L05 Phagocytosis Flashcards
Phagocytosis “Cell Eating”
The process by which cells bind, ingest or internalize foreign material or effete host cells and the subsequent destruction thereof
Is phagocytosis essential to life
Yes
All __________ cells are capable of this process to one extent or another
Nucleated
Professional Phagocytes
their main function is phagocytosis
Cells of Professional Phagocytes
Neutrophils
Monocytes
Dendritic Cells
Nonprofessional Phagocytes
can perform certain aspects of phagocytosis, but we recognize that they have other important functions
Cells of Nonprofessional Phagocytes
Basophils
Eosinophils
Quick acting phagocyte
Neutrophils
Comprises 60% of peripheral blood leukocytes
Neutrophils
Excellent at phagocytosing and killing bacteria
Neutrophils
Can kill intracellular or extracellularly
Neutrophils
Cannot renew their lysosome and die after digesting a few microbes
Neutrophils
Found in large amounts in the pus of wounds
Neutrophils (dead)
Multi-lobed Nucleus
Neutrophils
known as “large eaters”, make up 5-7% of the leukocytes in the blood
Monocytes/Macrophages
derived from monocytes and found in the tissues
Macrophages
Depending on the tissue their names can be different
Monocytes/Macrophages
Depending on their environment, can be activated as part of immune response
Monocytes/Macrophages
Can process and present antigen to T cells (adaptive immune system)
Monocytes/Macrophages
Act more slowly than neutrophils but have longer life span (2-4 months in tissue)
Monocytes/Macrophages
Can process and “present” antigens to T lymphocytes - can return to the secondary lymphoid organs to “show off” what was internalized
Monocytes/Macrophages
Examples of Tissue macrophages include:
Microglial cells (brain)
Kupffer cells (liver)
Alveolar macrophages (lungs)
Peritoneal macrophages (peritoneum)
Found throughout the body, but predominantly in potential sites of pathogen entry (skin, lungs, GI tract)
Dendritic Cells
Named for the “dendrites” or branch like cytoplasmic projections
Dendritic Cells
Use their projections to encircle and engulf fluid and extracellular pathogens
Dendritic Cells
Important antigen-presenting cell to T cells
Dendritic Cells
Important for phagocytosis, but do NOT actively induce generation of reactive oxygen species and/or other toxic products that induce local inflammation
Dendritic Cells
Which 2 cells have these characteristics:
- arrive slowly
-activated slowly
- have longer life span
- live on to process and present antigen to T cells
Monocytes and Dendritic cells
Which cell has these characteristics:
- arrive quickly
- quickly activated
- have a short half-life
-Ingest only a few microbes
Neutrophils
Mechanism of internalization: Endocytosis (3 ways)
Pinocytosis
Receptor-mediated endocytosis
Phagocytosis
Pinocytosis
nonspecific “cell drinking” of soluble molecules
Receptor-Mediated Endocytosis
(soluble molecules) selective binding of macromolecules to membrane bound receptors triggers internalization
Phagocytosis
Process whereby cells ingest and destroy insoluble particles (bacteria, viruses, fungi, cells, etc.)
