Basically, the Terminal Complement Complex (TCC) and Membrane Attack Complex (MAC) resemble the same protein complex. The complex can exist as membrane bound variant as well as a soluble variant, respectively in general referred to as MAC and soluble TCC (sTCC, also called sC5b-9).

Introduction

The complement system is a part of the innate immune system, initially described in the late 19th century by Jules Bordet. He observed that serum contains components enhancing antibody-mediated bacterial lysis. Subsequent research revealed that complement activation culminates in the formation of the MAC. This complex cascade consists of »50 proteins and can be triggered by three activation pathways (classical, lectin and alternative). As well as indirect by the extrinsic pathway of blood coagulation. Besides pathogen elimination by MAC-mediated lysis, complement contributes to numerous auto-immune and inflammatory diseases, like SLE, AMD and transplant rejection. Activation leads to the formation of the central C3 and C5 convertases. C5 derived C5b is considered the start of the terminal pathway (TP), eventually leading to TCC. TCC is a barrel-shaped structure that inserts itself into the cell membrane, thus creating a pore.

Tools for complement research

Mechanism and structure

During the Terminal Pathway, while still attached to the convertase, the sequential addition of C6, C7 to C5b leads to the induction of conformational changes. This addition results into release from the convertase. After membrane association, this opens the ability to bind C8 and multiple copies of C9. This process is quite complicated and inefficient, it turns out most of the C5b-7 complexes fail to associate with the membrane. Thereby releasing a soluble nonlytic form of TCC. This so called C5b-9 complex or sTCC represents the failure rate of MAC assembly.

There is no cellular receptor and distinct function for sTCC. Most consider sTCC as biologically inert. The amount of sTCC is considered to reflect the amount of MAC and as a measure of complement activation or at least of the TP.

One way to interfere with complement activation is inhibition of MAC formation. Factors playing a role are CD59, DAF and MCP. Understanding of these proteins offers therapeutic opportunities, but dysfunction or deficiencies can result in uncontrolled activation and can contribute to pathogenesis of disease.

Significance in disease and diagnosis

sTCC can be measured in plasma and body fluids. Multiple studies show changes in sTCC levels during infection, auto-immune disease and trauma. To quantify complement activation recognized immunoassays make in general use of monoclonal antibodies detecting a neo-epitope exclusively present on an activation product. Antibody aE11 (HM2167) is such tool. To measurement specifically the endpoint of complement activation, this antibody has been incorporated in several sTCC and pathway ELISAs (e.g. HK328, HK3010/HK3012). The measurement of sTCC has not been translated into common clinical use. However, with the new complement inhibitors making their way to the clinic in the coming years, it may be beneficial to use sTCC as a biomarker or companion diagnostics. This to monitor therapy and adapt dosing. Studies have shown that sTCC levels correlate well with Eculizumab dosing.

Overall, advancements in structural analysis, diagnostic tools, and understanding of its regulation offer promising avenues for elucidating role of TCC in health and disease. The complex, particularly its soluble form sTCC, presents a fascinating yet complex entity in immune biology. It holds promise for improved diagnostics and therapeutic interventions in various pathological conditions.

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