The C4 complement test quantifies the amount of Complement component 4 protein circulating in the bloodstream. C4 is part of the complement system, a network of immune proteins that defends the body against pathogens and clears damaged cells. Assessing C4 levels provides insight into immune system function and activity in response to inflammation or disease. The test is often ordered when an autoimmune condition or a systemic inflammatory disorder is suspected.
How the Complement System Works
The complement system is part of the innate immune system, functioning as a cascade of protein interactions to quickly identify and eliminate threats. Its purpose is to enhance the body’s defense mechanisms, including marking pathogens for destruction, promoting inflammation, and directly destroying microbial cells. The system activates through a sequence of steps involving the cleavage of inactive proteins into active fragments.
Three main pathways initiate this cascade: the Classical, the Lectin, and the Alternative pathways. The Classical pathway is triggered by the binding of antibodies to an antigen. The Lectin pathway begins when proteins bind to specific sugar molecules on microbes, while the Alternative pathway is triggered when components encounter foreign surfaces.
All three pathways converge to activate the C3 protein, creating the C3 convertase enzyme complex. This enzyme cleaves C3 into C3a and C3b, dramatically amplifying the immune response. This cascading effect ensures a robust and rapid defense action against a potential threat.
C4’s Specific Role in Immune Defense
C4 is positioned early within the immune cascade, acting as a bridge between initial threat detection and the main amplification step. It is a defining component of both the Classical and Lectin activation pathways. In the Classical pathway, the activated C1 complex cleaves C4, while the enzyme MASP-2 performs this cleavage in the Lectin pathway.
The C4 protein splits into two fragments, C4a and C4b, which serve distinct functions. C4a promotes inflammation and attracts immune cells to the site of infection. The larger fragment, C4b, binds covalently to the surface of a pathogen or an immune complex, tagging the target for destruction by phagocytic immune cells (opsonization).
C4b is also a building block for the Classical and Lectin pathway C3 convertase enzyme. It associates with the protein fragment C2a to form the C4b2a complex, which is responsible for cleaving C3. Its activity is directly linked to the activation of these two specific immune defense pathways.
Diseases and Disorders C4 Helps Monitor
The C4 complement test helps diagnose and monitor conditions involving overactive or deficient immune responses.
Systemic Lupus Erythematosus (SLE)
C4 monitoring is common in managing SLE, an autoimmune disease where immune complexes activate the complement system. This activation leads to the consumption of C4 and C3 proteins. Tracking C4 levels helps monitor the activity and severity of the disease, particularly in conditions like lupus nephritis.
Hereditary Angioedema (HAE)
The test is particularly important for diagnosing HAE, a rare genetic disorder causing recurrent episodes of severe swelling. In HAE, a deficiency in the C1 inhibitor protein allows the C1 complex to continuously cleave C4 and C2, leading to their depletion. Measuring C4 levels, often with C1 inhibitor function, is a standardized method for confirming this diagnosis.
Other Conditions
Low C4 levels can point toward the involvement of the Classical pathway in various forms of vasculitis and immune complex diseases. The test is also useful for screening rare, inherited deficiencies of the C4 protein itself. These deficiencies can predispose individuals to recurrent infections and autoimmune conditions.
Understanding Your C4 Test Levels
The clinical interpretation of C4 test results depends on the patient’s symptoms and the concurrent levels of other complement components, particularly C3.
Low C4 Levels
A low C4 level indicates the protein is being rapidly consumed due to active disease, such as an ongoing autoimmune flare or an acute immune complex disorder. For known autoimmune diseases like SLE, a falling C4 level signals increasing disease activity or a worsening condition.
High C4 Levels
A high C4 level suggests an acute phase response, where the liver produces more C4 as a reaction to inflammation or infection. C4 is an acute phase reactant, so its levels may rise significantly in response to tissue damage or systemic infection. If a patient is undergoing treatment, a rising C4 level can be a positive sign that therapy is effectively reducing immune system over-activation.
C3 and C4 Correlation
C4 results are reviewed alongside C3 levels to help pinpoint which pathway is activated. Low levels of both C3 and C4 indicate Classical pathway activation, a pattern seen in immune complex diseases. An isolated low C4 level with a normal C3 level suggests a problem higher up in the cascade, such as Hereditary Angioedema or an inherited C4 deficiency.