Pinocytosis “Cell Drinking”
Nonspecific invaginations in the cell membrane with coincidental internalization of accompanying extracellular molecules
Steps of Phagocytosis (4 steps)
(R) Recognition and attachment of Microbes
(I) Ingestion of Microbes and other material
(D) Destruction of Ingested Microbes or other products
(S) Secretion of effector molecules
Recognition and attachment of Microbes
Phagocytosis is initiated when several types of receptors are bound by pathogens
-Pathogen Recognition Receptors (PRR’s) (and/or Toll like receptors)
-Complement Receptors
-FC receptors (recognize the bottom 1/2 of Ab molecules)
- receptors for defenses and/or other molecules
Complement Receptors and Fc Receptors bind to ________ on the surface of microbes
Opsonins
Opsonins are defined as
molecules that, when bound to the surface of microbes, make them more attractive to phagocytic cells
Examples of opsonins are (2)
C3b - from complement pathway and IgG
When a microbe is covered with either C3b or IgG, receptors of these opsonins can
tightly grab onto the microbe and ingest it
Some organisms produce a __________ __________ that makes it challenging for phagocytes to surround and phagocytose these organisms
HydroPHILLIC capsule
Production of capsules that do not allow phagocytosis is
a major determinant of many pathogens’ ability to cause diseases (i.e. a virulence factor or a factor that enables a pathogenic organism to cause disease)
in the cases of capsules, opsonins become paramount in
the ability of a phagocyte to engulf and destroy these microorganisms
Ingest of Microbes and other materials
For Phagocytosis:
after attachment, the microorganism is engulfed by extensions of the cytoplasm and cell membrane
once internalized, a vesicle is formed called a Phagocytic Vesicle or Phagosome
The formation of the phagosome activates the phagocyte to:
- Increase in cell size
- Become more phagocytic
-initiate production of molecules that destroy the engulfed microorganism
Destruction of Ingested Microbes or other Products - the phagosome fuses…
the phagosome fuses with lysosomal in the cytoplasm to form the phagolysosome
Destruction of Ingested Microbes or other Products
Within the phagolysosome, multiple products are produced that attack and destroy the ingested pathogen
- the oxidative burst chemical reaction creates superoxide (O2-) hydroxyl radicals and hypochlorite (e.g bleach)
Individuals with mutations in enzymes in this pathway (destruction of ingested microbes) have
significant immunological deficiencies
Oxidative Burst
Oxygen dependent reaction in the phagolysosome
- generates molecules that have very potent anti-microbial activities (superoxide, hydrogen peroxide, hydroxyl radicals, hypochlorite ‘bleach’
- enzyme in the last step- Myleoperoxidase (deficiency in this enzyme can cause diseases)
Chronic Granulomatous Disease
X-linked disease, deficient in Myleoperoxidase and other enzymes
- body uses neutrophils instead which can phagocytose pathogen, but not kill it
- defect of intracellular killing
- Neutrophils become “trojan horse”
-Manifests within first 2 years of life
-Granulomatous lesions found in various organs
Destruction of Ingested Microbes or other Products: Toxic Nitrogen Oxides:
-Inducible Nitric Oxide synthase (iNOS) is induced by cytokines such as IFN-gamma and TNF-alpha
iNOS - modifies arginine and ultimately makes NO
Nitrous oxide (NO-) - inhibits iron/sulfur-dependent enzymes; damages DNA and oxidizes membrane lipids
Within the phagolysosome, other microbial products that contribute to killing:
Lysozyme - attacks bacterial cell walls
Lactoferrin - chelates iron, which is necessary for normal microbial metabolism
Defensins - small antimicrobial peptides that distrupt membrane function and can induce osmotic lysis
Secretion of effector molecules
Not only are molecules produced in the phagolysosome to kill ingested organisms, activated phagocytes produced secreted molecules to alert and activate the rest of the immune response:
Chemokines - recruit additional cell types
Cytokines - to activate infiltrating cells
Nitrous oxide - can be secreted
Degradative enzymes
Mechanism to increase phagocytosis and killing neutrophils
Neutrophils inherently don’t require significant stimulus to phagocytose and kill
However, certain stimuli have been shown to enhance neutrophil activation, phagocytosis and killing
- stimulation of PRR’s on neutrophils
-complement can increase oxidative burst in neutrophils
-cytokines can also help
Monocyte/Macrophages and Dendritic cells require activation of phagocytose
-Stimulation of PRR’s
- engagement of complement receptors and Fc receptors on the surface
-Cytokines, such as IFN-gamma, can signficantly impact monocyte differentiation into macrophages and activation to kill; IFN-gamma can also increase the ability of both macrophages and dendritic cells to present antigen
What happens after the pathogen is phagocytose and destroyed?
- Nucleic acids and amino acids are re-used
- Proteins are broken down into peptide fragments that are “presented” to T lymphocytes to activate T cells (only macrophages and dendritic cells) in a process called Antigen Presenting
