Hunter: Complement Flashcards
Group of > 30 constitutively expressed serum and cell surface proteins
complement
Is complement an innate or adaptive response to pathogens?
innate *works with antibodies in the humoral immune response to pathogens
The complement system plays an important part in eliminating (blank)
immune complexes
Genetic defects in various complement components can increase the risk for infections with pathogens, especially (blank), and can precipitate (blank)
pyogenic bacteria; immune complex diseases
The complement system is similar to which two cascade-like systems?
coagulation and kinin systems
In the complement system response, (blank) are cleaved which causes molecules downstream in the pathway to be cleaved as well. This (blank) the response to microbes.
zymogens; AMPLIFIES
What are the 4 major functions of the complement system?
- complement molecules bind directly to pathogens and coat them for phagocytosis
- complement molecules cause inflammation and promote chemotaxis and activation of immune cells
- some complement molecules help clear immune complexes (antigen-antibody complexes)
- some complement molecules form pores in pathogen membranes and directly cause lysis and death
What are the 3 components of the complement system?
- classical pathway
- lectin pathway
- alternative pathway
What do all 3 pathways ultimately lead to?
activation of C3 convertase and the formation of C3b which binds to complement receptors for destruction of pathogens and removal of immune complexes
What is odd about the order of complement protein activation?
C1, C4, C2, C3, C5-9
Which protein in the complement system is typically the “small” fragment, and which is the “large” fragment?
small fragment is “a,” while the large fragment is “b” *except in the case of C2, in which the small fragment is C3b
This is a pattern recognition receptor involved in the classical complement pathway that can bind to certain repeat molecular motifs on pathogens (ex: bacterial porins and LPS, as well as IgM, IgG)
C1q
Explain the generation of the C3 convertase by the classical pathway.
- C1q binds to the pathogen surface
C1s becomes an active serine protease and cleaves C4 into C4a and C4b - C4b binds to the pathogen surface or is quickly hydrolysed, while the small C4a floats away
- C1q then cleaves C2 into a small and large fragment, the large fragment (C2a) associates with C4b, the small C2b fragment floats away
- C4b2a complex is the C3 convertase and cleaves C3 into C3b which binds to the pathogen and C3a which floats away
- Lots of C3b molecules bind to the pathogen
What happens to C3b and C4b to ensure that they do not become highly reactive?
they are hydrolyzed rapidly if they don’t bind to pathogen surfaces
What happens once a pathogen is opsonized by C3b?
it is endocytosed and killed by phagocytic cells
What is the most important defense against extracellular pathogens?
the C3b mediated opsonization and killing of pathogens
Complement activation promotes clearance of (blank)
immune complexes
Antigen/antibody complexes form during infections and in some autoimmune diseases. (blank) binds and results in the deposition of C4b and C3b on the complexes. Immune complexes bind to complement receptor 1 on (blank) via C4b and C3b. When the RBCs pass through the spleen and liver, they are stripped and degraded.
C1q; RBCs
Antigen/antibody complexes form during infections and in some autoimmune diseases. C1q binds and results in the deposition of (blank) and (blank) on the complexes. Immune complexes bind to (blank) on RBCs via C4b and C3b. When the RBCs pass through the spleen and liver, they are stripped and degraded.
C4b; C3b; complement receptor 1 (CR1)
Deficiencies in which complement proteins result in immune complex disease?
C1, C4, C2
The lectin pathway is similiar in function to the classical pathway. What is the equivalent to C1q in the lectin pathway? What is the equivalent to C1r/s in the lectin pathway?
mannose bindng lectin and ficolins; MASP-1/2
What is the convertase that forms in the mannose binding lectin pathway?
C3 convertase *just like the classical pathway
This pathway can amplify both the classical and lectin pathways
alternative pathway
What engages the alternative pathway?
C3b deposition on the pathogen surface via the classical or lectin pathway
What two molecules are important in the alternative pathway? Also, what is the convertase called?
factor B *binds to C3b on pathogen surface then is cleaved to by factor D into Bb (which binds to pathogen) and Ba which floats away
the convertase is C3bBb
What does C3bBb do?
makes 1000+ opsonic C3 molecules which stick to the pathogen surface
Why is C3a important?
it is a potent anaphylatoxin
What stabilizes the C3bBb complex?
properdin (factor P)
When C5 convertases cleave C5 into a large fragment (C5b) and a small fragment (C5a), what does C5b do? What does C5a do?
