What Is the MAC Complement System and How Does It Work?

The immune system includes the complement system, a group of blood proteins that acts as a rapid-response force to eliminate pathogens and damaged cells. A primary tool of this system is the Membrane Attack Complex (MAC). This structure is the end product of the complement cascade, a sequence of events triggered by foreign invaders. The MAC’s formation provides a mechanism for destroying threatening cells directly by creating a pore in their membrane, an action this article will explore along with its regulatory controls.

What is the Membrane Attack Complex?

The Membrane Attack Complex (MAC) is a structure assembled from complement proteins on the surface of a target cell, like an invading bacterium. Its function is to form a pore, or channel, through the cell’s membrane, leading to its destruction. The MAC is the terminal effector of the complement system, as it is the final step in this defense pathway.

The complex is composed of five main complement proteins: C5b, C6, C7, C8, and C9. These components are brought together in a specific sequence, beginning with C5b as a foundation. Multiple copies of the C9 protein are the final components added, and they are responsible for forming the ring-like pore. The fully assembled structure, also known as the C5b-9 complex, punches a hole in the target cell’s defenses.

Building the MAC: A Step-by-Step Process

The assembly of the MAC is an ordered cascade that begins with complement system activation. This activation culminates in the action of an enzyme called C5 convertase. This enzyme cleaves the C5 protein into two fragments: C5a and C5b. While C5a signals other immune cells, the C5b fragment initiates MAC formation.

The newly generated C5b fragment is unstable and must quickly bind to the surface of the target cell. Once anchored, C5b recruits the next component, C6, to form a stable C5b-6 complex. This is followed by the binding of C7, which changes the structure of the growing complex.

The C5b-6-7 complex undergoes a conformational shift that exposes a hydrophobic, water-repelling region on the C7 protein. This change allows the complex to insert itself into the lipid bilayer of the pathogen’s membrane. Following this insertion, the C8 protein binds to the structure. The addition of C8 helps to anchor the complex and begins to create a small initial disruption in the membrane.

The C5b-8 complex then serves as a docking site for the final step: the recruitment and polymerization of C9 proteins. Multiple C9 molecules, between 10 and 16, are guided into place by the C8 component. These C9 molecules insert into the membrane and arrange themselves into a ring, creating the transmembrane pore that defines the MAC.

How the MAC Delivers Its Lethal Blow

Once the C5b-9 pore is fully assembled in the membrane of a target cell, it acts as an open channel. This breach disrupts the barrier between the cell’s interior and the outside environment. The balance of ions, such as sodium and potassium, is destroyed as they flow uncontrollably through the pore.

This unregulated movement of ions leads to a rapid influx of water into the cell due to osmotic pressure. The cell is unable to handle this sudden surge of fluid and begins to swell. The structural integrity of the cell membrane is overwhelmed by the internal pressure, causing the cell to rupture and die in a process known as cell lysis.

This mechanism is particularly effective against certain types of pathogens like Gram-negative bacteria, which have a thin cell wall. The MAC can also target other threats, including some parasites, enveloped viruses, and even the body’s own compromised cells.

The formation of just one or two MAC pores can be enough to kill a bacterium. The process is swift and irreversible once the pore is complete. This direct attack eliminates invaders without the need for ingestion by other immune cells like phagocytes.

Controlling the MAC: Protecting Healthy Cells

The destructive capability of the MAC requires strict regulation to ensure it only targets pathogens and not healthy host cells. The body uses control mechanisms involving specific regulatory proteins on the surfaces of its own cells to prevent self-damage.

One protective protein is CD59, also known as protectin. CD59 is a membrane-bound protein that interferes with the final step of MAC assembly. It binds to the C5b-8 complex and blocks the recruitment and polymerization of C9 molecules, preventing the formation of the pore.

Another control protein, S-protein (vitronectin), circulates in the blood plasma. If a C5b-7 complex forms in the fluid phase instead of on a cell surface, S-protein binds to it. This action prevents the complex from inserting into nearby healthy cell membranes, neutralizing it.

MAC Dysregulation and Disease

Improperly controlled MAC activity can lead to health problems. Deficiencies in the proteins that form the MAC can leave the body vulnerable to specific infections. Individuals lacking components C5 through C9 are susceptible to recurrent infections by Neisseria bacteria, which cause diseases like meningitis and gonorrhea.

Conversely, excessive MAC formation on the body’s own cells can drive several diseases. In the rare blood disorder paroxysmal nocturnal hemoglobinuria (PNH), red blood cells lack the protective CD59 protein. This absence leaves them defenseless against MAC formation, leading to their chronic destruction, severe anemia, and other complications.

Uncontrolled complement activation and MAC deposition are also implicated in other conditions. In atypical hemolytic uremic syndrome (aHUS), the MAC damages cells lining small blood vessels in the kidneys, leading to organ failure. The MAC also contributes to tissue injury in autoimmune disorders like lupus nephritis and rheumatoid arthritis, and in age-related macular degeneration, where it damages cells in the retina.