Fatima Adam
Phagocytosis (Pathology)
Learning Objectives • Define the process of phagocytosis • Identify different types of leukocytes that carry out phagocytosis • Describe the steps and cellular processes behind phagocytosis • Understand the purpose and outcomes of phagocytosis and efferocytosis • Describe how pathogens evade destruction during phagocytosis
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What are the 5 different roles of Phagocytosis?
• Destruction of the pathogen via respiratory burst
• Activation of genes leading to cytokine and chemokine release
• Antigen presentation
• Cell recruitment
• Elimination and disposal of dead, apoptotic and damaged cells
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What are effector phagocytes?
Effector phagocytes are immune cells involved in defence against pathogens.
Main types include neutrophils and macrophages
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Are neutrophils polymorphonuclear?
Yes
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What is the most abundant WBC?
Neutrophils
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When do Neutrophils act as effectors?
In early antibacterial responses (Inflammation)
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What is the lifespan of a neutrophil? (In blood and tissues)
-8-10hrs in blood
-4-5 days in tissues
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What enzymes are produced by the neutrophils? (3)
-lysozyme
-Collagenase
-Elastase
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Neutrophils perform NETosis; What is NETosis? What are NETs composed of? What is the Purpose?
-Neutrophils release web-like structures known as Neutrophil Extracellular Traps (NETs)
-NETs are composed of DNA, histones, and antimicrobial proteins
-Purpose: To trap and neutralize pathogens, especially bacteria and fungi, in the extracellular environment
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Where are phagocytes located?
-Tissue
-Mucosa
-Lymph Nodes
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Phagocytes link the....?
Innate and immune responses
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What are the 4 general steps of phagocytosis?
• Chemotaxis (mobilisation towards pathogens or site of infection/injury)
• Recognition and attachment to microbe/dead cells
• Engulfment
• Killing/digestion of ingested microbe/dead cells
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What is chemotaxis?
Movement of cells towards site of infection, guided by chemoattractants
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Chemoattractants can be released by? (In what form)
- Bacteria
N-formyl-methionine-leucine-phenylalanine peptides(fMLP)
-Inflammatory cells
chemokines (e.g. IL-8)
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For phagocytosis to occur, the body either must....?
1)React to Invading Pathogens (Foreign)
2)Regulated Reaction to Body’s Own Tissues (Self)
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What are Pathogen Associated Molecular Patterns (PAMPs)?
Structures shared by groups of related microbes
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PAMPS are shared by an entire class of...?
Pathogens
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PAMPS are essential for the survival of humans because they minimise pathogen evasion of immune responses; what are some examples of PAMPS?
e.g. ds viral RNA=> replicatione.g. lipopolysaccharide (LPS) => bacterial membrane
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What are pattern recognition receptors (PRRs)?
Proteins on the surface of immune cells that recognize specific PAMPs
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What are Damage-Associated Molecular Patterns (DAMPs)?
Molecules released by damaged or stressed cells
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Where are PRRs presented?
Present on phagocytes (and other cells, e.g. epithelia)
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What are the 2 main purposes of PRRs?
-Recognize PAMPs and DAMPs (Damage-Associated Molecular Patterns)
-Detect foreign invaders or aged/damaged host cells
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Detection and signals through PRRs lead to.....?
Phagocytosis
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Can you name the 5 types of PRRs? And can you name some types of these individual PRRs?
-Toll-like receptors (TLRs)
Located on the plasma membrane and endosomal membrane
-C-type lectin receptors (CTLRs)
e.g. mannose receptor
-NOD-like receptors (NLRs)
Reside as free proteins in cytoplasm
-RIG-like helicase receptors (RLRs)
Cytosolic receptors for viral dsRNA
-Scavenger receptors
Various bacterial wall components (CD14 scavenges LPS-LBP)
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Human TLRs will recognise what? Such as?
PAMPs
Such as:
Lipolysaccharide (gram negative)
Lipoteichoic acid (gram positive)Bacterial DNA sequences (unmethylated CpG)Single/double-stranded viral RNAGlucans (fungi)
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TLRs will stimulate the production of what?
