The complement system is a complex network of proteins that forms a major part of the body’s innate immune response, acting as a rapid defense mechanism against invading pathogens and damaged host cells. Numerous serum proteins circulate in the blood in an inactive form, waiting for a trigger to begin a chain reaction. Complement C3 and C4 are two of the most abundant and central proteins within this system, playing a significant role in initiating and propagating the immune response. When the system is activated, these proteins are cleaved into smaller, active fragments that help coordinate the body’s defense, becoming active only when they encounter a specific molecular trigger, such as a microbe or an immune complex.
Core Function of C3 and C4 in Immune Defense
The complement system can be initiated through three distinct pathways: the classical, the lectin, and the alternative pathway, all of which converge on the activation of C3. C4 is directly involved in the classical and lectin pathways, serving as an early component in those cascades. In the classical pathway, C4 is cleaved after an antibody-antigen complex binds to the initial complement protein, C1. The resulting C4 fragments then combine with cleaved C2 to form an enzyme complex known as the C3 convertase.
This C3 convertase is the central biological mechanism, regardless of the initiating pathway, as its function is to cleave the C3 protein. C3 is the most abundant complement protein, and its cleavage into C3a and C3b is a major turning point in the immune response. The C3b fragment rapidly coats the surface of pathogens, a process called opsonization, which tags the invader for engulfment and destruction by phagocytic cells. C3a is a smaller fragment that recruits immune cells to the site of infection and promoting inflammation.
Once C3b is attached to the pathogen surface, it can bind to the C3 convertase to form a C5 convertase, which then cleaves C5, leading to the final stage of the cascade. This terminal phase involves the assembly of the Membrane Attack Complex (MAC), a structure that creates a pore in the membrane of the target cell, causing the pathogen to lyse and die. C4’s initial involvement in the classical and lectin pathways ensures that C3 is cleaved, thus providing the C3b necessary for this entire amplification loop.
The Purpose of C3 and C4 Testing
A physician orders C3 and C4 blood tests to investigate the status of a patient’s complement system, which can be an indicator of various disease states. These tests measure the concentration of the circulating, inactive forms of these proteins in the serum. The results provide insight into whether the complement system is excessively activated, is deficient due to genetic or acquired reasons, or is consumed by a disease process.
The clinical application of these tests is broad, often used in the diagnosis and monitoring of autoimmune disorders, such as Systemic Lupus Erythematosus (SLE). They are also ordered when a patient presents with symptoms suggesting inflammation in the joints, kidneys, or connective tissues, such as glomerulonephritis or vasculitis. C3 and C4 levels can help investigate cases of recurrent infections, which may suggest a rare inherited deficiency in the complement system. The concentration of these proteins helps determine the severity and progression of an immune complex-related condition and tracks the effectiveness of treatment over time.
Understanding High and Low Levels
The interpretation of C3 and C4 levels is complex and depends on the pattern of elevation or reduction, as well as the patient’s symptoms. High levels of both C3 and C4 are often seen because they are acute-phase proteins, meaning their production increases during inflammation, infection, or trauma. This elevation is a non-specific response, reflecting the body’s attempt to mobilize its defenses, and can be found in conditions like cancer or ulcerative colitis.
Low levels, however, are clinically more significant, as they indicate that the complement proteins are being consumed faster than the liver can produce them. This consumption often occurs when the immune system is actively attacking the body’s own tissues, a hallmark of autoimmune disease. Low levels of both C3 and C4 suggest the activation of the classical complement pathway, which is triggered by the formation of immune complexes.
This pattern, where both C3 and C4 are reduced, is a frequent finding in active Systemic Lupus Erythematosus, especially when the disease is affecting the kidneys (lupus nephritis). A sudden drop in these levels in a patient diagnosed with lupus often signals a flare-up of disease activity. Conversely, a low C3 level combined with a normal C4 level suggests the primary activation of the alternative pathway. This pattern can be seen in infectious diseases, such as post-streptococcal glomerulonephritis, or in disorders involving abnormal regulation of the alternative pathway.
A deficiency in C4 alone, with a normal C3 level, may point toward a hereditary deficiency of C1-inhibitor, which is associated with hereditary angioedema. Genetic deficiencies of C3 are rare, but deficiencies in other proteins can also result in persistently low C3 levels, which increase the risk of recurrent bacterial infections. Analyzing the relative concentrations of C3 and C4 allows for a more targeted diagnosis and management plan.