C5b triggers assembly of the membrane attack complex
C5a is a potent anaphylatoxin
This anaphylatoxin has the highest specific biological activity and is able to act directly on neutrophils and monocytes to speed up the phagocytosis of pathogens
C5a
This anaphylatoxin works with C5a to activate mast cells, recruit antibody, complement, and phagocytic cells, and increases fluid in the tissue
C3a
This is the least active anaphylatoxin
C4a
What can overexpression of anaphylatoxins cause?
systemic anaphylaxis
These are peptide mediators of inflammation, they recruit phagocytes
C3a, C5a
This binds to complement receptors on phagocytes and causes opsonization of pathogens, and removal of immune complexes
C3b
What do terminal complement components cause?
formation of membrane-attack complex and lysis of certain pathogens and cells
C5b, C6, C7, 8, 9, 10-16 are all involved in formation of the membrane attack complex. What does this cause? What are the only two microorganisms that are routinely killed through this mechanism?
causes a pore to be formed in the microorganism, which disrupts the osmotic integrity and causes cell death; Neisseria meningitidis and Neisseria gonorrheae
Deficiencies in this pathway leads to immune-complex disease
classical pathway
Deficiencies in this pathway leads to bacterial infections, mainly in childhood
MBL pathway (mannose binding lectin)
Deficiencies in this pathway lead to infection with pyogenic bacteria and Neisseria spp. but no immune complex disease
alternative pathway
Deficiencies in this molecule lead to infection with pyogenic bacteria and Neisseria spp. and sometimes immune-complex disease.
C3
Deficiencies in these proteins lead to infection with Neisseria spp. only.
C5-C9
If complement is depleted in the bloodstream, there are two possible explanations. What are they?
- deficiency *usu a single component
2. temporary depletion if complement is active *usu multiple component depletion
What is the best screening test for deficiencies in the classical or terminal pathways?
measuring CH50
What is the best screening test for deficiencies in the alternative pathway?
measuring AH50
What does a low level of CH50 AND AH50 suggest?
a deficiency in one of the components shared by both pathways
What does a low AH50, but normal CH50 suggest?
deficiency in factor B, D, or properdin
What is used to demonstrate SPECIFIC complement protein deficiencies?
immunoassays
What do low C3 and C4 levels suggest? What does low C3 but normal C4 levels suggest?
activation of classical pathway; activation of the alternative pathway
This is the most common complement deficiency, and is found in up to 50% of certain populations
MBL deficiency
MLB deficiency increases the risk of (blank), esp in children
pyogenic bacterial infections
MBL deficiency is 2-3x more common in (blank) patients
Lupus
MBL deficiency presents with a clinical pattern similar to (blank)
agammaglobulnemia
This is the second most common complement deficiency, and is usu characterized by recurrent but mild infections in children >1 yo
C2 deficiency
What does C2 deficiency prevent?
the formation of C3 convertase after C1q binds to immune complexes
What do recurrent neisserial infections suggest a defect in?
a component of the membrane attack complex (C5-C9) OR
factor D and P of the alternative pathway
What is the first test performed in a suspected complement deficiency?
CH50 *measures total serum hemolytic complement
The complement system must be tightly regulated! What can deficiencies in regulation lead to?
tissue damage or depletion of critical complement components and increased susceptibility to infections and immune complex disease
Name one important complement system regulator protein
C1 inhibitor
This is caused by a deficiency in the complement regulatory protein C1 inhibitor (C1INH)
hereditary angioedema
What does C1 inhibitor do?
it prevents C1r/C1s overactivation of the classical complement pathway
What actually causes the clinical manifestations of hereditary angioedema (HAE)?
C1 inhibitor fails to inhibit a protease that generates bradykinin, so you get lots of bradykinin which causes recurrent swelling of skin, intestines, airway
How do you diagnose hereditary angioedema?
low C1 inhibitor protein
low C4 levels
normal C3 levels
*HAE does not respond to epinephrine like anaphylaxis
