the function of NETs?
Bind, neutralize and kill pathogens at sites of inflammation and in blood vessels
What happens to the neutrophils after it releases a NET?
It DIES
What are NK cells?
Lymphocytes with granules that do not require activation and lack immunologic specificity and memory
Are NK cells innate or adaptive?
Innate!
Which surface markers do NK cells usually express?
Ones for immunoglobulins like CD16 and Fc
How do NK cells recognize target cells?
They look for MHC1 complex on host cells. No MHC1 = death
What are activated NK cell functions?
- Kill altered self cells (tumours, virally infected)
- Directly killing pathogens
- Produce cytokines that induce adaptive responses against the altered self cell
How are cytotoxic functions regulated?
A balance between signals from activating and inhibitory receptors
What do inhibitory receptors recognize?
MHC 1 complex on nucleated host cells
What must the target cell display to induce apoptosis by an NK cell?
Altered MHC1 expression and activating ligand
What do activating receptors recognize?
Ligands (viral products) on target cells or IgG (ADCC)
What does ADCC stand for?
Antibody-dependent cell cytotoxicity
What occurs once a NK cell decides another cell must die?
The NK forms an immune synapse and degranulates. The granules contain perforins and granzymes which induce apoptosis
What are perforins?
C9 related proteins that form pores in the membrane of target cells
What are granzymes?
Proteases that enter target cells through perforin pores and initiate apoptosis
What is good about NK-mediated cytotoxicity?
Theres not collateral damage; its very precise and effective
What is the purpose of having ADCC?
Enhancement of an innate effector mechanism following adaptive immune response
How is NK’s cytotoxic function initiated with IgG?
NK cells recognize surface-bound IgG through Fc receptors, which stimulate the cytotoxic function
What is the best way for NK cells to kill target cells? EXAM QUESTION
Antibody-dependent cellular cytotoxicity (ADCC)
The antibodies binding to the pathogens antigens make killing it much more effective!
How can R. equi survive in a foal with rattles?
The bacteria block acidifcation and fusion with late endosomes and lysosomes
