Osmosis (check high yield notes)
Week 1: inflammation and repair
INFLAMMATION
Four signs of inflammation:
Heat (calor)
Pain (dolor)
Redness (rubor)
Swelling (tumor)
Sometimes they combine to cause loss of function (temporary).
Inflammation:
Starts with stimuli (e.g., pathogen, toxins, trauma).
Goal = to restore balance.
o Eliminate cause.
o Clearing out nectrotic cells.
o Tissue repair.
Inflammation can be triggered by:
- External factors:
o Non-microbial (allergens, irritants, or toxic compounds).
o Microbial. Can be two things:
Virulence factors = help pathogens colonize tissues and cause
infection.
Pathogen-Associated Molecular Patterns (PAMPs) = small
molecules with a conserved pattern that are shared across different
pathogens (peptidoglycan, LPS, lipoteichoic acid, mannan).
Might include viral RNA or DNA.
Our immune system recognizes microbial factors as different and can evoke an
immune response against them.
- Internal factors:
o Damage-Associated Molecular Patterns (DAMPs) (= endogenous equivalent
to PAMPs) = intracellular proteins that get released when plasma membrane is
injured or when a cell dies.
Signals serious cell damage trigger inflammation.
PAMPs and DAMPs are recognized by pattern recognition receptors (PRRs) on leukocytes.
This activates the leukocyte to spark inflammatory response. This is innate immune system:
- Non-specific.
- Fast (min / hours).
- No memory.
Two types of leukocytes:
(1) Granulocytes, which include:
a. Neutrophils
b. Eosinophils
c. Basophils
d. Mast cells
(2) Agranulocytes, which include:
a. Lymphocytes
b. Monocytes, which can differentiate into
, i. Macrophages
ii. Dendritic cells
Inflammatory reaction
Starts with macrophages or mast cells (within tissues). With tissue damage, these cells
respond to the PAMPs or DAMPs. Mast cells have granules with inflammatory mediators
(histamine, serotonin, cytokines, and eicosanoids (like prostaglandins and leukotrienes)).
These inflammatory mediators work on the endothelium surrounding the capillaries nearby,
causing them to separate. In addition, macrophages start to eat up invading pathogens.
The release of cytokines causes the capillaries to get larger and increase vascular permeability,
allowing proteins to leave the circulation.
Endothelial cells also help by releasing nitric oxide (NO), which helps vasodilation.
Also, endothelial cells express more adhesion proteins to help leukocytes attach and enter
the damaged site. More specific, they enter the damaged site because of the chemokines and
microbial products. The neutrophil then squeezes through the capillary to reach the tissue (=
extravasation).
Next, the leukocyte follows the gradient of inflammatory mediators to get to the site of
inflammation. Neutrophils are the first to be recruited. They immediately start phagocytosing
+ go into apoptosis. While this happens, the complement system gets activated (by the
presence of pathogens). They help:
- Attract leukocytes.
- With opsonization (bind to microbes so leukocytes can more easily phagocytose).
- Kill pathogens (by forming a channel in the membrane).
Simultaneously, dendritic cells continue to phagocytose and present bits of the pathogens to
T-lymphocytes. This activates the adaptive immune system (after few days).
Platelets and clotting factors help to clot the wound. This:
- Stops the bleeding.
- Prevents pathogens from entering blood.
- Provides framework for tissue repair.
The inflammatory response ends with tissue repair.
Tissue repair
Macrophages eat up dead and dying cells to make room for new cells. This is followed by
angiogenesis = formation of new blood vessels. This is triggered by growth factors, released
by macrophages.
Newly formed blood vessels are temporary. Once the wound is healed, these vessels
disappear.
Fibroblast also enter the tissue to synthesize collagen to help with wound healing.
Mild damage tissue returns to healthy state.
Severe damage damaged cells get replaced by a non-functional fibrous scar.
