Complement and Inflammation L6 Flashcards
what is the innate immune response for
recognition
what happens in the innate immune resposne
bacterial cell surface induces cleavage, complement activation
a complement covalently bonds to bacterium, other attracts effector cell
complement receptor on effector cell binds to complement on bacterium
effector engulfs bacterium, kills it
what is the complement system
Complement pathways need C3 molecule
All three pathways lead to lysis of C3 they then all expand out to different potential ways that they can have effect, depending what the immune system requires
what are the effects that the complement system lead to
Recruitment of inflammatory cells
Opsonization of pathogens
Killing of pathogens
how is the classical pathway - complement activation classical pathway
C3b bind to pathogen surface causing optimisation effect, so pathogen can be recognised by the innate immune system
how does the classical pathway in complement activation begin
engagement of C1q globular heads to the antibodies
what are the antibodies that bind to C1q
IgM - five of them stick together via the constant region to form a pentamer
IgG - when two or more in close proximity bound to the surface through dimer formations
how does IgM bind to pathogens
IgM binds to several epitopes on the surface of the pathogen, it is bent into the staple conformation, allowing the C1q globular heads to bind to the Fc regions of IgM
Bending where globular heads can bind to
Conformational change – c1q bind to surface
how does the IgM structure change
pentameric form is a flat planar like structure
turns to staple structure
how does IgG bind to pathogens
C1q can bind to two or more IgG molecules which have bound to epitopes on the pathogen surface, then can get activation of the complement cascade
what happens in the mannose binding lectin pathway
Mannose Binding Lectin (MBL) recognises
carbohydrates present at the surface of pathogens
Sugars bound on pathogen surface, mannose binding lectin recognizes
Can get activation of the pathway
C3 function in the complement cascade
Activation of complement cascade
takes C3 and breaks into C3b and C3a
C3b binds to the surface of the pathogens
C3a activate other parts of immune system
what does C3 convertase do
There is a slightly different variant of C3 convertase that can break and cleave C3 into C3a and C3b
what happens after C3 is bound to the pathogen surface
Activate more parts in complement cascade
what does the C3 convertase do
The two C3 convertases generated through the three pathways of complement activation can form a complex with C3b to generate a C5 convertase
what does C5 convertase do
cleave C5 into C5a and C5b
what does C5 cleavage cause
leads to the formation of the membrane attack complex
how is a membrane attack complex formed
C5 cleaves then c5b bind too c6 c7
C5b67 forms a complex that bind to surface via C7
C8 then binds to this complex and inserts into cell membrane
how do membrane attack complexes form holes in the membrane
C9 then can form a pore in the membrane - osmosis
So the cell dies
Complement cascade – kill the pathogen
what happens after the C3b is bound
opsonization of pathogens
how do macrophages recognise material
through opsonic and non-opsonic receptors
what is used in direct recognition
non-opsonic
what is used in indirect recognition
opsonic
Antibody-Fc receptor
Complement-Complement receptor
what does the pathogen bind to
the complement
how can clearance be enhanced
tagging the microbes
recognised by complement receptors in immune system
what happens after C3b is bound
recruitment of inflammatory cells = inflammation
what receptor do cells for innate immunity have
Cells relevant for innate immunity have receptors for the soluble cleavage products C3a and C5a
what contributes to inflammation initiation
Once C3a and C5a bind to their receptors cells become activated. This effect contributes to the initiation of inflammation
what happens when complement activation occurs to immune system
Other parts of the immune system are activated
what are the regulations in complement activation
Inactivation of the C3 convertase
Inactivation of C5 convertase
No formation of membrane-attack complex
what are the features of gram negative bacteria
Long polysaccharide chains in cell wall (LPS)
what are the features of gram positive bacteria
Layer of peptidoglycan in cell wall
what may some pathogens do to subvert complements
Proteins that mimic complement regulatory proteins
how do gram negative bacteria affect complements
LPS forms a barrier around e.g.E. coli so cant get the formation of MAC complex, so no pore formation
how do gram negative bacteria affect complements
Prevents insertion of MAC
how do some pathogens affect complements
Inhibit complement cascade
what is an inflammatory response
Complex response to local injury or trauma
what does vasodilation do
