The immune system is a network of cells and proteins that defend the body against infection. A part of this network is the complement system, a group of over 50 proteins primarily produced by the liver. These proteins circulate in the blood as inactive precursors, or zymogens. The system was named for its ability to “complement” the function of antibodies, but it is also a part of the body’s innate immunity, able to act without them. As a first line of defense, it clears damaged cells and protects against invaders like viruses and bacteria. Activation of these proteins sets off a cascade, where each activated protein triggers the next, amplifying the response to neutralize threats.
The Primary Functions of the Complement System
Once activated, the complement system performs several defensive actions. The first is the direct destruction of pathogens through a structure called the Membrane Attack Complex (MAC). Complement proteins assemble on a microbe’s surface, creating a pore that disrupts its cellular integrity, causing it to burst and die.
Another function is tagging pathogens for removal by other immune cells, a process called opsonization. Complement proteins, such as C3b, coat a microbe’s surface. This coating acts as a flag, making the pathogen more visible to phagocytic cells like macrophages. These phagocytes have receptors that recognize the bound complement proteins, allowing them to more easily identify, engulf, and destroy the invader.
The system also recruits other immune cells to an infection site. During the activation cascade, small protein fragments like C3a and C5a are released. These fragments act as chemical signals that attract immune cells, such as neutrophils, to the area in a process known as chemotaxis. This helps marshal an inflammatory response precisely where it is needed to fight the infection.
Activation Pathways
The complement system is initiated through three main pathways that lead to the same protective outcomes. The first is the classical pathway, which is activated when antibodies, specifically IgM or IgG, have bound to an antigen on a pathogen’s surface. The C1 complement complex recognizes these antibodies, initiating the enzymatic cascade.
A second trigger is the lectin pathway, which does not rely on antibodies. It is initiated when mannose-binding lectin (MBL) attaches to sugar molecules present on the surfaces of many microbes. This binding event activates associated enzymes, which then cleave other complement proteins to start the cascade in a manner similar to the classical pathway.
The third route is the alternative pathway, which functions as a constant surveillance system. It can be triggered directly by pathogen surfaces without antibodies or lectins. This pathway involves the spontaneous activation of the C3 protein in the blood. When this activated C3b protein encounters a pathogen surface, it binds and kicks off an amplification loop, rapidly depositing more C3b molecules and driving the cascade forward.
The Role of Complement in Health and Disease
Imbalances in the complement system can lead to medical conditions. An underactive system, caused by a protein deficiency, weakens the body’s ability to fight infections. This can result in recurrent infections, especially from bacteria that require opsonization for clearance, and is a form of primary immunodeficiency.
Conversely, an overactive or poorly regulated system can damage healthy tissues, contributing to autoimmune and inflammatory conditions. For example, in systemic lupus erythematosus (SLE), over-activation by immune complexes contributes to tissue damage. It is also involved in certain kidney diseases, like C3 glomerulopathy, and has been linked to the progression of age-related macular degeneration.
The system’s involvement extends to other conditions as well, including rheumatoid arthritis, certain types of anemia, and the rejection of transplanted organs. In these conditions, inappropriate activation of the complement cascade leads to chronic inflammation and cell injury. The location where complement is activated can determine whether its effects are helpful or harmful.
Regulation and Medical Assessment
The complement system is tightly controlled by regulatory proteins to prevent it from attacking the body’s own cells. Proteins like Decay-Accelerating Factor (CD55) and Factor H are present on host cells and in the blood. They inhibit the complement cascade by inactivating components like C3b if they land on a healthy cell, preventing unwanted damage.
When a problem with the complement system is suspected, doctors use specific blood tests to assess its activity. The most common tests measure the levels or function of individual complement proteins, such as C3 and C4. Another test is the CH50 assay, which evaluates the overall function of the classical pathway by measuring the ability of a patient’s serum to lyse antibody-coated red blood cells.
Low levels of complement proteins may suggest a deficiency or that the proteins are being consumed by ongoing inflammation or infection. Conversely, abnormal levels can point towards an autoimmune condition where the system is overactive. These measurements provide doctors with information to help diagnose and monitor conditions related to complement system dysfunction.