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Fundamentals of Pathology > W11 Phagocytosis > Flashcards

W11 Phagocytosis Flashcards

1
Q

Phagocytosis: Roles

A

protection from pathogens

disposal of damaged/dying (apoptotic) cells

processing and presentation of antigens (Ag)

activation of adaptive immune system

links innate and adaptive immunity

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2
Q

Phagocytes`examples + origin

A

neutrophils, macrophages (M), dendritic cells

origin: myeloid lineage; generated in bone marrow

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3
Q

Other cells (apart from phagocytes)

A

mast cells, eosinophils, basophils (myeloid lineage)

natural killer (NK) cells (lymphoid lineage; bone marrow)

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4
Q

Phagocytes def.

A

identify, ingest, destroy pathogens

neutrophils, M, dendritic cells

belong to the innate immune system

Phagocytes have receptors for opsonins

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5
Q

Phagocytes: Neutrophils (PMN)

A

polymorphonuclear (PMN) leukocytes

most abundant WBCs (circulating in blood)

early response (inflammation)

phagocytosis and killing of microbes

enzymes: lysozyme, collagenase, elastase

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6
Q

Phagocytes: Neutrophils (PMN) - life span

A

life span = 8-10h/blood; 4-5 days in tissues

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7
Q

Phagocytes: Macrophages (M)

A

monocytes (blood; 20-40hrs)

efficient phagocytosis

killing of microbes

secrete inflammatory factors (cytokines) => inflammation

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8
Q

Dendritic cells

A

skin, mucosa, tissues
capture microbes

phagocytosis
not just to eliminate
present Ag to T cells
link innate and adaptive immune response

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9
Q

Dendritic cells and signals for T cell activation

A

Signal 1 = antigen recognition by MHC:peptide (Major histocompatibility complex) onto TCR

Signal 2 = co-stimulation by CD80/CD86 (cluster of differentiation - protein on Dcells activated by B cells) onto CD28 (proteins on T cells that provide co-stimulatory signals for T cell activation/survival)

Signal 3 = cytokines released by macrophages

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10
Q

Phagocytosis: Steps

A

Chemotaxis (mobilisation to site of infection/injury)

Recognition and attachment to microbe/dead cells

Engulfment

Killing/digestion of ingested microbe/dead cells

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11
Q

Phagocyte mobilization: Chemotaxis

A

movement of cells towards site of infection

guided by chemoattractants

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12
Q

chemoattractants released by

A

bacteria
- N-formyl-methionine-leucine-phenylalanine peptides (fMLP)

  • inflammatory cells
    chemokines (IL-8)
  • damaged tissues
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13
Q

Phagocytosis: Recognition of pathogens

A

Requirements:
react to invading pathogens (foreign)

no reaction to body’s own tissues (self)

PAMPs = structures shared by groups of related microbes

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14
Q

Pathogen-Associated Molecular Patterns (PAMPs)

A

present on pathogens and not on host cells

invariant structures:
shared by an entire class of pathogens

essential for survival of pathogens
prevents pathogen evasion of immune responses
e.g. ds viral RNA=> replication
e.g. lipopolysaccharide (LPS) => bacterial membrane

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15
Q

Pattern recognition receptors (PRRs)

A

present on phagocytes (and other cells, e.g. epithelia)

recognize PAMPs

detect foreign invaders or aged/damaged host cells

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16
Q

Toll-like receptors (TLRs)

A

PRR

plasma membrane, endosomal membrane

17
Q

C-type lectin receptors (CTLRs)

A

PRR

e.g. mannose receptor

18
Q

NOD-like receptors (NLRs)

A

PRR

reside as free proteins in cytoplasm

19
Q

RIG-like helicase receptors (RLRs)

A

PRR

cytosolic receptors for viral dsRNA

20
Q

Scavenger receptors

A

PRR

various bacterial wall components (CD14 scavenges LPS-LBP)

21
Q

PRRs: Toll-like receptors (TLRs)

A

essential roles in innate immunity

conserved during evolution

stimulate production of inflammatory cytokines

22
Q

human TLRs recognize PAMPs:

A 
lipolysaccharide (gram negative)
lipoteichoic acid (gram positive)
bacterial DNA sequences (unmethylated CpG)
single/double-stranded viral RNA
glucans (fungi)
23
Q

Phagocytosis: Opsonization

A

facilitates phagocytosis (recognition of microbes)

  • Opsonized microbes can be phagocytosed easier
    (via receptors for opsonins on phagocytes)

Clinical note!
=> Encapsulated microorganisms require opsonization with antibodies to be effectively phagocytosed!

24
Q
  • coating of microbes with opsonins:
A

a) proteins of complement system (C3b, C4b) (CR1 recognizes breakdown products of C3)
b) antibodies (immunoglobulin, Ig)

25
Q

Phagosome formation and maturation

A

Microbe present w/actin cytoskeleton rearrangement

Membrane remodelling occurs w/formation of pseudopods (cytoplasmic projections of CM) which wrap CM around microbe = forming phagosome

Lysosomes fuse forming phagolysosome

Pathogen destruction

26
Q

Killing of pathogens is dependent/independent of oxygen

A

Killing of pathogens: oxygen-independent

27
Q

Lysosomes:

A

proteolytic enzymes (cathepsins): degrade microbes

lysozyme: breaks bacterial walls
lactoferrin: binds iron => not enough left for bacteria
defensins: destroy bacterial walls

28
Q

Killing of pathogens: oxygen-dependent

A

resting phagocyte = NADPH + oxidase are not bound

activated phagocyte = assembly of NADPH oxidase
generation of superoxide anion

29
Q

Killing of pathogens: oxygen-dependent - equations

A

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
30
Q

blocking phagocyte attachment

A

Streptococcus pneumoniae – encapsulated bacteria

31
Q

blocking engulfment

A

Yersinia

32
Q

blocking destruction

A

Salmonella – resistant to ROS

Mycobacterium – blocks phagosome-lysosome fusion

33
Q

killing of phagocytes

A

Staphylococcus aureus – toxin => damages membranes

34
Q

Phagocytosis: Other types of prey

A

Micro-organisms
Damaged or dying cells

normal turnover of cells = 100-200 billion cells/day
apoptosis (programmed cell death)
fast, efficient removal by phagocytes
‘silent removal’: no inflammation
phagocytes: discriminate apoptotic vs. viable cells

35
Q

Phagocytosis of apoptotic cells

A

eat-me signals
apoptotic cell
attraction as Ptdser on apoptotic cell binds to phagocytic receptor
Triggers Rac w/GDP → Rac w/GTP
which then generates myosin-II and force generation for wrapping by pseudopods

Repulsion on viable cell

36
Q

Discrimination apoptotic / viable cells:

A

Apoptotic cells
‘Eat-me’ signals
Recognized by phagocytes => promote engulfment

Viable cells
‘Don’t eat-me’ signals
Recognized by phagocytes => no engulfment

37
Q

Phagocytes that have taken up apoptotic cells:

A
  • secrete‘pro-healing’ cytokines
    reduce inflammation (e.g. IL-10)
    promote wound healing (e.g. TGB-β)
  • presentation of self antigens
    role in maintenance of self tolerance

Fundamentals of Pathology (23 decks)

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