Exam 1: Dr. Kaplan Inflammation: Mechanisms 2 Flashcards
What are the 3 ways on innate immune cell killing?
Phagocytosis
Release of antimicrobial products
Targeted destruction of infected host cells
What do the innate immune cell killings defend against?
A variety of pathogens without eliciting help from the adaptive system
How quickly can the innate immune cell killing mechanisms be deployed?
Immediately without previous exposure, but can continue to work after adaptive immune response has been mounted
What are 3 types of phagocytes?
Macrophages
Neutrophils
Dendritic cells
What are the 3 stages of phagocytosis?
Recognition and adhesion of particles on plasma membrane of phagocyte
Membrane and cytoskeletal reorganiztion to mediate particle engulfment and creation of a phagosome
Maturation of phagosome to microbicidal and degradative phagolysosome
What are examples of some PRRs?
MR/CD206
Dectin-1
Scavenger receptor A1
Phosphatidyl serine receptor
What does MR/CD206 recognize?
Mannose and fucose on bacteria, fungi, and viruses
What does dectin-1 recognize?
β-glucan residues on fungi
What does scavenger receptor A1 recognize?
Polyanionic ligands on various microbes
What does phosphatidyl serine receptor recognize?
Phosphatidyl serine on apoptotic cells
What is recognition mediated by?
PRRs and opsonic receptors
What is opsonization?
Process whereby particles are coated with a protein-binding enhancer to enhance phagocytosis
What are the 2 major opsonins that mammals have?
Complement (C3b)
Antibody (IgG)
What can also act as an opsonin when bound to microbes?
CRP
What are 2 examples of opsonic receptors?
CR3
FCγ1R/CD64
What does CR3 recognize?
C3b on an surface bound by C3b
What does FCγ1R/CD64 recognize?
The Fc portion of the IgG antibody on any surface bound by IgG
What does the phagocytosis of irregularly shaped microbes or several microbes require?
Alteration in morphology
What does recognition of particle by phagocytic receptors result in?
Tight adhesion of microbe to phagocyte and clusters the receptors together
How long does the phagosome last?
Only a few seconds, but quickly evolves to an acidic, oxidative, degradative, antimicrobial chamber
What does the evolution of the phagolysosome evolution involve?
Fusion of the phagosome with endosomes and lysosomes in the cell
What does the phagosome do?
Recruits protein complexes that actively pump protons into it, reducing pH
What can the lower pH reduced by the protein complexes recruited by phagosomes do?
Kill microbes and activate antimicrobial enzymes that have been delivered to the phagosome
What does a phagosome do in neutrophils?
It also fuses with a modified lysosome containing high concentrations of antimicrobial proteins
What is an oxidative or respiratory burst?
Assembly of NADPH oxidase on phagosomal membrane
What does NADPH oxidase do?
Transfers unpaired electrons from NADPH to molecular oxygen generating superoxide
What is superoxide?
Extremely reactive and damaging
Reacts with hydrogen ions to form hydrogen peroxide
What is hydrogen peroxide?
A powerful oxidant that can be converted to hydroxyl radicals in presence of ferrous ions, which is damaging to all macromolecules
What can neutrophils make?
The antimicrobial enzyme myeloperoxidase
What does myeloperoxidase do?
Combines hydrogen peroxide with chloride ion to make hypochlorite ion (bleach)
What are the antimicrobial enzymes, proteases, improtant for?
Bridging innate with adaptive immunity
What can the amino acid arginine be converted to?
Nitric oxide
Why is nitric oxide important?
It is a signaling molecule
How is nitric oxide antimicrobial?
By reacting with DNA and microbial enzymes
What can nitric oxide combine with?
Superoxide to form peroxynitrite
What is peroxynitrite extremely reactive with?
Lipid, DNA, and proteins
What does bleach do?
Kills bacterium
What can nitric oxide cause?
Vasodilation
What are the 3 reactive oxidative burst products that cause damage to proteins and DNA in the bacterium?
Superoxide anion
Hydrogen peroxide
Hydroxyl radical
What oxidative compounds do macrophages and neutrophils generate in the phagosome?
