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Complement System: Biology of The Immune System: Complement Activation Pathways

The complement system is an enzyme cascade that helps defend the body against infection. It has three pathways of activation - the classical, lectin, and alternative pathways. The classical pathway is antibody-dependent, while the lectin pathway is activated by mannose-binding lectin binding to sugars on microbes. The alternative pathway is activated by microbial surfaces. All three pathways converge on C3 and result in the formation of the membrane attack complex to lyse foreign cells. Complement components also have roles in opsonization, chemotaxis, and regulating the immune response.

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66 views5 pages

Complement System: Biology of The Immune System: Complement Activation Pathways

The complement system is an enzyme cascade that helps defend the body against infection. It has three pathways of activation - the classical, lectin, and alternative pathways. The classical pathway is antibody-dependent, while the lectin pathway is activated by mannose-binding lectin binding to sugars on microbes. The alternative pathway is activated by microbial surfaces. All three pathways converge on C3 and result in the formation of the membrane attack complex to lyse foreign cells. Complement components also have roles in opsonization, chemotaxis, and regulating the immune response.

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Basic Immunology/ Complement System/Third Year/L2/ Dr. Batool A.

Al-Haidary

Complement System
The complement system is an enzyme cascade that helps defend against infection.
Many complement proteins occur in serum as inactive enzyme precursors
(zymogens); others reside on cell surfaces. The complement system bridges innate
and acquired immunity by
 Augmenting antibody (Ab) responses and immunologic memory
 Lysing foreign cells
 Clearing immune complexes and apoptotic cells
 Complement components have many biologic functions (eg, stimulation of
chemotaxis, triggering of mast cell degranulation independent of IgE).
 Complement activation: There are 3 pathways of complement activation

Biology of the Immune System: Complement activation pathways


 Classical
 Lectin
 Alternative

Classical pathway components are labeled with a C and a number (eg, C1,
C3), based on the order in which they were identified. Alternative pathway components
are often lettered (eg, factor B, factor D) or named (eg, properdin).

 Classical pathway activation


It is Ab-dependent, occurring when C1 interacts with Ag-IgM or aggregated
Ag-IgG complexes, or Ab-independent, occurring when polyanions (eg, heparin ,
protamine, DNA and RNA from apoptotic cells), gram-negative bacteria, or bound C-
reactive protein reacts directly with C1. This pathway is regulated by C1 inhibitor (C1-
INH).

 Lectin pathway activation


It is Ab-independent; it occurs when mannose-binding lectin (MBL), a serum
protein, binds to mannose or fructose groups on bacterial cell walls, yeast walls, or
viruses. This pathway otherwise resembles the classical pathway structurally and
functionally. The lectin pathway is a type of cascade reaction in the complement system,
similar in structure to the classical complement pathway, in that, after activation, it
proceeds through the action of C4 and C2 to produce activated complement proteins
further down the cascade. In contrast to the classical complement pathway,
the lectin pathway does not recognize an antibody bound to its target. The lectin pathway
starts with mannose-binding lectin (MBL) or ficolin binding to certain sugars.
In this pathway, mannose-binding lectin binds to mannose, glucose, or other
sugars with carbohydrate or glycoprotein components of microorganisms including
bacteria such as Salmonella, Listeria, and Neisseria strains. Fungal pathogens such

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Basic Immunology/ Complement System/Third Year/L2/ Dr. Batool A. Al-Haidary

as Candida albicans and Cryptococcus neoformans as well as some viruses such as HIV-


1 and Respiratory syncytial virus (RSV) are bound by MBL.
Mannan-binding lectin, also called mannose-binding protein, is
a protein belonging to the collectin family that is produced by the liver and can initiate
the complement cascade by binding to pathogen surfaces.
MBL forms oligomers of subunits, which are trimers (6- to 18-heades
correspond to a dimer and a hexamer, respectively). Multimers of MBL form a complex
with MASP1 (Mannose-binding lectin-Associated Serine Protease),
MASP2 and MASP3, that are protease zymogens. The MASPs are very similar to C1r
and C1s molecules of the classical complement pathway, respectively, and are thought to
have a common evolutionary ancestor. When the carbohydrate-recognising heads of
MBL bind to specifically arranged mannose residues on the surface of a pathogen,
MASP-1 and MASP-2 are activated to cleave complement components C4 and C2into
C4a, C4b, C2a, and C2b. 
Mannose-binding Lectin deficiency - These individuals are prone to recurrent
infections, including infections of the upper respiratory tract and other body systems.
People with this condition may also contract more serious infections such as pneumonia
and meningitis. Depending on the type of infection, the symptoms caused by the
infections vary in frequency and severity.

 Alternate pathway activation


It occurs when components of microbial cell surfaces (eg, yeast walls,
bacterial cell wall lipopolysaccharide [endotoxin]) or Ig (eg, nephritic factor,
aggregated IgA) cleave small amounts of C3. This pathway is regulated by properdin,
factor H, and decay-accelerating factor.
The 3 activation pathways converge into a final common pathway when C3
convertase cleaves C3 into C3a and C3b:
C3 cleavage may result in formation of the membrane attack complex
(MAC), the cytotoxic component of the complement system. MAC causes lysis of
foreign cells.
The classical pathway, which is activated by certain isotypes of antibodies
bound to antigens; the alternative pathway, which is activated on microbial cell
surfaces in the absence of antibody; and the lectin pathway, which is activated by a
plasma lectin that binds to mannose residues on microbes. Although the pathways of
complement activation differ in how they are initiated, all of them result in the
generation of enzyme complexes that are able to cleave the most abundant complement
protein, C3.

Biologic activities
Complement components have other immune functions that are mediated by
complement receptors (CR) on various cells.

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Basic Immunology/ Complement System/Third Year/L2/ Dr. Batool A. Al-Haidary

 CR1 (CD35) promotes phagocytosis and helps clear immune complexes.


 CR2 (CD21) regulates Ab production by B cells and is the Epstein-Barr virus
receptor.
 CR3 (CD11b/CD18), CR4 (CD11c/CD18), and C1q receptors play a role in
phagocytosis.
 C3a, C5a, and C4a (weakly) have anaphylatoxin activity: They cause mast cell
degranulation, leading to increased vascular permeability and smooth muscle
contraction.
 C3b acts as an opsonin by coating microorganisms and thereby enhancing their
phagocytosis.
 C3d enhances Ab production by B cells.
 C5a is a neutrophil chemoattractant; it regulates neutrophil and monocyte
activities and may cause augmented adherence of cells, degranulation and
release of intracellular enzymes from granulocytes, production of toxic oxygen
metabolites, and initiation of other cellular metabolic events.

Hereditary angioedema is due to a genetic deficiency of C1-INH.

Figure 1: Classical Complement Activation


Figure2: Alternative Pathway activation
component pathway

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Basic Immunology/ Complement System/Third Year/L2/ Dr. Batool A. Al-Haidary

The classical, lectin, and alternative pathways converge into a final common pathway when C3 convertase
(C3 con) cleaves C3 into C3a and C3b. Ab = antibody; Ag = antigen; C1-INH = C1 inhibitor; MAC =
membrane attack complex; MASP = MBL-associated serine protease; MBL = mannose-binding lectin; P =
properdin. Overbar indicates activation.

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Basic Immunology/ Complement System/Third Year/L2/ Dr. Batool A. Al-Haidary

Three Pathways for Complement Activation

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