Complement Flashcards
part of which immunity
humoral- soluble
consists of how many serum and membrane proteins
30
how does complement mediate the immune reaction
- triggering inflammation
- attraction of phagocytes to sites of infection
- degradation of membrane or virus envelope
- stimulation of antibody production
activation of complement
the active components of complement ar egernated from inactive precursors by a cascade of proteolytic reactions
how many pathways trigger activation of complement
3
name the three complement pathways
1) the lectin pathway
2) the classical pathway
3) the alternative pathway
the lectin pathways
recognition of carbohydrate molecules e.g. by collectins such as mannose-binding lectin
the classical pathway
pathway which was first described
- antibody binding to antigen in immune complexes
the alternative pathway
directly activated by microbial cell surfaces
all initiations of complement pathways start
differently but end in the same way
complement reactions
can be divided into early events, in which components are not the same for the three pathways and the late event, in which they are identical
early events
1) function of the early events is to generate to functionally equivalent forms of a proteases, known as C3 convertase
2) C3 convertase then initiates the late events to produce the effector components of complement
3) C3 convertase covalently attaches to the cell surfave at which the complement activation was initiated
4) cleavage of complement component C3 leads to effector activation- effects of complement activation aere confined to the infectious organism that triggered it
what activates the classical pathway
antibodies or pentraxins
pentraxins
primitive form of Ig
- Pentameric serum proteins that participate in innate immunity and can also activate the Classical pathway of complement
pentraxins are important for
acute phase infections
classical pathway
- Antibody binds to target antigen
- C1Q/R/S complex (proteolytic complex) binds to the Fc domain of antibody and C1R is activated by C1Q, C1R cleave activates C1S
- Conformational change as it binds to Fc which triggers proteolytic cascade that then heads down to the C3 convertase
- C1 cleaves C4
- C4B then binds to the cell surface and binds to C2
- C1S cleaves c2 bound to C4B and C3 convertase is produced
- C3 convertase then cleaves C3 to C3a and C3b which have effector actions
collectins and ficolins (as part of the lectin pathway)
Bind to carbohydrates
epithelium of the respiratory tract is lubricated by a layer of phospholipids and proteins known as surfactants
- Two of these, Surfactant Protein-A (SP-A) and Surfactant Protein-D (SP-D) are Collectins and function as opsonins,
coating microorganisms (e.g. Pneumocystis in AIDs patients - Lecture 8) and stimulating uptake by phagocytes
what bind to carbohydrates
collecitins and ficolins
the collectin family
- The Collectin family also includes Mannose-Binding Lectin (MBL) - binds to mannose-containing carbohydrates on surface of viruses, bacteria and fungi
ficolins bind to
N-acetylglucosaine (not found in humans)
polypeptide chain of the collectin family of proteins consists of
an amino-terminal cysteine-rich region followed by a collagen-like region, an a-helical neck region and a carboxy-terminal globular domain (a C-type lectin known as the carbohydrate recognition domain [CRD])
- polypeptide chain trimerise
both MBL and SP-A are
hexameric structures
- multiple array of CRDs give high affinity binding to polysaccharides ligands in microbial cell walls
In the collectin pathway the particle recognition is translated into immune action
- By phagocytes, which are stimulated to internalize bound microorganisms or,
- By conformational changes in the collectin that activate pre-bound protease subunits and initiate the complement cascade
when six proteins of the collectin family come together
they bind to mannose- this causes conformational change which pulls legs apart and this triggers proteases which starts the cascade
lectin pathway after collectin bound to mannose and causes conformational change
1) MASP (mannose-binding, lectin Associated Serine protease) in the legs are activate during conformational change when mannose binds
2) MASP-2 cleaves C4
3) C4b attaches to cell surface
4) C2 binds to C4b
5) MASP-2 cleaves C2 bound to C4b
6) Which produces C3 convertase
7) This causes C3 to be cleaved and this causes effector actions
what is MBL
mannose binding lectin
what are mannose binding lectins
a lectin that is instrumental in innate immunity[5][6] as an opsonin and via the lectin pathway
what to MBLs facilitiate
MBL recognizes carbohydrate patterns, found on the surface of a large number of pathogenic micro-organisms, including bacteria, viruses, protozoa and fungi. Binding of MBL to a micro-organism results in activation of the lectin pathway of the complement system.
MASPs are complexed with…
MBL in the blood is complexed with (bound to) another protein, a serine protease called MASP (MBL-associated serine protease).
what do MASPs do?
when MBL binds to its target (for example, mannose on the surface of a bacterium), the MASP protein functions to cleave the blood protein C4 into C4a and C4b. The C4b fragments can then bind to the surface of the bacterium, and initiate the formation of a C3-convertase
the membrane attack complex..
a structure typically formed on the surface of pathogen cell membranes as a result of the activation of the host’s complement system
structure and role
The membrane-attack complex (MAC) forms transmembrane channels. These channels disrupt the cell membrane of target cells, leading to cell lysis and death.
allows free diffusion of molecules in and out of the cell. If enough pores form, the cell is no longer able to survive.
