Lecture #3 Flashcards
Complement protein synthesis
Mainly in the liver as proenzymes, but can be synthesized by immune cells as well
(over 30 circulating/ membrane bound types of complement proteins)
C1q molecules forms a __________ , later on 3 ________ will form a __________ structure and bind ______ and _____ for stabilization.
a dimer 3 dimers a hexameric C1r C1s
Activation of the C1qrs complex
- By binding to cell surfaces (certain retroviral surfaces, LPS, CRP)
- By binding to an Ab bound to a cell surface Ag
- It can bind 2 or more IgG Fc regions
- It cam bind IgM (BEST ACTIVATOR)
What is the sequence of events in the classical pathway once C1qrs binds to the cell surface
- C1qrs gets activated and cleaves C4 and C2
- C4bC2b fragments will form the classical C3 convertase
* C4b is bound to the cell surface by thioester bond - C3 convertase will then cleave C3
- C4bC2bC3b fragments will form C5 convertase
* C3b is bound to the cell surface by thioester bond - C5 convertase will cleave C5
- C5a and C3a fragments ‘anaphylatoxins’ dissociate
- C5b attracts C6-C8 and polyC9 to form MAC
What are the complement related molecules initiating the lectin pathway?
MBL mannose binding lectin, very similar in structure to the C1q hexamer and is able to bind to mannose residues on the surface of the cells
3 MASPs mannose associated serine proteases are linked to the MBL
*ficolin-MAPS or collectin-MAPS complexes can as well activate the lectin pathway.
(ficolin and collectin are oligomeric lectins)
What is the sequence of events in the lectin pathway once MBL complex binds to the cell surface?
- MASP will cleave C2 and C4
- C4bC2b fragments will form the lectin C3 convertase
* C4b is bound to the cell surface by thioester bond - C3 convertase will then cleave C3
- C4bC2bC3b fragments will form C5 convertase
* C3b is bound to the cell surface by thioester bond - C5 convertase will cleave C5
- C5a and C3a fragments ‘anaphylatoxins’ dissociate
- C5b attracts C6-C8 and polyC9 to form MAC
Initiators of the alternative pathway
LPS, LTA, fungal and yeast zymogen, some viruses, tumor cells and parasites
What are the events leadind to the activation of the alternative pathway?
C3 if found extracellularily at low concentrations and can be spontaneously hydrolized by any ser protease in the plasma.
C3b is able to bind to oligosaccharides (positive pathogen surfaces)
What is the sequence of events in the alternative pathway once C3b binds to the cell surface?
- B factor binds to C3b and factor D
- factor D cleaves factor B forming C3bBb
- C3bBb binds properdin (stabilizes it) together they form the alternative C3 convertase
- new C3 is cleaved by the C3 convertase forming C3bBbC3b
- C3bBbC3b is the alternative C5 convertase
- C5 convertase cleaves C5 forming C5b and C5a
- C5b attracts C6-C8 and poly C9 forming MAC
Classical C3 and C5 convertases are
C4bC2b - C3 convertase
C4bC2bC3b - C5 convertase
Alternative C3 and C5 convertases are
C3bBb - C3 convertase
C3bBbC3b - C5 convertase
Immune defense function of the complement system
- MAC complex formation and cytotoxicity
- Opsonization - C3b C3bi C3dg are opsonins which bind to complement receptors on phagocytes and induce phagocytosis
- C3a C5a anaphylatoxins
Inducing mast cell degranulation
Increase vascular permeability + vasodialation
C5a is also a chemokine for neutrophils and promotes leukocyte adhesion
The different opsonins
C3b binds to CR1 expressed on RBC and WBC
iC3b binds to CR1,2,3,4
C3dg binds to CR2 expressed on B cells
iC3b is formed by the proteolytic cleavage of C3b in order to deccelerate complement activation
C3dg is formed by the proteolytic cleavage of iC3b
and it is a strong opsonin
Inhibitor of C1q
C1inh
Inhibitors of C4bC2b association
C4BP, I factor, MCP
Inhibitors of C3bB association
CR1, H factor, MCP
Inhibitor of MAC complex insretion to the membrane
Protein S
Inhibitors of polymerization of C9
CD59, HRF
Induction of convertase dissociation and cleavage of C4b C3b by factor I
C4BP, CR1, H factor, DAF
Deficiency of early complement components
Until C3 convertase (C1, C4, C2, C3)
In autoimmune diseases like SLE
Deficiency of late complement components
C5-C9
Due to recurrent pyogenic bacterial infections
What is the most frequent withborn complement deficiency?
C2
Cinh deficiency causes
HEA hereditary angioneurotic edema
DAF deficiency causes
Paroxysmal nocturnal hemoglobinuria
MAC attacks RBCs
The genomic region of C3 convertase components
MHC III region on chromosome 6 (B factor, C4, C2) Between class I and II
APR acute phase reaction
Acute systemic reaction initiated 6-12h after a severe inflammatory response
Cytokines activating the APR
IL1, IL6, IL8, TNF alpha
What are the organs participating in the APR
Liver, bone marrow, adipose tissue, CNS, skeletal m
The role of the liver in APR
Liver secretes CRP (opsonization) SAA (cholesterol transport) Fibrinogen, vWF (clotting) Ceruloplasmin (freeradical scavenger) Complement proteins (C3, C1inh) Alpha 1 antichymotrypsin (protease inhibitor) Haptoglobin (inhibit macrophages)
albomin, apolipoproteins and transferrin secretion is attanuated
The effects on the hypothalamus in APR
Hypothalamus induces fever, loss of apatite, and secretion of cortisol
The effects on bone marrow, adipose tissue and skeletal m in APR
Bone marrow - Leukocytosis
Adipose tissue - Lipolysis
Skeletal m - muscle breakdown and release of m enzymes like CPK
Cortisol is important in limiting the immune response by
Promoting the expression of IL6R
Inhibiting the production of further IL6
