The complement system Flashcards
The (blank) is composed of more than 30 constitutively expressed proteins and their cleavage products that play and important role in the early stages of innate immunity.
complement system
What are the three pathways of complement activation that converge to make C3 convertases?
classical, lectin and alternative
What does C3 convertases generate?
opsonic C3b molecules on pathogen surfaces
Phagocytic cells recognize and destroy pathogens opsonized by (blank)
C3b
(blank) and (blank) bind to potentially harmful immune complexes and promote their blood clearance
C4b and C3b
(blank) and (blank) are anaphylatoxins that recruit and activate inflammatory cells
C5a and C3a
Formation of the (blank) promotoes assembly of the membrane attack complex (C6-C9) that kills certain bacteria
C5 convertase
complement is very potent so its activation is (blank)
tightly regulated
Deficiencies in complement results in what?
suscpetibility to microorganisms and immune complex diseases
a 67 year old women is hospitalized with a fever of unknown orgin. An elevate C reactive protein and erythrocyte sedimentation rate suggests an ongoing systemic inflammatory response. Which cytokine is especially important in these elevations?
IL 6 (remember that is the interluekin on the liver where c reactive protein will be found)
A 4 year old male presents with serious recurrent bacterial infections and has a big liver and spleen. an immunodeficiency disease is suspected, Everything is normal except a dihyrdorodamine test reveals that the patients neutrophils didnt reduce the dye. Why?
deficiency in NADPH oxidation
A 3 week old female with omphalitis has a diaper rash and bacterial pneumonia. Radiology is clear. Staph skin ulcer was looked at and there was very few neutrophils. What happened?
Deficiency in CD18
A 4 month old child has a staph skin infection without puss formation. has delayed umbilical cord separation and has some umbilicus. Has luekocytosis (too many whiteblood cells) but no b2 integrins. What immunological problem will this lead to?
Reduced diapedesis of neutrophils.
What is an important component of the immediate innate immune response to pathogens?
complement
How does the complement system work with the adaptive immunity?
works with antibodies in response to pathogens
The complement system is critical for innate and adaptive immunity. AND it plays an important role in eliminating (blank)
immune complexes
What does the complement system share with the coagulation and kinin systems?
cascades of proteolytic steps
zymogens (need to be cleaved to become activated)
amplification
What all can complements do besides kill?
they can cause inflammation, promote chemotaxis and activate immune cells
Some complement components can form (blank) in pathogen membranes that case lysis and death
pores (super rare)
What is the most important component of the complement?
its ability to opsonize
What do all three pathways of the complement system create?
C3 convertase
C3 convertase creates what 3 things?
C3b and C3a, C5a
What is the most important component of the complement system and why?
C3b because it is a potent opsonate
What does C3a and C5a promote?
inflammation and recruitment of phagoytic cells
What does C3B do?
removes immune complexes
What do terminal complement components do?
create pores in membrane
What is the order of the classical pathway?
C1, C4, C2, C3, C5-9
What does a capital letter designate?
What does a lower case letter designate?
complement
fragment
What is an A fragment, what is a B fragment?
A-> small fragment
B-> large fragment
What does a letter i indicate?
an enzymatically inactive form (can still bind to receptors)
In the classical pathway how are you going to detect pathogens?
by forming the the C1qrs complex
(blank) is a pattern recognition receptor that can bind to certain repeating molecular motifs on pathogens (e.g. bacterial porins and LPS)
C1q
What besides molecular motifs on pathogens can C1q bind?
IgM, IgG, or C-reactive protein deposited on pathogen surfaces
From the C1qrs complex how do you generate C3 convertase in the classical pathway?
C1q binds to pathogen surface, C1s beomes an active serine protease, this cleave C4 into C4a and C4b. C4b binds covalently to pathogen surface (or is hydrolysed), C1q then cleaves C2 and the large fragment associates w/ C4b. C4a floats away. This creates C4b2a which is the C3 convertase of the classical pathway.
What is cool about C3b and C4b?
if they are not instanteously bound to the microbe surface, water will come and hydrolyze it into an inactive substnace.
since ic3b is in active what can it do?
it works as a potent opsonate
Pathogens opsonized by (blank) are endocytosed and killed by phagocytic cells.