Reactive oxygen species Reactive nitrogen intermediates Reactive hypochlorite (Neutrophils only)
What cells do degranulation?
Neutrophils and eosinophils
What is released in mast cell degranulation?
Vasoactive substance
What is released in neutrophil and eosinophil degranulation?
Cytotoxic and degradative proteins and peptides
What does degranulation result in?
Injury to surrounding tissue
What are eosinophils specialists at?
Antiparasite leukocytes
Why are eosinophils the early responders to parasites?
They are often too big to phagocytose
What do eosinophil granules contain?
Major basic protein (an anti-helminthic cytotoxin)
Eosinophil cationic protein
Eosinophil-derived neurotoxin
Eosinophil peroxidase
What is the eosinophil cationic protein?
A pore forming protein that punches holes in cell membranes and/or can digest RNA
What can punch holes in the cell membranes?
Eosinophils and complement
What is the eosinophil-derived neurotoxin?
A ribonuclease with antiviral properties
What does eosinophil peroxidase do?
Facilitates oxidative damage by generating hydrogen peroxide
What are neutrophil extracellular traps?
Sticky, meshlike substance neutrophils can extrude into extracellular space to which bacteria and yeast stick and are killed
What do NETs allow?
Immobilization of microbes and protects from surrounding tissue from destruction
What are fibers of the NET?
Neutrohils own DNA, which results in the death of the neutrophil
What do NK cells identify?
Potentially infected host cells since some microbes are intracellular and cannot be engulfed, ensnared in a NET, or killed by extracellular release of cytotoxins
What are NK cells classified as?
Lymphocytes, but do not possess antigen specific receptors
What do NK cells express?
Several receptors that recognize sick and stressed host cells
Receptors to recognize cells that are not displaying their self markers because they have not been altered by the pathogen
What do NK cells kill?
Infected or transformed cells
What do NK cells serve as?
The bridge to adaptive immunity
What do NK cell recognize?
Receptors on host cells
What happens if the receptors on host cells are not expressed?
The NK cell will destroy that cell
What receptors do NK cells use?
Killer lectin-like receptors
Killer cell immunoglobulin-like receptors
What do receptor sense?
Ligands that indicate abnormality
What do NK cell-activating receptors do?
Directly detect conserved viral proteins on surface of infected cells
May also detect modified ligands
What do all nucleated cells express on the surface?
MHC I
What do NK cells do with MHC I?
Recognize it as an indication of normal function
What do inhibitory signals to NK cells do?
Override the activating signal from identifying an altered protein
What happens once an NK cell encounters a host cell that triggers it activating receptor without triggering its inhibitory receptor?
The NK cell will kell the infected/altered cell
What is the killing mechanism of NK cells similar to?
The killing mechanism of Tc cells
What do NK cells release?
Lytic granules
What is different about the release from NK cells when compared to the release from neutrophils or eosinophils?
It is directed
What do NK cells form with the target cell?
A tight are of adhesion with the target cell (NK immunological synapse)
What is the NK immunological synapse?
Collection of adhesion molecules carefully arranged by NK cytoskeleton
What does the NK immunological synapse act to do?
Dock the NK cell with target cell
What does the NK immunological synapse form?
Tight seal so that granule contents are only released to the target cell
What are the cytotoxic molecules associated with the NK immunological synapse?
Perforin
Granzyme
What does perforin do?
Inserts itself into plasma membrane of target cell forming pores
What is granzyme?
A family of serine proteases that enter via pores made by perforin
Why does an NK cell not die as a result of killing a target cell from the release of perforin and granzyme?
It is resistant to its own perforin and granzyme
What is antibody-dependent cell-mediated cytotoxicity by NK cells?
Similar to how antibodies enhance phagocytosis, antibodies can also augment NK cell-mediated cytotoxicity
After an adaptive humoral response generates circulating antibodies to the microbe, what can the antibodies do?
Attach to a viral or neoplasm-associated antigens on the surface of cells
What can NK cells recognize antibody-coated cells with?
Their Fc receptors