Inflammatory cytokines
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TLRs have been highly ________ in evolution
What is the missing word?
Conserved
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What is opsonisation?
Process where pathogens are marked for phagocytosis (engulfment and destruction) by phagocytic cells
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Opsonized microbes can be _______ easier via receptors for ______ on phagocytes.
What are the missing words?
1)Phagocytosed
2)Opsonins
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What contributes to the coating of microbes with opsonins (2)? Can you name some examples for each point?
Proteins of Complement System:
Complement proteins, particularly C3b and C4b, can act as opsonins
Antibodies (Immunoglobulin, Ig):
Antibodies, which are produced by B cells as part of the adaptive immune response, can also act as opsonins. Immunoglobulins (Ig), such as IgG, can bind to specific antigens
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A picture demonstrating Phagosome formation and maturation:
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State the steps of phagosome formation (1-3):
Recognition and Attachment:
Phagocytic cells recognise and attach to the particle, facilitated by receptors
Recognition triggers signalling cascades that lead to actin cytoskeleton rearrangement
Pseudopod Formation:
Actin cytoskeleton rearrangement results in the extension of pseudopodia (membrane projections) around the particle
Engulfment of the particle occurs
Membrane Remodelling:
As the pseudopodia surround the particle, membrane remodeling occurs, leading to the closure of the phagosome
Early phagosome produced
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State the steps of phagosome maturation (4-9):
Early Phagosome:
Undergo fusion with endosomes, vesicles derived from the Golgi apparatus
Phagosome Acidification:
Proton pumps actively acidify the phagosome, transforming it into a late phagosome
Acidification is critical for the activation of enzymes
Fusion with Lysosomes:
Late phagosomes undergo fusion with lysosomes, specialized organelles containing various hydrolytic enzymes
Forms a phagolysosome
Enzymatic Digestion:
Enzymes within the phagolysosome, including proteases, nucleases, and lipases
Residual Body Formation:
Forms a residual body within the phagolysosome
Exocytosis or Antigen Presentation:
Processed antigens may be presented on the cell surface, initiating an adaptive immune response
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The killing of pathogens by lysosomes is independent of what?
Oxygen
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There are 4 components of the lysosome essential for pathogen destruction; can you name them and state their purposes?
-Proteolytic enzymes (cathepsins): degrade microbes-Lysozyme: breaks bacterial walls-Lactoferrin: binds iron, leads to not enough iron left for bacteria-Defensins: destroy bacterial walls
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Killing of pathogens can also be oxygen dependent, a picture demonstrating this:
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Killing of pathogens leads to the production of oxidising ________
What is the missing word?
Radicals
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Phagocytosis dcan be prevented (evaded) by pathogens sadly
There are 4 ways this can occur, state these 4 ways and maybe specific pathogens/bacteria that cause it
-Blocking phagocyte attachment
Streptococcus pneumoniae – encapsulated bacteria
-Blocking engulfment
Yersinia
-Blocking destruction
Salmonella – resistant to ROSMycobacterium – blocks phagosome-lysosome fusion
-Killing of phagocytesStaphylococcus aureus – toxin => damages membranes
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What is the normal turnover for cells (for the average human) a day?
100-200 billion cells/day
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Phagocytes will discriminate between....?
Apoptotic vs. viable cells
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Does apoptosis cause inflammation?
No - Silent removal
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Phagocytosis of apoptotic cells is also called what?
Efferocytosis
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A picture demonstrating how efferocytosis occurs:
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Phagocytes that have taken up apoptotic cells reduce inflammation by what mechanisms? (4)
• Blocking TLR signalling• Blocking proinflammatory cytokine signalling (IFN-• Blocking (TNF- expression)• Promote (IL-10 secretion)
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Phagocytes that have taken up apoptotic can change to a 'pro-healing' phenotype by what mechanism? (1)
• Secreting ‘pro-healing’cytokines (e.g. TGB-β)
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Phagocytosis allows for antigen processing and presentation and helps to link the innate and adaptive immune responses
A picture outlining this:
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A picture overview of phagocytosis:
