Complement System - Hunter Flashcards
complement system is involved in (innate/adaptive) immunity
innate and adaptive!
complement proteins are (constitutively/variably) expressed
constitutively
where are complement proteins expressed?
serum and on cell surfaces
the complement system is important in eliminated immune (blank)
complexes
genetic defects in the complement system increase the risk for infecions of (blank) bacteria and can precipitate immune (blanks)
pyogenic bacteria; immune complexes
the complement system shares features with what two other systems?
coagulation and kinin systems
complement functions by cleaving (blanks) into active enzymes
zymogens
one protease cleaves and activates many molecues of the next component, (blanking) the response to bugs
amplifying
what are the major functions of complement?
- opsonization
- inflammation and chemotaxis and activation of immune cells
- clearance of immune complexes
- form pores and causes lysis of pathogens
what does a capital letter indicate on a complement protein?
that it is a whole protein
what does a lower case letter indicate on a complement protein?
that it is a cleavage fragment
what are the two exceptions to the lower case letter rule?
C1r and C1s
what is the letter for the small fragment and what is it for the big fragment?
a for small, b for big; BUT C2b is often the small one
what does “i” before a name indicate?
that it is the inactive form, BUT CAN STILL BIND TO C RECEPTORS
what is the order of activation in the classical pathway?
C1 C4 C2 C3 C5-9
What complement protein is involved in binding to Ag:Ab complexes and pathogen surfaces?
C1q
What complement protein is involved in binding to CHO structures like mannos or GlcNAc on micbrobial surfaces?
- MBL
- Ficolins
- C1q
- properdin (factor P)
What complement protein is involved in activating enzymes?
- C1r
- C1s
- C2a
- Bb
- D
- MASP-2
What complement protein is involved in membrane binding proteins and opsonins?
- C4b
2. C3b
What complement protein is involved in peptide mediators of inflammation?
- C5a
- C3a
- C4a
What complement protein is involved in membrane attack complexes?
- C5a
2. C6-9
What complement proteins are complement receptors?
CR1-4 and CRIG
What are the complement regulatory proteins?
C1INH C4BP CR1 MCP DAF H I P CD59
(blank) is a pattern recognition receptor that can bind to repeating molecular motifs on pathogens like bacterial porins and LPS
C1q
(blank) also binds IgM, IgG, or CRP deposited on pathogen surfaces
C1q
What other two proteins is C1q associated with to form the complete C1 complex?
C1r and C1s
What structural protein makes a large tube at the top of the C1 complex?
collagen
After C1q binds to a pathogen, (blank) becomes an active serine protease
C1s
When activated, C1s will cleave (blank) into small and large fragments (blank-a/b)
C4 into C4a/b
If C4b is not immediately hydrolyzed, how does it bind to the pathogen surface?
covalently!
After cleaving C4, what next does C1q do?
It cleaves C2, which then associates with C4b
The C4b2a complex is the (blank) of the classical pathway
C3 convertase
What is the function of C3 convertase?
Cleaves C3 into C3b that binds covalently to the pathogen; C3a floats away
After C3 convertase activity, what is the new total complex called?
C4b2a3b
Thousands of (blank) C3b molecules are deposited on the pathogen surface when it is cleaved by C3 convertase
opsonic
C3b and C4b are highly reactive and (blanks) quickly if no bound to pathogen surfaces
hydrolyzes
what holds together the a and b portions of C3?
disulfide bonds
Does the a or b chain of C3 contain TED?
alpha
What is the type of bond within TED that allows C3b to bind to the pathogen surface?
thioester
Pathogens opsonized by C3b are endocytosed and killed by (blank) cells
phagocytic cells
what three phagocytic cells have receptors for C3 and its breakdown products?
Macrophages
neutrophils
dendritic cells
What is the MOST IMPORTANT INNATE defense against extracellular pathogens?
C3b-mediated opsonization and killing
What can the CR3 receptor bind besides C3?
iC3b
Complement activation promotes clearing of immune (blanks)
complexes
When clearing immune complexes, what happens when C1q binds to the complex?
C4b and C3b molecules are deposited onto the complex
To what receptor do immune complexes bind on RBCs?
CR1
Which complement proteins bind the CR1 receptor on RBCs?
C4b and C3b strangely enough
Where are immune complexes stripped from the RBCs and degraded?
spleen and liver
Deficiencies in which complements can lead to immune complex diseases such as SLE?
C1, C4, or C2
What receptor does the immune complex bind in the spleen to transfer it from the RBC to the phagocytic cell?
FcR
(blank) binds mannose and other common bacterial sugars
Mannose binding lectin
(blanks) L-, M-, and H- bind microbial oligosaccharides like GlcNac
Ficolins
MBL and ficolins are homologous to what complement protein?
