Contact us to learn more about our Complement System Solutions

Complement System Overview

The complement system is part of the intricate immune surveillance system to discriminate among healthy host tissue, dead cells and foreign intruders.

The immune system is traditionally divided into two parts, the innate immune system and the adaptive immune system. The adaptive immune system is one of the key elements in the development of specific antibodies to specific targets. The innate immune system, which complement is part of, on the other side reacts in a generic way to patterns of pathogen- or damage-associated molecules.

The Complement System and Disease

An intact complement system is required for host defense and healthy tissue. However, the system it does not always act as our friend. Improper, enhanced, or uncontrolled activation causes major injury and serious illness.

Disturbances in the complement system is an effector in a large variety of disorders. Autoimmune diseases, septic shock, rejection of transplants and adverse reactions against drugs and biomaterials are just a few of all conditions where complement is part of the disease process.

The question is: In how many diseases is the complement system NOT involved in the pathogenesis in some way or another?

 

The Complement System and Innate immunity

Complement was originally described in the late nineteenth century and the word complement was coined by the famous German physician Paul Ehrlich in his general theory of immunity. Today we know that the proteins of complement both act on its own and as a “complement” to the antibodies and immune cells in our host defense system.

The complement system is a complex hub like network of proteins, reactions and processes. More than 50 proteins, fluid-phased, cell-surface associated and intra-cellular proteins functions together to maintain immunosurveillance and homeostasis of our body.

The complement system is described as a double-edged sword. If not properly controlled and regulated, the complement system has the potential to harm the host. Therefore, complement activation is precisely modulated in a very specific manner and under control by many regulatory proteins.

Depending on the nature of the activating surface, complement activators initiate the classical (CP), lectin (LP) or alternative (AP) pathways.

Classical Pathway

Link between innate and adaptive immune system

The classical and lectin pathways are identical except for the factors responsible for the initial activation. The classical complement pathway is typically activated by the C1 complex reacting with antibody-antigen complexes or molecules like CRP, SAP, or PTX3.( C-reactive protein, pentraxin 3 and serum amyloid P component)

Lectin Pathway

Activated by carbohydrates on pathogen surfaces

The activation of the lectin pathway is mediated by mannose-binding lectin (MBL), ficolins or collectins. The recognition of MBL, ficolins or collectins to carbohydrates residues on the pathogen surface or structures of damaged host cells activates the MBL-associated serine proteases, MASP-1, and MASP-2. 

Alternative Pathway

Provides a potent amplification loop

The alternative pathway lack a specific recognition molecule, like the C1q in CP and MBL in LP, instead it is continuously activated at a low level as a result of spontaneous C3 hydrolysis, analogous to a car engine at idle. The alternative pathway can also be activated by foreign surfaces in biomaterials like dialysis machines and nanomedicines.

Terminal Pathway

Cell lysis by MAC

All three pathways lead to the formation of homologous variants of the C3 convertase that cleaves C3 to form C3a and C3b. C3b is part of the C5 convertase that cleaves C5 which leads to the formation of C5b-9 complex, either integrated in a cell membrane as the Membrane Attack Complex (MAC) or soluble as the Terminal Complement Complex, TCC.