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Term Paper on Complement Activation

Term Paper # 1. Pathways of Complement Activation:

There are 3 pathways of complement activation viz.:

These three activation pathways then converge into a 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 then causes lysis of foreign cells.

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1. Classical Pathway:

The classical pathway begins with the formation of Ag-Ab complex. It utilizes C1, which is activated by binding of an antibody to its cognate antigen. Inactive C1 circulates as a serum molecular complex which consists of 6 C1q molecules, 2 C1r molecules, and 2 C1s molecules. The constant regions of some antibodies bind C1q and activate C1r and C1s.

The activated C1s cleaves C4 and C2 into small inactive fragments (C4a, C2a) and larger active fragments, C4b and C2b. The active component C4b binds to the sugar moieties of surface glycoproteins and binds non-covalently to C2b, forming another serine protease C4b-C2b, which is called C3 convertase because it cleaves C3, releasing an active C3b opsonin fragment.

Macrophages and neutrophils possess receptors for C3b, so the cells coated with C3b are targeted for opsonization. The small C3a fragment is released into solution where it can bind to basophils and mast cells, triggering histamine release and also participate in anaphylaxis.

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C3 amplifies the humoral response because of its abundance and its ability to auto-activate (as a C3 convertase). Breakdown of C3b generates an antigen-binding C3d fragment that enhances antigen uptake by dendritic cells and B cells. Binding of C3b to C5 induces an allosteric change that exposes C3b-C5 to cleavage by C4b-C2b, which now acts as C3/C5 convertase.

The alternative pathway possesses a distinct C5 convertase, so the two pathways converge through C5. Cleavage of C5 by the C3/C5 convertase releases – anaphylotoxic C5a, which promotes chemotaxis of neutrophils, C5b which complexes with one molecule of each of C6, C7, and C8. The resultant C5b-6-7-8 complex assists polymerization of as many as 18 C9 molecules to form a cytolysis-promoting pore (membrane attack complex) through the plasma membrane of the target cell, which then suffers osmosis-induced cytolysis.

2. Alternative Pathway:

The alternative pathway is initiated by cell-surface constituents that are foreign to the host and is Ab-independent. It relies upon spontaneous conversion of C3 to C3b, which is rapidly inactivated by its binding to inhibitory proteins and sialic acid on the cell’s surface.

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Because bacteria and other foreign materials lack these inhibitory proteins and sialic acid, the C3b is not inactivated and it forms the C3b-Bb complex with Factor B. The C3b-Bb complex acts as a C3 convertase, forming C3b-Bb-C3b, which acts as a C5 convertase that can initiate assembly of the membrane attack complex. C3b-Bb, acting as a C3 convertase, provides a positive feedback loop that amplifies production of C3.

3. Lectin Pathway:

The lectin pathway (MBL – MASP) is activated by the binding of mannose-binding lectin (MBL) to mannose residues on glycoproteins or carbohydrates on the surface of micro-organisms. It is Ab-independent and is homologous to the classical pathway. It utilizes opsonin, mannan-binding lectin (MBL, MBP) and ficolins instead of C1q.

Binding of mannan-binding lectin to mannose residues on the pathogen surface activates the MBL-associated serine proteases, MASP-1, MASP-2, MASP-3, which cleave C4 into C4b and C2 into C2b. As in the classical pathway, C4b and C2b bind to form the C4b C2b C3 convertase. Ficolins are homologous to MBL and function through MASPs.

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Term Paper # 2. Biological Consequences of Complement Activation:

1. Cell Lysis:

The membrane-attack complex can lyse a broad range of cells such as gram negative bacteria, parasites, viruses, erythrocyte, nucleated cells (tumor cells).

2. Inflammatory Response:

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Various peptides generated during activation of complement play a decisive role in the development of an effective inflammatory response. C3a, C4a, C5a (anaphylatoxin) bind to the complement receptors on mast cells and basophils and induce degranulation with release of histamine.

3. Opsonization:

C3b is the major opsonin of the complement system. C4b and iC3b also have some opsonizing activity.

4. Viral Neutralization:

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Formation of large viral aggregates reduces the number of infectious viral particles. The deposits of Ab and complement on viral particle neutralizes viral infectivity by blocking attachment to susceptible host cells and facilitates binding of the viral particle to cells possessing FcR or CR1.

5. Clearance of Immune Complexes:

Clearance of circulating immune complexes by reaction with receptors for complement products on erythrocytes and removal of these complexes by receptors on macrophages in the liver and spleen.

As erythrocytes have fewer receptors than macrophages, they can strip the complexes from the erythrocytes as they pass through the liver or spleen. Deficiency in this process can lead to renal damage due to accumulation of immune complexes.