Phagocytosis Flashcards
What is phagocytosis?
- Mechanism of the innate immune system where phagocytes internalise certain matter (in this case, pathogens, dying cells, etc.)
- Destroys the pathogen by digesting it.
What are the main roles of phagocytosis?
- to protect the body from pathogens by destroying them with a ‘respiratory burst’
- to dispose of damaged/dying (apoptotic) cells (i.e efferocytosis)
- to process and present antigens (Ag)
This processing/presenting of antigens activates the adaptive immune system. It links the innate and adaptive immune system.
What are the effector (and other) cells of the innate immune system?
The effector cells are phagocytes which identify and digest pathogens. Phagocytes have receptors for opsonins. Most cells will phagocytose, but there are special cells that excel at it. These cells are:
- neutrophils
- macrophages
- dendritic cells
Their origin is the myeloid lineage i.e generated in the bone marrow.
Other cells in the innate immune system include:
- mast cells (myeloid lineage)
- eosinophils (myeloid lineage)
- basophils (myeloid lineage)
- natural killer (NK) cells (lymphoid lineage, made in bone marrow)
Describe neutrophils.
- Polymorphonuclear leucocytes.
- Most abundant white blood cell circulating in the blood.
- Respond early to infection (inflammation).
- Have a lifespan of about 8-10 hours in the blood and about 4-5 days in the tissue.
- Function is to phagocytose and kill microbes that enter the body.
- Release enzymes, such as lysozymes, collagenases, and elastases, which help destroy the pathogen.
Describe macrophages and dendritic cells
- Monocytes have a kidney-shaped nucleus, and when they enter tissue, they differentiate into macrophages.
- Very efficient at phagocytosis and secrete inflammatory factors (cytokines).
DENDRITIC CELLS
- Have extensions that allow them to sample the environment and detect pathogens.
- found in the skin, mucosa and tissues.
- Phagocytose and also present the pathogen’s antigens to T cells, to activate the adaptive immune system. Behaves as link between innate and adaptive immune systems
- Signal for T-cell activation using antigen recognition by MHCs on the TCRs (T-cell receptors).
- May not be enough to activate naïve T cells, so we have a second signal (costimulation) by CD80/CD86 in the antigen-presenting cell and CD28 in T cells. The third signal can be the cytokines released by the dendrites/macrophages.
Describe chemotaxis, ie. phagocyte mobilisation (the first step of phagocytosis).
- Movement of cells towards the site of infection.
- When a foreign body (e.g a pathogen or foreign cells) enters the tissue, the macrophages go towards and attach themselves to it.
- This causes it to release certain substances called chemoattractants; they attract phagocytic cells.
- Chemoattractants are released by many cells, such as bacteria (e.g fMLP), inflammatory cells (chemokines such as IL-8) and damaged tissues.
- Chemoattractants create a chemoattractive gradient towards the tissue, spreading out to surrounding blood vessels.
- Neutrophils that are circulating in the bloodstream have receptors on them that allow them to recognise and follow the chemoattractive gradient, and migrate towards the infected tissue.
- They can then aid in the removal of foreign bodies.
Describe the recognition and attachment of foreign bodies (the second step of phagocytosis).
- The recognition of pathogens can occur because they present PAMPs (protein-associated molecular patterns).
- These are present on pathogens and not on host cells, helping the phagocyte differentiate between self and non-self cells.
- They are invariant structures that are shared by an entire class of pathogen. These are essential for the survival of the pathogens, and they need to be so that they erase the possibility of the pathogen mutating and not expressing that PAMP anymore.
- Some examples of PAMPs would be double-stranded viral RNA, or lipopolysaccharides (LPS) found in bacterial membranes.
- The PAMPs are recognised by PRRs (pattern recognition receptors) that are present on phagocytes. They help detect foreign bodies or aged/damaged cells.
- Another way in which foreign bodies can be recognised is through opsonisation.
List the five PRRs.
TOLL-LIKE RECEPTORS:
- found on the plasma membrane and endosomal membrane
- play essential roles in innate immunity
- conserved throughout evolution.
- Human TLRs recognise PAMPs (eg. lipoteichoic acid, lipopolysaccharides, single or double stranded RNA) and stimulate the production of inflammatory cytokines.
