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COMPLEMENT SYSTEM

The Major Pathways of Complement Activation

• The classical pathway is initiated by antibody binding


• The lectin pathway is initiated when soluble proteins recognize
microbial antigens
• The alternative pathway is initiated in three distinct ways
• The three complement pathways converge at the formation of the C5
convertase
• C5 initiates the generation of the MAC

Introduction to CS

-A set of serum proteins


-cooperates with both the IIS and the AIS to eliminate blood/tissue
pathogens
-components (proteins) interact with one other through cascades, just like
the blood-clotting system

functions
-opsonize/receptor-mediated phagocytosis
-elicit inflammatory responses
-signal/interface with AIS components
-clear immune complexes
-eliminate apoptotic cells
-directly kill via forming MACs

biological importance of the system


-pathological consequences of mutations in the genes encoding
complement proteins
-broad range of strategies that pathogens have developed to evade CS
-development of CS early in development and evolution

research and history


-activity of the serum, that completes/complements the action of the
antibody

Components of CS
-the activity of CS is the result of complex interactions between >30
glycoproteins
-Synthesized by liver/monocytes(blood)/macrophages, fibroblasts
(tissue)/epithelial cells (of GIT, Genitourinary tracts)
-15% of globulin protein fraction
-3mg/dl
-distributed among blood and cell membranes
-CS components can be categorized into 7 functional categories:
1. Initiator proteins-when activated, initiates the various complement
cascades. Activated through conformational change, which occurs
when they bind to certain membrane ligands.
Example: C1q complex, MBL, ficolins
2. Enzymatic mediators-proteases, which activate other members of
the catalyic cascade through cleavage. They themselves are
activated by other proteases or through binding-induced
conformational change-induced activation.
Example: C3 convertase, C5 convertase, C1r, C1s, MASP2, factor B
3. Opsonins- bind to microbial surface and enhance phagocytosis, serve
as binding tags for phagocytic cells bearing receptors for the opsonins
Example: C3b, C4b (often the larger component from enzymatic
cleavage, except C2a)
4. Complement receptors – are found on immune cells, like
neutrophils. They bind complement proteins/fragments, and signal a
specific cell function like phagocytosis or degranulation etc..
Example: CR1(receptor) binds C3b on pathogen surface and signals
phagocytosis of the C3b-bound pathogen, C5aR(receptor on
neutrophil) binds C5a causing its degranulation.
5. Membrane attack proteins – they
6. Inflammatory mediators
7. Regulatory proteins

Activation pathways of CS
Functions of CS
Regulation of complement activity
Deficiencies of CS
Microbial complement evasion strategies
Evolutionary origins of CS