C3 deficiency is a rare, genetic condition classified as a primary immunodeficiency, meaning it impairs the body’s immune system from birth. This condition is characterized by extremely low levels of Complement Component 3 (C3), a protein central to immune defense. Inherited C3 deficiency is an autosomal-recessive disorder, requiring a person to inherit a mutated gene from both parents. The resulting lack of C3 leaves the body vulnerable, leading to serious health consequences that affect the ability to fight infection and manage inflammation.
Understanding the Function of Complement Component 3
Complement Component 3 is the central protein of the complement system, which is a major part of the innate immune response. This protein acts as the point where the three main pathways of complement activation—the classical, alternative, and lectin pathways—all converge. Once C3 is activated, it is cleaved into smaller, highly active fragments that perform essential immune functions.
One of C3’s main roles is opsonization, where a fragment of the protein, C3b, attaches to the surface of a foreign invader like a bacterium. This tagging process effectively labels the pathogen, making it recognizable and an easy target for phagocytes—specialized immune cells that engulf and destroy foreign material. Without this C3b tag, the immune system’s scavenger cells struggle to identify and eliminate the threat efficiently.
A second major function involves the formation of the Membrane Attack Complex (MAC). C3b is a necessary component for the subsequent activation of other complement proteins (C5 through C9) that assemble to form the MAC. The MAC inserts itself into the outer membrane of a target cell, such as a bacterium, creating a pore or hole that causes the pathogen to rupture and die. C3 is therefore essential for both tagging pathogens for internal destruction and actively killing them through cell lysis.
Health Consequences of C3 Absence
The absence of functional C3 leads to a failure in these fundamental immune processes, resulting in two main categories of serious health problems. The most immediate and life-threatening consequence is a profound susceptibility to severe, recurrent bacterial infections, which often begin early in life. This heightened vulnerability is particularly pronounced for encapsulated bacteria, which possess a protective outer layer that makes them difficult to clear without C3-mediated opsonization.
Common pathogens include Streptococcus pneumoniae and Haemophilus influenzae, which frequently cause infections in the respiratory tract like pneumonia, tonsillitis, and sinusitis. Individuals with C3 deficiency also face an increased risk of severe infections caused by the Neisseria species, such as Neisseria meningitidis, which can lead to life-threatening meningitis and sepsis. The inability to form the Membrane Attack Complex means the body cannot efficiently lyse these bacteria, allowing infections to become invasive and rapidly progress.
Beyond infections, C3 deficiency is also associated with a higher risk of immune complex-mediated diseases. Normally, C3 is involved in clearing immune complexes—clumps of antibodies bound to foreign material—from the bloodstream. When this clearance mechanism fails, these complexes can deposit in organs, leading to inflammatory conditions.
This failure is linked to the development of autoimmune disorders that resemble systemic lupus erythematosus (SLE) and various kidney diseases. A specific and severe kidney condition, C3 glomerulopathy (C3G), can occur, resulting from the uncontrolled deposition of C3 protein fragments in the kidney’s filtering units. Regular monitoring of kidney function is therefore a necessary part of managing this deficiency.
Diagnosis and Management Strategies
Identifying C3 deficiency typically begins with functional laboratory tests that measure the overall activity of the complement system. The CH50 assay assesses the classical complement pathway, while the AH50 assay evaluates the alternative pathway. In C3 deficiency, both tests show very low or zero activity, indicating a shared component problem.
Following functional tests, C3 protein levels are measured directly. A confirmed diagnosis of inherited C3 deficiency shows extremely low or undetectable C3 levels, which can be further confirmed through genetic testing for mutations in the C3 gene. This testing differentiates the primary, inherited form from secondary C3 consumption, which is often seen in autoimmune or acquired kidney diseases.
Management of C3 deficiency is primarily focused on prevention and prompt treatment of infections. Due to the persistent vulnerability to encapsulated bacteria, patients are often placed on long-term prophylactic antibiotics to reduce the frequency and severity of bacterial episodes. Vaccination is essential, targeting bacteria the patient is most susceptible to, such as Streptococcus pneumoniae and Neisseria meningitidis. While complement protein replacement is generally not a practical option, regular medical follow-up with an immunologist is essential to address any infections quickly and monitor for the development of autoimmune or renal complications.