Complement Flashcards
Complement components generate products that: (4 things)
- Recruit inflammatory cells
- opsonize microbial pathogens and immune complexes (facilitating antigen clearance)
- Kill microbial pathogens
- Generate an inflammatory response
where does complement activation takes place
on antigenic surfaces (Antigen-Ab complexes, microbial surfaces, mammalian cell surfaces
the three pathways of activation of complement
classical, lectin, and alternative
Designation of components of the alternative pathway
Capital letters such as factor B, and factor D
designation for the lectin pathway
acronyms such as MASP-2
Classical pathway activation is initiated after
immune complex formation
what does C1 bind to
A site on the Fc portion of an antibody that is exposed after it has bound to antigen
C1 structure
macromolecule, of
Clq: 6 globular heads and extended tails
C1r
C1s
what activates C1qrs
at least 2 of the C1q globular heads are simulaneously bound to antibody. This requires 2 Fc portions to be close together on the antigenic surface. (would need 2 antigens with IgG but only one on IgM due to its pentameric structure)
C1r is activated by _____ and does _____
C1q binding to antigen; C1r cleaves C1s which activates C1s
C1s becomes active after
it is cleaved from the C1qrs molecule by C1r
Why does IgM require a smaller concentration to activate complement?
bc of its pentameric structure one IgM bound to antigen can bind to multiple of the globular heads of C1q
The Lectin pathway is itiated by
a protein- Mannan Binding Lectine (MBL) or ficolis (which are homologous to C1q)
MBL binds to
Mannose and other complex carbohydrates on the surface of many microbial pathogens
Ficolins bind
oligosaccharides
MASP- and MASP-2
Mannose binding lectin-associated serine protease: serine proteases that are physically associated with MBL/ficolins. similar to C1r and C1s
MASP-1 and MASP-2 are activated by
MBL/ficolins binding to a surface and undergoing a conformational change
difference between MBL and ficolins
similar structures but bind different carbohydrate domains
MBL-mannose and fructose residues
Ficolins- oligosaccharides w/ acetylated sugars
acitivated C1qrs or activated MASP- and MASP-2 cleave
C4 to C4a and C4b
C4b
binds to a cell surface (eg a microorganism) and the bound C4b binds C2
C2 bound to C4b
C2 is cleaved by C1s forming the C4b2a complex which remains bound to the cell surface.
C4b2a
cleaves C3 to C3a and C3b ( C3 convertase)
major amplification step
C4b2a formation bc it can cleave up to 1000 molecules of C3
C3b
binds to antigenic surfaces and is a power opsonin. enhances uptake of antigenic particle by phagocytes
C5 covertase
aka: C4b2a3b. cleaves C5 into C5a and C5b
C5a
soluble inflammatory mediator
C5b
complexes with other complement components . its generation initiates the final phase of complemtn activation which is the formation of the Membrane Attact Comple (MAC)
Alternative Pathway initiation
depends on slow, spontaneous hydrolysis of C3 in the cytoplasm. hydrolyzed C3 can bind factor B froming C3(H2O)Bb complex
C3(H2O)Bb complex
C3 convertase that generates additional C3b
C3b
is degraded rapidly or bound to a pathogenic surface
Factor B is cleaved
after binding to C3b attached to a pathogenic surface, by Factor D. Forms- C3bBb
C3bBb is stabilized by _____ and acts as ______
Factor P; C3 convertase. analogous to C4b2a of the classical pathway
C3bBb + C3b =
C3bBbC3b which is a C5 covertase analogous to C4b2a3b of the classical pathway
3 pathways converge at
the formation of a C5 covertase leading to the formation of a MAC complex
MAC complex actions
creates a pore in the ell membrane and disrupts cell homeostasis by cellular lysis. can work on some viruses with a membrane coat too
Opsonization
antigenic particles covered with C3b which is bound by CR1 (C3b receptors) and assist in the binding and ingestion of the particle by the phagocyte
clearance of immune complexes
removal depends on C3b which bids to complement receptors on RBC which bring them to the spleen and liver where they are stripped off and destroyed by phagocytes
inflammation is increased by
soluble fragments of complement C4a and C5a
Chemotaxis
C5a attracts neutrophils, eosinophils, basophils, and monocytes via a C5 gradient
vascular changes are caused by
C3a, C4a, and C5a via binding to receptos on mast cells and basophils which triggers granule release of histamine. Increase vascular permeability.
anaphylatoxins
C3a, C4a, and C5a bc of their affects on vascular permeability.
C1INH
C1 inhibitor- dissociates C1r and C1s from the complex
What 5 things inhibit C3 covertase
Decay-accelerating factor (DAF) C4 binding protein (C4BP) Complement receptor 1 (CR1) Membrane cofactor protein (MCP) Factor I (I)
what inhibits C5 covertase
Factor I (I) Factor H (H) Complement receptor 1 (CR1)
CD59
prevents assembly of membrane attack complex
Classical pathway deficiency
leads to immune complex disease
lectin pathway deficiency
deficiency of MBL leads to bacterial infections maily in childhood (usually outgrown)
Alternative pathway deficency
leads to infection with pyogenic bacteria and Neisseria spp. not no immune complex disease
C3b defficiency
leads to infection with pyogenic bacteria and neisseria spp. sometimes immune-complex disease
Membrane-attack component deficiencies
lead to infection with neisseria spp. only
Hereditary angioneurotic edema
C1INH deficiency- failure to regulate C1 resulting in fluid accumulation, epiglottal swelling
paroxysmal nocturnal hemoglobinurea
CD59 failure to function, lack of complement regulation leads to RBC lysis and blood in urine
C8
binds the cell and interts into the membrane
C9
forms the pore
MAC works on what type of bacteria
gram negative