C3b
What three things have various receptors (CR3) for C3 and its breakdown products (iC3b)
macrophages, neutrophils and dendritic cells
What is the most important innat defense against extracellular pathogens
C3b mediated opsonization
What form complexes during infections and in some autoimmune diseases?
antigen/antibody
How do you get rid of immune complexes? (give detailed answer)
C1q binding results in deposition of C4b and C3b onto immune complex, C4b and C3b allows the immune complex to bind to CR1 (complement receptor 1) on RBCs. RBCs go through spleen and liver and immune complexes are stripped from the RBCs here and are degraded
Deficiencies in which three complexes can result in immune complex disease? WHat is an example of a disease such as this?
C1, C4, C2
Lupus
What is the lectin pathway?
it has mannose binding lectin (MBL) and Ficolins (similiar to the C1q in the classical pathway) and recognize certain patterns on pathogens. There are MASP 1/2 (like C1r/s) that act as proteases to create C3 convertase
THe (blank) pathway can amplify the classical and lectin pathway
alternative pathway
How can you engage the alternative pathway?
C3b deposited on a pathogen surface by the classical or lectin pathway
Explain the alternative pathway
C3b deposits and activates the pathway
Factor B binds to C3b
Factor D cleaves this into Bb
You now made C3bBb which is the new C3 convertase.
C3a which is left over is a potent anaphylatoxin and the C3bBb is stabilized by properidin
How do you stabilize C3bBb of the alternative pathway?
with properdin (factor P)
What happens to the small C3a fragment that isnt used to make the C3bBb in the alternative pathway?
it sticks around as a potent anaphylatoxin
What does C5 convertase do?
cleaves C5 into a large fragment called C5b and a small component called C5a
What are the two ways you can get C5 convertase?
classic pathway and lectin pathway (C4b2a3b) and alternative pathway (C3b2Bb)
What does C5b do?
triggers assembly of the membrane attack complex
What is C5a?
it is a potent anaphylatoxin
(blank) has the highest specific biological activity and isable to act directly on neutrophils and monocytes to speed up the phagocytosis of pathogens
C5a
(blank) works with C5a to activate mast cells, recruit antibody, complement, and phagocytic cells (chemotaxis), and increase fluid in the tissue (edema)
C3a
What is the least active anaphylatoxin?
C4a
Overexpression of (blank) can cause the medically important systemic anaphylaxis,
anaphylatoxins
What are anaphylatoxins?
they are complement fragments that are chemotactic agents and promotors of inflammation.
If (blank) binds to its receptors on a phagocytic cell, this phagocytic cell will increase phagocytosis 10 fold.
C5a
HOw do you change a C3 converatase into a C5 convertase?
by adding a C3b molecule to it
What does C3a and C5a do?
peptide mediators of inflammation, phagocute recruitment
What does C3b do?
binds to complement receptors on phagocytes-> opsonization of pathogens, removal of immune complexes
What do terminal complement components do;
C5b, C6, C7, C8, C9
membrane-attack complex, lysis of certain pathogen and cells
Explain the membrane attack complex
C5b will call over C6 and C7 and form a complex. C7 will burrow the complex into the lipid bilayer of the cell. Then C8 will be called over to do the heavy work and will really borrow the complex in the bilayer. Then a bunch of C9 will polymerize and form a pore with the complex and those destroy the cell
the MAC (membrane attack complex) is awesome but only can really kill which 2 microbes?
Neisseria meningitidis
Neisseria gonorrheae
Most common deficiency is (blank)
mannose binding lectin deficiency
If you have low levels of complement does that mean you have a complement deficiency?
no, it could mean that you had a large infection and your using up your complement so your immune system is functioning fine
What are three deficiencies you can get in the classical pathway and what will this lead to?
C1
C2
C4
leads to immune complex disease
What are 5 deficiencies you can get in the MBL pathway (mannose binding lectin)?
MBL MASP1 MASP2 C2 C4 deficiency of MBL leads to bacterial infections mainly in children
What are 2 deficiencies you can get in the alternative pathway?
Factor D
Factor P
deficiency leads to infection with pyogenic bacteria and neisseria but no immune complex problems
What is the most common complement deficiency
MBL
Why does a deficiency in the classical pathway make us have immune complex disease?
because C4 tags immune complexes
What happens if you have a deficiency in C3?
infection w/ pyogenic bacteria, Neisseria, immune complex disease and often death
What will a deficiency in the membrane attack complex cause?
if C5-C9 are deficient you can be susceptible to Neisseria only (gonnorhea or menigitidis)
How can you tell if you have a reduced amount of complement is due to a genetic issue or just depletion from an infection?
if its infection, then all of your complements should be reduced rather than only one specific complement being reduced
When complement is activated by pathogens, multiple components are temporarily (blank)
depleted
When you work up complement deficiencies, what do you use to make a diagnosis>
the membrane attack complex
How does the membrane attack complex tell you whether or not you have a complement deficiency?