, COMPLEMENT SYSTEM
Is formed by a group of plasma proteins (= complement proteins) that are produced in the
liver. It helps destroy pathogens: they ‘complement’ the work of antibodies.
Three complement pathways:
(1) Classical pathway.
(2) Lectin pathway
(3) Alternative pathway (always at work)
They begin differently, but all end with a membrane-attack complex to make a hole in the cell
membrane of the pathogen (destroys mainly gram negative bacteria).
Classical pathway
Formed by the proteins C1-C9. Normally inactive, until cleaved, then active.
C1 has three components (6xC1q, C1s, C1r).
- C1q binds to Fc portion of an antibody bound to an antigen. One C1 molecule can
thus bind up to 6 antibodies. C1q has no enzymatic activity.
- C1s and C1r are serine proteases. Typically hidden, so can’t perform enzymatic
activity.
All this sits together in a calcium bone, so lack of calcium lack of C1.
When C1q binds an antibody, it induces a conformational change, releasing the C1r and C1s
sites. C1r now cleaves C1s. Then:
- Activated C1 cleaves C4 into C4a and C4b.
- Activated C1 cleaves C2 into C2a and C2b.
C4a floats away but C4b binds to the surface of the pathogen.
C2a floats away and C2b joins C4b on the surface of the pathogen, forming a complex called
C4b2b or C3 convertase.
C3 convertase cleaves C3 into C3a and C3b.
This really amplifies things, because one C1 can make 10 C3 convertases, and one C3-
convertase can cleave >1000 C3-molecules per second. C3 stays active for 2 min, so you get a
lot of C3b very quickly.
C3b, aka opsonin, helps phagocytes get a grip on bacteria. Normally, bacteria have an
antiphagocytic capsule. Opsonization = attachment of C3b molecules on bacteria to make it
easier to help macrophages with phagocytosis.
Once there is enough C3b, a part binds to the C3-convertase (= C4b2b) and turns it into a C5-
convertase (= C4b2b3b-complex).
Week 1: inflammation and repair
INFLAMMATION
Four signs of inflammation:
Heat (calor)
Pain (dolor)
Redness (rubor)
Swelling (tumor)
Sometimes they combine to cause loss of function (temporary).
Inflammation:
Starts with stimuli (e.g., pathogen, toxins, trauma).
Goal = to restore balance.
o Eliminate cause.
o Clearing out nectrotic cells.
o Tissue repair.
Inflammation can be triggered by:
- External factors:
o Non-microbial (allergens, irritants, or toxic compounds).
o Microbial. Can be two things:
Virulence factors = help pathogens colonize tissues and cause
infection.
Pathogen-Associated Molecular Patterns (PAMPs) = small
molecules with a conserved pattern that are shared across different
pathogens (peptidoglycan, LPS, lipoteichoic acid, mannan).
Might include viral RNA or DNA.
Our immune system recognizes microbial factors as different and can evoke an
immune response against them.
- Internal factors:
o Damage-Associated Molecular Patterns (DAMPs) (= endogenous equivalent
to PAMPs) = intracellular proteins that get released when plasma membrane is
injured or when a cell dies.
Signals serious cell damage trigger inflammation.
PAMPs and DAMPs are recognized by pattern recognition receptors (PRRs) on leukocytes.
This activates the leukocyte to spark inflammatory response. This is innate immune system:
- Non-specific.
- Fast (min / hours).
- No memory.
Two types of leukocytes:
(1) Granulocytes, which include:
a. Neutrophils
b. Eosinophils
c. Basophils
d. Mast cells
(2) Agranulocytes, which include:
a. Lymphocytes
b. Monocytes, which can differentiate into
, i. Macrophages
ii. Dendritic cells
Inflammatory reaction
Starts with macrophages or mast cells (within tissues). With tissue damage, these cells
respond to the PAMPs or DAMPs. Mast cells have granules with inflammatory mediators
(histamine, serotonin, cytokines, and eicosanoids (like prostaglandins and leukotrienes)).