- C-TYPE LECTIN RECEPTORS (CTLRs):
eg. mannose receptor - NOD-LIKE RECEPTORS (NLRs):
reside as free proteins in the cytoplasm - RIG-LIKE HELICASE RECEPTORS (RLRs):
cytosolic receptors for viral double-stranded RNA - SCAVENGER RECEPTORS:
they scavenge dead/damaged cells, but can also detect various bacterial cell wall components (CD14 scavenges LPS-LBP)
Describe opsonisation.
- Facilitates phagocytosis.
- Coating of microbes with opsonins (such as proteins of the complement system, C3b, C4b, and antibodies, immunoglobulin).
- Opsonised microbes can be phagocytosed easier (via receptors for opsonins on phagocytes).
- Opsonisation is required for encapsulated bacteria for effective phagocytosis. The capsule on these bacteria deflect phagocytes, so the opsonin coating helps the phagocytes get access to these kinds of microorganisms.
Describe engulfment (the third step of phagocytosis).
- When the microbe makes contact with the membrane, the actin cytoskeleton rearranges to make membrane protrusions called pseudopodia that surround the microbe, bringing it inside of the cell within a specialised vesicle.
- This vesicle that it is encapsulated in is called a phagosome.
- Phagosome combines with lysosomes in the cell to form a phagolysosome. This is done so that the enzymes present in the lysosome can get access to the microorganism to destroy it.
Describe pathogen destruction (the fourth step of phagocytosis).
The pathogen destruction occurs because of the lysosome. It contains digestive enzymes that it releases into the phagolysosome. Some of these enzymes are:
- proteolytic enzymes (cathepsins): degrade microbes
- lysozyme: breaks bacterial walls
- lactoferrin: binds iron, stealing it away from the bacteria
- defensins: destroy bacterial walls
Describe the two different ways in which phagocytes kill pathogens.
- Phagocytes can kill pathogens in an oxygen-dependant or oxygen-independant manner.
- A superoxide is biologically toxic and is deployed by the immune system to kill invading microorganisms.
- In phagocytes, superoxide is produced in large quantities by the enzyme NADPH oxidase for use in oxygen-dependent killing mechanisms of invading pathogens
- Oxidising radicals, such as NOS and ROS, kill phagocytosed microbes; however, they can also damage other tissues, so they need to be carefully controlled.
There are some enzymes that work in an oxygen-independent manner, ie. they can work under anaerobic conditions.
EQUATIONS
O2 → O2- (superoxide)
Through oxidase
H2O + O2- → H2O2;OH (hydrogen peroxide; hydroxyl radicals)
Through dismutase
arginine + O2 → NO + citruline
Through iNOS (inducible NO synthase)
NO + H2O2 → peroxynitrite radicals
Oxidising radicals (ROS and NOS)
kill phagocytosed microbes
What are some ways in which pathogens escape the immune system mechanisms?
- BLOCKING PHAGOCYTE ATTACHMENT
encapsulated bacteria - BLOCKING ENGULFMENT
Yersinia - BLOCKING DESTRUCTION
Salmonella: resistant to ROS, because they have enzymes that catalyse it
Mycobacterium: blocks phagosome-lysosome fusion - KILLING PHAGOCYTES
some have toxins that damage the phagocyte’s membrane
Describe the other types of pathogens that phagocytes go after.
In addition to pathogens, phagocytes also target:
- microorganisms e.g fungi
- damaged or dying cells - cells that have been worn out, on point of undergoing apoptosis, or damaged by pathogens
Phagocytosis occurs when cells undergo apoptosis; it is a fast, efficient removal by phagocytes. It is a ‘silent removal’ in the sense that there is no inflammation. Cells undergoing apoptosis release signals for engulfment by phagocytes, allowing discrimination between viable and apoptotic cells.
- Apoptotic cell binds to phagocytic receptors
- Engulfed and broken down
What are the consequences of apoptotic cell removal?
When phagocytes take up apoptotic cells, they:
- secrete ‘pro-healing’ cytokines’
they reduce inflammation (eg. promotion of IL-10 and blocking proinflammatory cytokine signalling IFN-1α and TLR signalling ; blocking TNR-α) and promote wound healing (TGB-β)
- present self antigens:
this has a role in maintaining self-tolerance