You use either a CH50 assay (to assess classical pathway or terminal pathway) or the AH50 assay to assess the alternative pathway and tag RBCs with antibodies and add serum from patient. If there is hemolytic complement actiivity it will bind to the antibodies and cause lysis of the RBC. SOOOO if there is no lysis occuring then there is a deficiency.
What does a low level of boh CH50 and AH50 suggest?
there is deficiency of one of the components shared by both pathways which could be C3-C9
What does a low AH50 with normal CH50 suggest?
a deficiency in factor B, Factor D, or properdin
(blank) are used to demonstrate specific complement protein deficiencies
immunoassays
What does Low C3 and C4 levels indicate?
activation of the classical pathway
What does low C3 ad normal C4 levels suggest?
activation of the alternate pathway
What happens if you have a deficiency in MBL?
pyogenic bacterial infection in children, common in lupus, compensation w/ opsonic antibodies
What is the second most common complement deficiency?
C2 (problems with classical pathway)
What happens if you have a C2 deficiency?
prevents formation of C3 convertase and thus lack of removal of immune complexes.
(blank) is a three chain molecule, and deficiency in Caucasians is caused by mutations in the beta chain.
C8
Recurrent neisserial infections strongly suggest a defect in a component of the (blank), or of factors (blank and blank) of the alternative complement pathway.
membrane attack complex (C5-C9)
D and P
Is the complement system potent?
yes, very potent and must be tightly controlled to prevent tissue damage
A variety of (blank) have been identified that control all three complement pathways
complement regulatory proteins
Deficiency in reglatory proteins can lead to what?
tissue damage
depletion of complement components
increased susceptibility to infections and immune complexes
What disease can you get with deficiency of CD59?
paroxysmal nocturnal hemoglobinuria
What are these: C1 inhibitor (C1INH) C4-binding protein (C4BP) Complement receptor 1 (CR1) Factor H (H) Factor I (I) Decay-accelerating factor (DAF) Membrane cofactor Protein (MCP) CD59 (protectin)
complement regulatory proteins
(blank) is a protease inhibitor belonging to the serpin superfamily. Its main function is the inhibition of the complement system to prevent spontaneous activation
C1-inhibitor
What is this:
diminished C4 levels but C3 levels are normal. swelling of lips and hands. Deficiency of C1 inhibitor.
hereditary angioedema
Hereditary angioedema (HAE) is caused by a deficiency in the (blank)
complement regulatory protein C1 inhibitor (C1INH)
C1INH is a serine protease inhibitor that prevents (blank) overactivation of the classical complement pathway
C1r and C1s
Why do you get the clinical manifestations (swelling) that you see in HAE?
because C1 INH usually inhibits a serine protease that (when not inhibited) increases vasodilation through bradykinin
Where does bradykinin cause recurrent swelling?
skin, ntestine, airways
How can you make the diagnosis of HAE (hereditary angioedema)?
very low C1INH and low C4 levels
C3 levels normal
HOw do you treat C1INH?
human recom C1INH
HAE resembles anaphylaxis but epinephrine wont fix this problem
What is this:
diminished C4 levels but C3 levels are normal. swelling of lips and hands. Deficiency of C1 inhibitor.
hereditary angioedema
Hereditary angioedema (HAE) is caused by a deficiency in the (blank)
complement regulatory protein C1 inhibitor (C1INH)
C1INH is a serine protease inhibitor that prevents (blank) overactivation of the classical complement pathway
C1r and C1s
Why do you get the clinical manifestations (swelling) that you see in HAE?
because C1 INH usually inhibits a serine protease that (when not inhibited) increases vasodilation through bradykinin
Where does bradykinin cause recurrent swelling?
skin, ntestine, airways
How can you make the diagnosis of HAE (hereditary angioedema)?
very low C1INH and low C4 levels
C3 levels normal
HOw do you treat C1INH?
human recom C1INH
HAE resembles anaphylaxis but epinephrine wont fix this problem
