The immune system protects the body from harmful invaders like bacteria and viruses. Part of this defense is the complement system, a complex network of proteins in the bloodstream. Within this system, the Membrane Attack Complex (MAC) eliminates threats by disrupting their cellular integrity.
The Complement System
The complement system is part of the innate immune response against pathogens. It consists of over 30 proteins that circulate in the blood and tissues, typically inactive. These proteins activate in a cascade, where one protein activates the next, amplifying the immune response.
This system can be triggered through three distinct pathways: the classical, alternative, and lectin pathways. Each is initiated by different cues, such as antibodies bound to a pathogen (classical), direct recognition of pathogen surfaces (alternative), or specific sugar molecules on microbial surfaces (lectin). All pathways converge to a common terminal pathway, which culminates in the assembly of the Membrane Attack Complex, the final destructive component of this protein cascade.
Membrane Attack Complex Formation
MAC formation begins with the activation of complement protein C5, which cleaves into C5a and C5b. C5b then binds to the target cell’s surface. This initial binding provides a platform for the sequential recruitment of other complement proteins.
Next, C6 attaches to C5b, forming a C5bC6 complex. C7 then joins, creating a C5bC6C7 assembly. C7 undergoes a conformational change, exposing a hydrophobic region that allows the complex to insert into the target cell’s lipid bilayer.
C8 binds to the membrane-inserted C5bC6C7 complex. C8 also has a hydrophobic domain, anchoring the complex within the cell membrane. Multiple C9 protein molecules are then recruited, typically 10 to 18. These C9 units polymerize, forming a cylindrical, pore-like structure that spans the target cell’s membrane.
How MAC Destroys Cells
The assembled Membrane Attack Complex creates a pore or channel that punctures the target cell’s outer membrane. This channel directly compromises the cell’s integrity. The pore size, ranging from 7 to 10 nanometers in diameter, allows the uncontrolled passage of molecules.
Once the pore is formed, the cell’s ability to regulate its internal environment is disrupted. Water, ions, and small molecules from the external environment rapidly rush into the cell, driven by osmotic pressure differences. This uncontrolled influx of water causes the cell to swell.
The continuous influx of fluid and the disruption of the cell’s internal balance lead to the eventual bursting of the cell, a process known as osmotic lysis. This direct lytic action is an effective mechanism for the immune system to eliminate cellular threats, such as bacteria, fungi, and virally infected host cells.
MAC’s Role in Health and Disease
The Membrane Attack Complex helps maintain health by providing defense against pathogens. It is effective against Gram-negative bacteria, whose outer membranes are susceptible to MAC-mediated lysis. This direct killing mechanism is part of the body’s innate immune response.
However, MAC function can be dysregulated. Deficiencies in complement proteins required for MAC formation (C5, C6, C7, C8, or C9) can increase susceptibility to certain bacterial infections. Individuals with these deficiencies are vulnerable to recurrent infections caused by Neisseria species, including Neisseria meningitidis.
Conversely, uncontrolled activation of the complement system, leading to excessive MAC formation, can contribute to tissue damage in various disease states. In certain autoimmune conditions, MAC can mistakenly target and damage healthy host cells and tissues, contributing to inflammation and pathology.