module 08 section 05 (membrane attack complex) Flashcards
what is the purpose of the membrane attack complex (MAC)?
form a pore in the target cell membrane leading to its destruction
what is step 1 of the complement cascade after C5 convertase formation?
- cell-associated C5 convertase cleaves C5 into C5a and C5b
- C5b remains bound to C5 convertase
what is step 2 of the complement cascade after C5 convertase formation?
- C6 and C7 sequentially bind to C5b
- C5bC6C7 complex becomes directly inserted into the lipid bilayer of the target cell membrane
what is step 3 of the complement cascade after C5 convertase formation?
after insertion of the C5bC6C7 complex into the lipid bilayer, C8 is bound to C7 to stabilize the complex
what is step 4 of the complement cascade after C5 convertase formation?
up to 15 C9 molecules polymerize around the C5bC6C7C8 complex to form the membrane attack complex (MAC)
each pore made by the MAC is made of what protein?
C9
what does a pore in the membrane result in?
spilling of the inracellular components, initiating cell death
can complement activation result in normal cell damage? why or why not?
- yes - constantly occuring at a low level, so can cause damage if not regulated
- also fragment complement proteins can diffuse to adjacent cells and injure them
what is complement activation inhibited by?
regulatory proteins present on normal host cells but not on microbes
what are C1r and C1 complexess inactivated by? how?
- plasma protein called C1 inhibitor (C1 INH)
- normally C1q binds to antigen-complexed antibodies resulting in activation of the C1 complex, C1 INH prevents C1 complex from becoming proteolytically active
what is the formation of C3 convertase inhibited by (in all pathways)?
- DAF (decay-accelerating factor)
- MCP (membrane cofactor protein)
- CR1 (type-1 complement receptor
what is C3b inactivated by? how?
MCP and CR1 act as cofactors for Factor I which mediates the proteolytic cleavage of C3b, producing iC3b and a fragment C3f
how is the formation of MAC inhibited?
by membrane protein CD59 and plasma protein S
what does the timeline for complement pathway activation depend on?
the type of activator component
explain the lectin pathway timeline
lectin pathways involved in the first line of defence as its activated by pathogen surfaces
explain the alternative pathway timeline
involved in the first line of defense (after lectin tho) as its activated by pathogen surfaces
explain the classical pathway timeline
involved later, after antibodies have been produced
what pathway(s) are C5-C9 involved in
all three (classical, lectin and alternative)
what pathway(s) is MBL involved in?
lectin only
what pathway(s) is factor B involved in?
alternative only
what pathway(s) is C4 involved in?
classical and lectin
what pathway(s) is C3 involved in?
all three (lectin, classical and alterantive)
what pathway(s) is C1 involved in?
classical only
what pathway(s) is MASP-1/2 involved in?
lectin only
what pathway(s) is factor D involved in?
alternative only
recall - each of the fragments produced through the complement activation act as:
mediators of inflammation and phagocytic recruitment
what is an anaphylatoxin?
a substance produced by complement activation that causes the release of histamine and other mediators, from basophils and mast cells, producing signs and symptoms of anaphylaxis
explain anaphylatoxin in terms of the fragments produced by complement activation
each of the fragments has a unique anaphylatoxin potency
what is the most anaphylatoxin potnent complement protein?
C5a
what does anaphylatoxin potency promote?
mast cell degranulation and contraction of the vasculature
what are the anaphylatoxin complement proteins?
C3a, C4a, and C5a (because they can trigger degranulation of mast cells)
how does degranulation of mast cells cause anaphylaxis?
mast cells secrete mediators which enter the capillaries, cause contraction of the vessel and elict an anaphylaxis reaction
what are the systemic anaphylaxis effects on the GI tract?
increased fluid secretion and peristalsis
what are the systemic anaphylaxis effects on the airways?
constriction and increased mucus
what are the systemic anaphylaxis effects on the bvs?
increased flow and permeability
explain how complement pathways result in phagocytosis
- during opsonization, C3b (opsonin) binds to pathogens, and is then recognized by the complement receptor on phagocytic cells
- this leads to phagocytosis od the pathogen
- C3b can also bind immune complexes to modify their solubility for removal from circulation
explain the role of complememt proteins in MAC
- MAC’s composed of 6 unique glycoprotein macromolecules
- C3b binds to the pathogen to activate the late components of the complement system, resulting in the formation of MAC
- MAC results in lysis of pathogens and cells by forming a pore in the target cell membrane
have complement deficiencies been discovered for all complement proteins?
almost all the ones we covered in three early/late systems yes
what can complement deficiencies be caused by?
- partial or complete loss of protein synthesis in pyogenic infections caused by streptococcus pneumoniae
- or due to the formation of an incomplete or abnormal protein
less then 10% of complement disorders are diagnosed, why?
redundancy in the immune system
list complement diseases and their associated outcomes (4)
- C1, C2, C4 deficiency - immune complex disease
- MAC deficiency - increased risk of infection
- C3, factor D, factor I deficiency - pyogenic infections
- MBL deficiency - susceptibility to recurrent infections and decreased lung function is cystic fibrosis patients
are homozygous deficiencies rare or more common?
rare
are heterozygous deficiencies more easy or harder to detect?
not easily detected
a genetic deficiency of C1-INH results in an overproduction of C2b and is the cause of:
hereditary angioedema
recap: the biological functions of the complement system include: (5)
- opsonization
- activation of inflammatory cells by anaphylaxis
- cytolysis mediated by MAC formation
- solubilization and clearance of immune complexes
- enhancement of humoral immune responses
