Complement system Flashcards
What is complement?
How many do we have?
Where are they present?
It was first named by Paul Ehrlich to describe the activity in serum, which could “complement” the ability of specific antibody to cause lysis of bacteria.
Complement historically refers to fresh serum capable of lysing antibody-coated cells.
Complement system is composed of more than 25 different proteins produced by hepatocytes, macrophages and intestinal epithelial cells
During activation, some complement components are split into two parts:
What are they and what are their roles?
What is the exception to their genereal function/.
The larger part of the molecule called “b” while the smaller fragment called “a” may diffuse away.
In most cases it is the “b” fragment that binds to the surface of the cell to be lysed
the fragments of C2 are an exception to this rule: C2a binds to the membrane while C2b is freed into serum or tissue spaces.
Inactivated fragments are indicated by a small “i“.
What does the activation of complement result in?
Activation of complement results in the production of several biologically active molecules, which contribute to nonspecific immunity and inflammation.
Complement is not antigen-specific but it is activated immediately in the presence of pathogen
Since antibody also activates some complement proteins, complement activation is also part of humoral immunity.
What are the PATHWAYS OF COMPLEMENT ACTIVATION?
What do they result in?
The complement activation can be divided into three pathways:
- classical, lectin (mannose binding protein) and alternative,
- all of which result in the activation of C5 and lead to the formation of the membrane attack complex (MAC).
*The three pathways differ in the way C5 is broken down to but after that the formation of MAC is essentially the same.
What is the classical pathway?
The classical pathway is triggered primarily by immune complexes
Generation of C5 convertase marks the end of the classical pathway.
C5b initiates the formation of membrane attack complex
What is the alternative pathway?
Alternate pathway is so called because it bypasses the requirement of antigen-antibody complex, C1, C2 and C4 components.
It begins with the spontaneous activation of C3 in serum and requires Factors B and D and Mg2+,
Stabilized C3 convertase cleaves more C3 and produces C3bBb3b complex (C5 convertase), which cleaves C5 into C5a and C5b.
C5b initiates the formation of membrane attack complex.
What is the lectin pathway?
C4 activation can be achieved without antibody and C1 participation via the lectin pathway.
Three proteins initiate this pathway namely a mannan-binding lectin/protein (MBL), and two mannan-binding lectin-associated serine proteases (MASP and MASP2),
All present in normal serum.
MBL binds to certain mannose residues on many bacteria and subsequently interacts with MASP and MASP2.
The MBL-MASP-MASP2 complex is similar to AbC1qrs complex (of classical pathway) and leads to activation of C4, C2 and C3. The rest follows as in classical pathway
How is MAC formed?
C5 convertase, generated by any of the pathways described above, cleaves C5 into C5a and C5b.
C5b instantaneously binds C6 and subsequently C7 to yield a hydrophobic C5b67 complex, which attaches quickly to the plasma membrane.
Subsequently, C8 binds to this complex and causes the insertion of several C9 molecules. The insertion of membrane attack complex causes formation of a hole in the membrane thus lysing the cell.
If complement is activated on an antigen without a lipid membrane to which the C567 can attach, the C567 complex may bind to nearby cells and initiate bystander lysis
How is complement activation regulated?
C1 Inhibitor inhibits the production of C3b by combining with and inactivating Cq1rs complex. This prevents formation of the C3 convertase
Protein H inhibits the production of C3b
Decay accelerating factor (DAF) accelerates breakdown of C3 convertase.
What is the biological activity and effect of C2b?
BA: Accumulation of body fluids
E: Edema
What is the biological activity and effect of C3a, C4a?
BA: Degranulation of mast cells and basophils, inceases vascular permeability, smooth muscle contraction
E: Immunoregulation
What is the biological activity and effect of C3b?
BA: Opsonisation and activation of phagocytes
E: Phagocytosis
What is the biological activity and effect of C4b?
BA: Opsonisation
E: Phagocytosis
What is the biological activity and effect of C5a?
BA: Basophil and mast cell activation, enhanced vascular permeability, smooth muscle contraction, chemotaxis, neutrophil aggregation,Oxidative metabolism stimulation, stimulation of leukotriene release and induction of helper T-cells
E: Inflammation, anaphylaxis, Immunoregulation.
What is the biological activity and effect of C5b67?
BA: Chemotaxis; attachment to other cell membranes
E: Inflammation and lysis of bystander cell