C1q
MBL-associated serine proteases (MASP-1/2) are equal to what complement protein?
C1r/s
T/F: the MBL pathway forms the C3 convertase (C4b2a)
True
The Alternate pathway can (amplify/dampen) the classical and lectin pathways
amplify
(blank) protein deposited on the pathogen surface by the classical or lectin pathway can engage the alt. pathway
C3b
Factor (blank) binds to C3B, and is then cleaved to Bb by factor (blank)
Factor B, Factor D
What makes up the C3 convertase in the alternate pathway?
C3bBb
C3a is also known as the potent (blank)
anaphylatoxin
C3bBb is stabilized by (blank)
properdin aka factor P
What are the two C5 convertases?
C4b2a3b
C3b2Bb
What is the function of the C5 convertase?
cleave C5 into C5b and C5a
C5b triggers the assembly of (blank)
THE MEMBRANE ATTACK COMPLEX
C5a is also known as a potent (blank)
anaphylatoxin
Which anaphylatoxin has the highest specific biologic availability?
C5a
Which anaphylatoxin acts directly on neutrophils and monocytes to speed up phagocytosis of pathogens?
C5a
What are the functions of C3a?
activate mast cells, recruit Ab, complement, and phagocytic cells via chemotaxis and increase fluid in the tissues
What is the least active anaphylatoxin?
C4a
Overexpression of anaphylatoxin can cause (blank)
systemic anaphylaxis
which proteins are involved in forming the memrane attack complex?
C5b
C6-9
Describe the process of the MAC formation?
- C5b binds to C6 and C7
- C8 binds to C5b67 and INSERTS INTO THE MEMBRANE
- C9 binds and polymerizes to form a pore
What bugs are routinely killed used the MAC?
Neisseria miningitidis or gonorrheae
Deficiencies in the classical pathway lead to (blank)
immune-complex disease
Deficiencies in the MBL pathway leads to (blank)
childhood pyogenic bacterial infections
Deficiencies in the alternate pathway leads to (blank)
infections with pyogenic bacteria and Neisseria BUT NO IMMUNE COMPLEX
T/F: when complement is activated by pathogens, some components can become depleted
True
use CH50 to screen for the (bank or blank) pathways, AH50 to screen for the (blank) pathway
CH50 for the classical or terminal pathways; AH50 for the alternate pathway
A low level of both CH50 and AH50 indicates (blank)
a deficiency of a complement shared by both pathways, i.e. C3-9
low levels of C3 AND C4 suggest activation of which pathway?
classical
low levels of C3 and NORMAL C4 suggest activation of which pathway?
alternate
What is the most common complement deficiency?
MBL deficiency; can be up to 50% in certain populations
MBL deficiency is 2-3x more common in what disorder?
SLE
How do adults with MBL def. compensate?
upregulate production of opsonic Abs
A clinical pattern similar to agammaglobulinemia suggest what deficiency?
MBL
what is the second most common complement deficiency?
c2
what are the characteristics of C2 def?
recurrent MILD infections before 1 year of age
What is the molecular defect/result of c2 deficiency?
inability for C1q to form C3 convertase after C1q has bound an immune complex
Can C3b from lectin and alt. pathways be used in removing immune complexes?
NO
t/F: there are inherited deficiencies for all complement proteins
true
What is the molecular cause for inhertied C8 deficiency?
mutations in the B chain of C8
What infection characterizes a C8 deficiency?
RECURRENT NEISSRIA, especially neisseria meningitidis or
besides a C8 def, what else does recurrent Neisseeria suggest?
defect in the MAC (C5-9), or of factors D and P of the alt. pathway
can vaccination overcome complement deficiencies?
yes, thorugh production of protective Abs
What results in poorly controlled complement system?
tissue damage
depletion of critical complements
increased susceptibility to infections and immune complex disease
What is the most important complement inhibitor?
C1 inhibitor (C1INH)
Which complement inhibitor causes paroxysmal nocturnal hemoglobulinemia?
CD59 aka protectin
What causes hereditary angioedema (HAE)?
def. in C1INH
C1INH is a (blank) protease inhibitor that prevents C1s and C1r from the (blank) pathway from overactivation
serine
classical
What vasoactive mediator is overactivated in C1INH def?
bradykinin
In HAE, bradykinin causes swelling of what?
face, intestines, and airways
How do you diagnose C1INH def?
super low C1INH
NORMAL C3
Does HAE respond to epinephrine?
NO, that’s how you tell it apart from anaphylaxis!
What is the Tx for HAE?
human recombinant C1INH
