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In addition to Ig molecules in blood or body fluids, another type of macromolecules involved in immune effects are also found, called complement molecules. Its chemical composition is a group of immunoglobulins with enzymatic activity, accounting for about 10% of the total serum globulins. Early immunological studies found that this substance is essential in immune hemolytic reaction and bacteriolytic reaction, so it is called complement. Research in recent years has proved that complement is composed of 11 serum proteins, which are named C1...C9 according to the order of their discovery. Among them, C1 is composed of three subunits: Clq, Clr, and Cls, collectively referred to as the complement system.

The complement system, also known as the complement cascade, is a part of the immune system that enhances the ability of (complement) antibodies and phagocytes to remove microorganisms and damaged cells from the organism, promote inflammation and attack the cell membrane of pathogens. The complement system is composed of many small proteins, which are synthesized by the liver and circulate in the blood as inactive precursors. When stimulated by one of several triggers, the proteases in the system cleave specific proteins to release cytokines and trigger an amplification cascade of further cleavage. Therefore, the complement system is an important effector system and effect amplification system in the body, and its activation process is represented by a series of cascade enzymatic hydrolysis reactions of serine proteases. Three activation pathways of complement:

More specifically, complement triggers the following immune functions:

• Phagocytosis-by opsonizing antigens. C3b has the most important conditioning effect
• Inflammation-by attracting macrophages and neutrophils
• Membrane attack-by destroying the cell wall of bacteria

Complement System Pathways

Three biochemical pathways activate the complement system: the classical complement pathway, the alternative complement pathway, and the lectin pathway.

Fig.1 Overview of three pathways of complement system.^{1, 2}

1. Classical pathway

The classical pathway is triggered by the activation of the C1 complex. The activator (antigen-antibody complex) binds to C1q to activate C1r, C1s, C4, C2, C3 in order to form a cascade enzymatic reaction process of C3 convertase (C4b2a) and C5 convertase (C4b2a3b).

C5b ~ C9 of the complement system constitute the MAC (membrane attack complex). The membrane attack complex (C5b6789n) is firmly attached to the surface of the target cell, and eventually causes the cell to rupture and die.

2. Alternative pathway

The difference between the alternative activation pathway and the classical activation pathway is that, the activation of the alternative pathway bypasses the three components of C1, C4 and C2 and directly activates C3. With the participation of factor B, factor D and properdin (P), C3 convertase and C5 convertase are formed, and a cascade of enzymatic reactions is initiated. In addition, the activating substances of the alternative activation pathway are not antigen-antibody complexes but bacterial cell wall components-lipopolysaccharides, as well as polysaccharides, peptidoglycans, teichoic acid, and aggregated IgA and IgG4. The alternative activation pathway can play an important anti-infective effect in the early stage of bacterial infection when no specific antibodies are produced.

Fig.2 The classical and alternative complement pathways.

3. Lectin pathway / Mannose-Binding Lectin (MBL) pathway

The lectin pathway is a cascade reaction in the complement system. Its structure is similar to the classical complement pathway. After activation, it proceeds through the action of C4 and C2, thereby further producing activated complement proteins downstream of the cascade reaction. Contrary to the classical complement pathway, the lectin pathway cannot recognize antibodies that bind to its target. The lectin pathway starts with mannose-binding lectin (MBL) or ficolin (Ficolin-1, Ficolin-2, and Ficolin-3) that bind certain sugars.

In this pathway, mannose-binding lectins bind to mannose, glucose, or other sugars with 3- and 4-OH groups. After binding to the target molecule, MBL, CL-K1 (collectin 11) and ficolins form a complex with MBL-related serine proteases 1 and 2 (MASP-1 and MASP-2), which cleave C4 and C2 to form C3 convertase (C4b2a), the complement cascade is then activated to form a membrane attack complex.

The complement system plays an extremely important role in innate immune regulation, and there are more and more researches on the complement system. As a well-known supplier of products and solutions in the field of life sciences, Creative Biolabs provides you with the world's leading innate immune research reagent. Our complete complement research tools include: proteins/peptides involved in the complement system, ELISA assay kits suitable for a variety of samples, and affinity antibodies of a variety of species.

For more detailed information, please feel free to contact us or directly sent us an inquiry.

References

1. Beltrame, Marcia Holsbach, et al. "The lectin pathway of complement and rheumatic heart disease." Frontiers in Pediatrics 2 (2015): 148.
2. under Open Access License CC BY 4.0, without modification.