The human immune system contains a network of proteins known as the complement system, which protects the body from pathogens. Complement C5 is the fifth component of a cascade of over 30 proteins that, when activated, defend against infection and cellular injury. C5’s activation is a point where multiple immune surveillance pathways converge, making it a central hub in this defensive network.
The Role of C5 in the Complement System
The complement system is part of the innate immune response, serving as a first line of defense. It can be triggered through three primary activation pathways: the classical, lectin, and alternative. Although each pathway uses different molecules to recognize threats, they all converge to generate a specialized enzyme called C5 convertase.
The formation of C5 convertase is the commitment point in the complement cascade. The enzyme’s purpose is to find and cleave the C5 protein, initiating a series of events in the immune response. This cleavage unleashes the protein’s biological activities.
The Dual Functions of C5 Activation
When C5 convertase cleaves the C5 protein, it splits into two fragments: C5a and C5b. The smaller fragment, C5a, is a potent anaphylatoxin and a chemoattractant. This means it acts as an alarm signal, causing localized inflammation and sending a chemical trail that recruits immune cells, such as neutrophils and macrophages, to the site of infection.
The larger fragment, C5b, initiates the formation of the Terminal Complement Complex, more commonly known as the Membrane Attack Complex (MAC). C5b binds to a pathogen’s surface and recruits other complement proteins (C6, C7, C8, and C9). Together, these proteins assemble into a structure that inserts into the pathogen’s cell membrane, creating a pore that leads to cell lysis and death.
Consequences of C5 Deficiency
The absence of a functional C5 protein is a rare, inherited disorder known as C5 deficiency. This condition impairs the body’s ability to form the Membrane Attack Complex. While other parts of the complement system may be intact, the inability to complete this final step leaves individuals vulnerable to specific bacterial infections.
This vulnerability is most pronounced with bacteria of the Neisseria genus. Individuals with C5 deficiency experience recurrent infections, particularly with Neisseria meningitidis, the bacterium responsible for meningitis, and Neisseria gonorrhoeae. This susceptibility underscores the MAC’s function in defending against this class of bacteria, which have thin cell walls that are susceptible to the complex’s pore-forming action.
C5’s Role in Disease and Inflammation
While C5 defends against pathogens, its effects can become destructive if the complement system is activated inappropriately against the body’s own cells. This dysregulation can lead to inflammatory and autoimmune diseases where signals from C5a and the MAC are misdirected, causing chronic inflammation and tissue injury.
One example is Paroxysmal Nocturnal Hemoglobinuria (PNH), a blood disorder where the MAC destroys red blood cells. In Atypical Hemolytic Uremic Syndrome (aHUS), uncontrolled complement activation leads to MAC formation on cells lining small blood vessels, particularly in the kidneys, which can trigger blood clots and lead to kidney failure. In the autoimmune disorder Myasthenia Gravis, the MAC contributes to the destruction of the neuromuscular junction, resulting in muscle weakness.
Therapeutic Targeting of C5
C5’s role in driving inflammation and cell damage in certain diseases has made it a target for therapeutic intervention. Drugs known as C5 inhibitors have been developed to control complement over-activation. These therapies are typically monoclonal antibodies, which are proteins designed to recognize and bind to the C5 protein.
These inhibitors work by binding to C5, which physically blocks the C5 convertase enzyme from cleaving it. This prevents the generation of both the C5a fragment and the C5b fragment that initiates the MAC. By halting these effects, C5 inhibitors can stop the damage in diseases like PNH, aHUS, and Myasthenia Gravis. A consequence of this blockade is an increased risk of Neisseria infections, making vaccination a necessary precaution for patients.