Ch. 7. The complement system

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Ch. 7. The complement system Important effector
in both innate and acquired immunity Over 30
circulating and membrane-bound proteins
(synthesized in liver and other cells- immune
and epithelial) Acts as a cascade (one event
must occur before another takes place)
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Cascade Many of the components are enzymes
that become activated when cleaved into two
peptides One peptide binds to the immune complex
and becomes a functional part of it The other
peptide diffuses away and can become an
inflammatory mediator (binds to a receptor)
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Four important functions Lysis
Opsonization Activation of inflammatory
response Clearance of immune complexes
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p. 169
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Three pathways classical, alternative,
lectin Final steps identical in all 3
pathways Classical - Initiated by formation of
an Ag-Ab complex Alternative -
Antibody-independent Part of innate
immunity Initiated by foreign cell
surfaces Lectin - Initiated by host proteins
binding microbial surfaces
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p. 170
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p. 171
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Classical pathway Classical was discovered first
(but actually evolved later) Initiated by
-formation of a soluble Ag-Ab complex -binding
of antibody to a target such as a bacterial
cell Only certain antibodies can initiate this
(IgM, some classes of IgG)
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p. 172
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p. 175
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Alternative pathway Four components C3, factor
B, factor D, properdin Triggering substances may
be pathogens or nonpathogens (see p. 173, Table
7-1) bacterial cell wall components,
fungi, viruses, parasites immune complexes,
RBCs, polymers
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p. 173
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p. 174
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Lectin pathway Lectin is a protein that binds to
carbohydrate MBL (mannose-binding lectin) binds
to mannose on many bacterial cells MBL is
produced by liver in acute-phase inflammatory
reactions Once MBL binds to target cell, 2
serine proteases (MASP-1, MASP-2) bind Acts
like C1
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p. 176
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Regulation of complement system Because it is
nonspecific, several regulatory mechanisms are
involved (otherwise there would be a lot of
collateral damage) Many components are very
labile Many regulatory proteins block activity
through binding to target (p. 177)
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p. 178
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p. 178
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Biological effects of complement
activation Complement fragments must bind to
complement receptors expressed by various
cells
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p. 180
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p. 181
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Amplifies humoral response Destroys invading
bacteria and viruses (lysis by
MAC) Inflammatory response Opsonization of
antigen (enhances phagocytosis) Virus
neutralization Clearance of immune complexes
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Some bacteria can resist lysis Gram-positive
bacteria Some microbes produce inactivating
enzymes Nucleated cells are harder to lyse Not
particularly effective against tumor cells (they
can endocytose MAC and repair damage)
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p. 182
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Inflammation many of the released fragments
help develop an inflammatory response C3a, C4a,
C5a- anaphylotoxins bind to receptors on mast
cells and basophils degranulation (smooth
muscle contraction capillary dilation fluid
influx) also play a role in blood cell
chemotaxis
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p. 184
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Viral neutralization Some viruses activate
alternative or lectin pathway Antibody-mediated
(classical) pathway is more common Causes
aggregation of viruses cant infect host cells
more vulnerable to phagocytes Enveloped viruses
can be lysed
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p. 186
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Consequences of complement deficiency Early
components of classical pathway (C1, C4, C2)-
immune complex disease cant generate C3b, which
is needed for solubilization Recurrent Staph
and Strep infections (cant lyse bacteria but
seem to control infections) Early components of
alternative pathway- not as serious tendency to
infections by Neisseria
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C3 deficiencies (cant activate C5 and form
MAC) Recurrent severe bacterial infections MAC
deficiencies- recurrent Neisseria infections no
immune complex disease Regulatory protein
deficiencies edema RBC lysis
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Summary The complement system comprises a
group of serum proteins which, when
activated, plays an important role in
antigen clearance. The classical, alternative
and lectin pathways have been described. Elabora
te regulatory mechanisms are required to prevent
damage to normal cells.