These inflammatory mediators work on the endothelium surrounding the capillaries nearby,
causing them to separate. In addition, macrophages start to eat up invading pathogens.
The release of cytokines causes the capillaries to get larger and increase vascular permeability,
allowing proteins to leave the circulation.
Endothelial cells also help by releasing nitric oxide (NO), which helps vasodilation.
Also, endothelial cells express more adhesion proteins to help leukocytes attach and enter
the damaged site. More specific, they enter the damaged site because of the chemokines and
microbial products. The neutrophil then squeezes through the capillary to reach the tissue (=
extravasation).
Next, the leukocyte follows the gradient of inflammatory mediators to get to the site of
inflammation. Neutrophils are the first to be recruited. They immediately start phagocytosing
+ go into apoptosis. While this happens, the complement system gets activated (by the
presence of pathogens). They help:
- Attract leukocytes.
- With opsonization (bind to microbes so leukocytes can more easily phagocytose).
- Kill pathogens (by forming a channel in the membrane).
Simultaneously, dendritic cells continue to phagocytose and present bits of the pathogens to
T-lymphocytes. This activates the adaptive immune system (after few days).
Platelets and clotting factors help to clot the wound. This:
- Stops the bleeding.
- Prevents pathogens from entering blood.
- Provides framework for tissue repair.
The inflammatory response ends with tissue repair.
Tissue repair
Macrophages eat up dead and dying cells to make room for new cells. This is followed by
angiogenesis = formation of new blood vessels. This is triggered by growth factors, released
by macrophages.
Newly formed blood vessels are temporary. Once the wound is healed, these vessels
disappear.
Fibroblast also enter the tissue to synthesize collagen to help with wound healing.
Mild damage tissue returns to healthy state.
Severe damage damaged cells get replaced by a non-functional fibrous scar.
, COMPLEMENT SYSTEM
Is formed by a group of plasma proteins (= complement proteins) that are produced in the
liver. It helps destroy pathogens: they ‘complement’ the work of antibodies.
Three complement pathways:
(1) Classical pathway.
(2) Lectin pathway
(3) Alternative pathway (always at work)
They begin differently, but all end with a membrane-attack complex to make a hole in the cell
membrane of the pathogen (destroys mainly gram negative bacteria).
Classical pathway
Formed by the proteins C1-C9. Normally inactive, until cleaved, then active.
C1 has three components (6xC1q, C1s, C1r).
- C1q binds to Fc portion of an antibody bound to an antigen. One C1 molecule can
thus bind up to 6 antibodies. C1q has no enzymatic activity.
- C1s and C1r are serine proteases. Typically hidden, so can’t perform enzymatic
activity.
All this sits together in a calcium bone, so lack of calcium lack of C1.
When C1q binds an antibody, it induces a conformational change, releasing the C1r and C1s
sites. C1r now cleaves C1s. Then:
- Activated C1 cleaves C4 into C4a and C4b.
- Activated C1 cleaves C2 into C2a and C2b.
C4a floats away but C4b binds to the surface of the pathogen.
C2a floats away and C2b joins C4b on the surface of the pathogen, forming a complex called
C4b2b or C3 convertase.
C3 convertase cleaves C3 into C3a and C3b.
This really amplifies things, because one C1 can make 10 C3 convertases, and one C3-
convertase can cleave >1000 C3-molecules per second. C3 stays active for 2 min, so you get a
lot of C3b very quickly.
C3b, aka opsonin, helps phagocytes get a grip on bacteria. Normally, bacteria have an
antiphagocytic capsule. Opsonization = attachment of C3b molecules on bacteria to make it
easier to help macrophages with phagocytosis.
Once there is enough C3b, a part binds to the C3-convertase (= C4b2b) and turns it into a C5-
convertase (= C4b2b3b-complex).
