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L5 – Inflammation is usually beneficial
Inflammation is a normal tissue response to infection or injury
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It results in swelling, redness, elevated temperature and pain
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The
complement system comprises of approximately 20 or more different proteins
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Rather than direct activation by infectious agents, antibody antigen complexes
activate the complement components
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The C1
complex is composed of one C1q, two of each of the zymogens C1r
and C1s, which forms a calcium-stabilised trimolecular complex
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• Once antibody is bound to the microbe, they are able to bind
complement component C1q
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• This is followed by a conformational change, leading to the
autoactivation of the proteolytic activity in C1r, which subsequently
cleaves C1s to generate an active serine protease
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• C4b binds with complement component C2 to form C4b2
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• Many bacteria have on their surface mannose, which would bind the
mannose-binding lectin/protein (MBL/P)
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The C1-like complex has C1 activity and splits complement component
C4 into C4a and C4b, similar to the classical complement pathway
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Alternative pathway
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The alternative pathway is activated by microbial surfaces
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• C3b combines with another plasma protein Factor B in the presence of
magnesium ions to form the complex C3bB, which in turn is acted upon
by a normal plasma enzyme Factor D to generate the active complex
C3bBb
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This completes a feedback loop, which
enables the product of C3 cleavage to generate an enzyme which will
split further molecules of C3
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• This regulation occurs in the following manner
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This in turn is highly susceptible to another proteolytic enzyme
Factor I, which cleaves C3b in such a way to produce the inactivated
form iC3b, which cannot participate in the feedback loop
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This stabilization can be
reinforced by another complement component, properdin, to achieve
biologically significant activity
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On cleavage, the
C3b molecule is extremely active chemically for a transient period
during which time it can link to any amino or hydroxyl groups on the
bacterial surface
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Irrespective of how complement becomes activated, the key event is the
formation of an enzyme complex called the C3 convertase, which splits
complement component C3 into two fragments, C3a and C3b
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It is only after the splitting of C3 that the complement components
have physiological activity
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For the lectin and classical pathways, the C3 convertase has the
designation C4b2a, whilst for the alternative pathway it is C3bBb
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C5b then forms a trimolecular complex with two further components C6
and C7
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This In turn recruits the terminal component of the complement
pathway, C9, which it turns inside out and converts to an amphipathic
molecule capable of insertion into the lipid bilayer, where it can
polymerize to form and annular membrane attack complex (MAC)
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Activities generated by the triggering of the complement cascade
The complement components involved in immune responses are C3a, C3b,
C5a and the MAC
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• C5a also acts as a chemotactic factor to attract phagocytic cells such
as neutrophils to the site of infection
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• The MAC inserts into bacterial membranes forming a channel through
which small water-soluble solutes can flow, thereby upsetting the
integrity of the cell and usually leading to lysis through osmotic influx of
water and therefore leading to the death of the bacterium
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C3d is produced when C3b is cleaved into C3c and C3d
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Inflammation involves mediators released from tissue mast cells
C3a and C5a produced from the complement reaction can trigger
degranulation of mast cells by binding to the surface receptors (encounter
with PAMPs, damage to tissues and binding to IgE antibodies can also do
this)
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This acts on arachidonic acid on the
membrane to produce mediators, which belong to two different pathways
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These include:
• Histamine (a major component) - induces vasodilation, increases
capillary permeability, induces chemokinesis in polymorphs (increases
their random motions) and causes constriction of the bronchi
• Proteoglycan - probably controls the activity of proteases within the
granules prior to degranulation of the mast cells
• Neutral proteases - activate C3
• Glucosaminidase - can split terminal glucosamine from
oligosaccharides
• Powerful chemotactic factors for both eosinophils and neutrophils are
released, as is platelet-activating factor, which releases mediators,
which can increase capillary permeability
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Of the newly synthesized mediators produced by splitting arachidonic acid,
those belonging to the lipoxygenase pathway include leuoktrienes, which are
vasoactive and induce bronchi constriction
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Inflammation involves neutrophils entering the tissues
C3a and C5a fragments, sometimes referred to as the anaphylatoxins, trigger
the mast cells to release various vascular permeability mediators and
chemotactic factors
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The permeability mediators
increase blood flow by dilation of the arterioles and then of the capillary
endothelials, which allow exudation of plasma proteins and in particular,
provides a further source of complement components for the ongoing
reactions
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• This process involves the upregulation of adhesion molecules on the
blood vessels that are near the site of infection
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• Other similar interactions that occur following this initial interaction are
the recognition of upregulated ICAM-1 expression on the endothelium
by integrin molecules on the neutrophil, which subsequently squeezes
through the blood vessel endothelium In a process called diapedesis
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As long as inflammation is acute (short-term), it is simply the immune
response doing its job
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This inflammatory response usually subsides following the
clearance of the infection by the immune system
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