The Complement Flashcards
What is a complement?
Proteins circulating in the blood and some found in tissue that bind to pathogens and mainly bacteria leading to its death.
Most abundant complement is—-. It is synthesized in the —-. All complement activation systems involve —-.
C3, liver, C3–>C3b transformation
C3–> C3b is done through 3 different pathways. What are they?
After transformation of C3 into C3b what happens?
1- Alternative pathway, lectin pathway, and classical pathway
2- Attack membrane complex formed to kill the bacteria
Alternative Pathway Characteristics.
- Spontaneous conversion of C3 into C3b
- C3b is not stable so it gets immediately degraded unless stabilized by binding to the amino group or hydroxyl group found on bacterial lipopolysaccahrides, fungal cell walls, and viral envelopes.
What is special about C3b ?
It forms a positive feedback loop that transforms more C3 into itself.
Once C3b is stabilized it binds to factor B which gets cleaved by Factor D to Ba and Bb. Bb remains bound to C3b forming CbBb which is C3 convertase transforming more C3 into active C3b.
How are human cells protected from degradation by C3b binding?
Due to the presence of the H Factor.
Where is the H factor synthesized and how does it work?
In the liver. It is a plasma protein that will be expressed on the surface of cells blocking the activity of C3b by cleaving or inactivating it or by increasing decay of convertase CbBb.
What cells used the Human H factor to their own benefit? How? Name some.
The cancer cells and some bacterial cells found ways to extract the H factor from the plasma and use it to block the activity of the alternative pathway against them.
Some examples are:
H. influenza, some streptococci, N. Meningitidis, and pseudomonas.
Explain the Lectin Pathway.
MBL (mannose-binding lectin) produced by the liver circulates with MASPs 1 and 2 (mannose associated serine proteases) which bind to mannose on membranes (mostly microbes). Ficolin is similar to MBL.
The complex cleaves C2 into C2b and C4 into C4b. Then C2b and C4b form a complex C2b4b which is a C3 convertase. C3 into C3b leads to formation of MAC and destruction of bacteria.
Explain the Classical Pathway.
Some Antigen-antibody complexes bind to C1 which cleaves C2 into C2b and C4 into C4b. C2a4b complex forms and it’s a C3 convertase so it transforms C3 into C3b.
What is C1 complement made up of? How is it activated?
It is a large complex made up of C1q, C1s, C1r, and C1- inhibitor. Once two Fc portions very close to each other on antibody bind to C1, the C1- inhibitor falls off and C1s and r will be activated forming C2b4b.
What is C1 complement made up of? How is it activated?
It is a large complex made up of C1q, C1s, C1r, and C1- inhibitor. Once two Fc portions very close to each other on antibody bind to C1, the C1- inhibitor falls off, C1q changes conformation and allows C1r to cleave C1s. C1s be activated to cleave C2 and C4.
What immunoglobulin is best for C1 activation? What is okay?
IgG is best because it is a pentamer so there are a lot of Fc portions close to each other that it’s easy to bind to C1.
IgM is okay but it will require 2 IgMs together to form Fc portions that bind to C1.
IgA in aggregated form also.
What is CRP? Why is it called acute phase reactant? Where is it produced? How is its production induced? How does it work?
It is a C reactive protein.
Because its levels rise at the beginning of an inflammation.
Produced in the liver in response to IL-6 secreted by the macrophages.
It binds to bacterial polysaccharides. It binds to C1 activating the early Classical pathway. Then C3 and C4 are cleaved and C3b is generated.
However, it has no effect on the late pathway. No consumption on C5 and C9.
From where does C3a come and what is its function? Are there other functions for the C3b than the MAC production?
C3a is a byproduct of the cleavage of the C3 into C3b. It is also called an anaphylatoxin which induces histamine release from mast cells and increases vascular permeability.
Yes, C3b acts as an opsonin which attracts macrophages to the site of infection.
What is MAC formed from? What is another name they have? How does it happen?
Formed from C5–> C9, called terminal or late complement proteins.
C3b cleaves C5 into C5a and C5b. Then, C5b will bind to C6,7,8,9 and they will form the active MAC Complex that will cause holes in the bacterial wall —> swell & burst
What is the function of C5a?
It is an anaphylatoxin like C3a & acts as a neutrophil chemotaxis agent that draws neutrophils into the site of action.
Two ways our cells protect against complements (other than the H factor, C1 inhibitor, and MRP &CR1)? What does a deficiency in these cause ?
There are membrane proteins that protect our cells like DAF (CD55) and MAC inhibitory protein (CD59). DAF dissociates C2a from C4b and Bb from C3b to prevent C3 convertase activity. CD59 inhibits C9 assembly and S protein binds to the C5-8 complex to prevent the insertion into lipid bilayer.
Deficiency causes hemolysis in RBCs.
Talk about PNH: Causes, Effects, Why fatal, Onset?
PNH is paroxysmal nocturnal hemoglobinuria. It is nocturnal because the patient has episodes of hemolysis at night. They wake up with fatigue and dyspnea due to the anemia. They have abdominal pain, dysphagia, and erectile dysfunction due to increased smooth muscle tension
(when NO decreases due to binding to free hemoglobin). They also have dark colored urine due to hemoglobinuria which could lead to renal failure. And they have thrombosis due to free hemoglobin in the blood which happens in weird locations such as mesenteric, portal, and cerebral veins.
What are the effects of Inherited C3 deficiency?
1- Recurrent encapsulated bacterial infections such as H. pneumonia and pneumococcal infections which begin in infancy.
2- Autoimmunity despite the loss of part of the immune system.
Because the IC complexes can’t be cleared by binding to C3 or C4b that will be recognized by the macrophages.
Glomerulonephritis from IC deposition in kidneys.
3- Type III hypersensitivity syndrome (always involve IC complex deposition)
C5-C9 deficiency (terminal complement pathway deficiency):Causes, Effects, Why fatal, Onset?
- Impaired infancy defense against encapsulated bugs.
- Not as severe as C3 deficiency because C3a (anaphylatoxin) and C3b (have opsonin effect) are still present.
- Neisseria infections are most common and lead to meningitis
Hereditary Angioedema: Causes, Effects, Why fatal, Onset, Diagnosis, Treatment ?
- Deficiency in the C1 inhibitory protein which inhibits factor XII.
- Doesn’t affect mainly the complement system because C1i has many other functions such as the breakdown of bradykinin which is a vasodilator and causes inflammation. This accumulation of bradykinin causes swelling and edema without urticaria or hives.
- Starts in childhood.
- Swelling could be to skin, GI tract, tongue, airways. Fatal when upper airways swells and breathing is interrupted.
- Diagnosed by low C4 and C2 levels.
- Treated by C1 inhibitor concentrate (like Danazol adrenergic steroid) and not antihistamines used for allergies.
Can people with Hereditary Angioedema be given ACE inhibitors? What are ace inhibitors given for?
NEVER
ACE inhibitors inhibit the change of Angiotensin I to II. It is used to treat hypertensive individuals. It also prevents the breakdown of bradykinin into an active metabolite. This leads to cough and angioedema in normal patients.
In Patients with HA, it could cause an episode of acute swelling that may lead to death.
What is the C3 nephritic factor? How does it affect the complement system?
It is an autoantibody found in 80% of patients with MPGN II.
It causes overactivity of the classical pathway by stabilizing the C3 convertase.
Characterized by hypocomplementemia and inflammation.