increase in the diameter of blood vessels, responsible for tissue redness and increase tissue temperature
what does vasoconstriction do
influx of white cells and fluid (exudate) from the capillaries into the tissue, responsible for swelling (oedema)
what happens after injury occurs to the body
Injury then the different inflammations :pain swelling, warmth, redness
Recruitment to try clear
what happens in the body when injured
innate immune system activated
C3 and C5 cleaved off by the C3 convalutase and C5 convalutase, increase the vascular permeability – vasodilation, more components can come inside the tissue – build complement cascade to help start inflammation response
Cells recruited to site, all have different function - amplification effect to clear infection
how are macrophages and dendritic cells ‘aware’
‘aware’ of the presence of infection because they express multiple receptors
- Pattern recognition receptors
- Complement receptors
- C5a, C3a and C3b
what is macrophages and dendritic cells response to infection
producing cytokines and chemokines
how is cytokine production activated by macrophages
activated macrophages secrete cytokines
Act as messengers – tell need to clear infection
Different cytokines have different effects on different parts of the body
what does interleukin - 1beta (IL-1beta) do when cytokines released
activated vascular endothelium
activates lymphocytes
local tissue destruction
increases access of effector cells
what does tumour necrosis factor alpha (TNF-alpha) do when cytokines released
activated vascular endothelium
increase vascular permeability = more IgG, complement and cells enter tissues
increased fluid drainage to lymph nodes
what does Interleukin-12 (IL-12) do when cytokines are released
activates natural killer cells
induces differentiation of CD4 T cells into TH1 cells
what are chemokines
Small proteins mainly chemo attractant for leukocytes
what do chemokines fo
Recruit cells to site of inflammation
Recruit cells to secondary organs
how are chemokines released
activated macrophages release range of cytokines
in normal epithelium what is the interaction between leukocytes
selectin-mediated adhesion to leukocyte is weak, allows leukocytes to roll along vascular endothelial surface
what are the stages when activated epithelium - interaction between leukocytes and epithelium
rolling adhesion
tight binding
diapedesis
migration
what happens when infection in body (endothelium)
chemokines(IL-8) high concentration nearest to the site of infection – help tell immune system where the site of infection is
what occurs in rolling adhesion
Neutrophil will bind to a E-selectin and the chemokine (IL-8) binds to help hold the neutrophil in the same place
what occurs in tight binding
complex is attached to the LFA that is bound to the ICAM-1, through the LFA and ICAM-1 binding is really strong, so stops cell disappearing off
what happens in diapedesis
diapedesis of the cell into the capillary to the site of the infection
what happens in migration
once the cell is in the tissue can migrate to the site of infection due to the chemokine gradient, and help to kill pathogen
what happens after 24h in inflammatory cells
neutrophil - phagocytosis and activation of bactericidal mechanisms
eosinophil - killing of antibody coated parasites
what happens after 3-4 days in inflammatory cells
basophil present
what are the systematic effects of inflammation when more neutrophils made
help to clear infection
neutrophils formed in bone marrow, different signals from cytokines
what are the systematic effects of inflammation when increase body temperature
reduced pathogen replication, boost of immune response (why you get a fever)
what are the systematic effects of inflammation - liver
Production of acute phase proteins by the liver. These molecule include MBL and C-reactive protein (CRP) which help to clear infection
what can cause septic shock
response to an overwhelming inflammatory response
what happens in a local infection with gram negative bacteria
macrophages activated to secrete TNF-alpha in tissue
how is infection removed that is caused by local - gram negative
phagocytosis of bacteria
local vessel occlusion
plasma and cells drain to local lymph node
what does the release of TNF-alpha in the local infection stage cause
increase plasma protein into tissue, increase phagocyte and lymphocyte migration to tissue
increase platelet adhesion to blood vessel wall
what happens when systematic infection with gram positive bacteria (sepsis) occurs
macrophages activated in liver and spleen secrete TNF-alpha into the bloodstream
what happens when TNF-alpha is released into the bloodstream - gram positive infection
systematic edema causing decreased blood volume
hypoproteinemia and neutropenia, follwed by neutrophilia
decreased blood volume caused collapse of vessels
how does death occur due to gram positive bacteria
disseminated intravascular coagulation leading to wasting and multiple organ failure
