Complement component 4 (C4) is a protein that serves as part of the body’s immune defense system. Found in blood plasma and on cell surfaces, C4 helps defend against harmful bacteria and viruses. Monitoring C4 protein levels can assist medical professionals in diagnosing and managing various chronic conditions.
The Complement System and C4’s Role
The complement system is a complex network of many proteins that forms part of the innate immune system, providing immediate defense against microbes. These proteins, mostly produced in the liver, circulate in the blood as inactive precursors. When activated, proteases within the system cleave these proteins, initiating a cascade that amplifies the immune response.
The complement system identifies and eliminates pathogens, clears dead cells, and regulates inflammation. It enhances the ability of antibodies and phagocytic cells (immune cells that engulf foreign particles) to clear microbes and damaged cells. The system also promotes inflammation, attracting additional immune cells to infection sites, and can directly attack pathogen cell membranes.
C4 holds a position within the classical pathway of the complement system. This pathway activates when complement protein C1 binds to antibodies attached to antigens on a pathogen’s surface or a damaged cell. Once activated, C1 cleaves C4 into fragments, including C4b, which then binds to the pathogen surface.
C4b, with C2b, forms an enzyme complex known as C3 convertase. This convertase cleaves C3, a central complement protein, into C3a and C3b. C3b then binds to the pathogen surface, a process called opsonization, tagging the pathogen for destruction by phagocytic cells. The classical pathway also clears immune complexes (antigen-antibody clusters) and apoptotic bodies (dead cells), helping prevent autoimmune reactions.
Understanding C4 Gene Variations
C4 is not a single gene but exists in two main forms, C4A and C4B, which have slightly different functions. These genes are located within the major histocompatibility complex (MHC) region. Individuals can have varying numbers of C4A and C4B gene copies, a phenomenon known as copy number variation (CNV). The total number of C4 copies can range from two to eight in a diploid genome.
The varying copy numbers of C4A and C4B influence the amount of C4 protein produced. For example, approximately 80% of individuals of European ancestry have three to four C4 genes. The number of C4A gene copies can range from zero to five, and C4B copies can range from zero to four.
C4 gene variation includes the presence of a human endogenous retrovirus (HERV-K) insertion within some C4 genes. This retroviral insertion is found in intron 9 of about 60-76% of human C4 genes, leading to a longer gene variant (C4L), while those without the insertion are considered short C4 genes (C4S). The HERV-K insertion may influence gene expression and potentially offer a defense mechanism against retroviral infections.
How C4 Variations Influence Health
Variations in C4 gene copy numbers and forms of C4A and C4B are associated with various health conditions. Low C4 copy numbers or deficiencies are linked to an increased risk of autoimmune diseases, such as Systemic Lupus Erythematosus (SLE), rheumatoid arthritis (RA), and Grave’s disease. In SLE, low C4 levels, often alongside low C3 levels, are observed during active inflammation or disease flares. This impaired immune complex clearance (where the body struggles to remove antigen-antibody clusters and cellular debris) can contribute to autoimmune disorders.
High C4A copy numbers are linked to an increased risk of schizophrenia. Research indicates that individuals with forms of the C4 gene leading to higher C4A expression have an elevated risk of schizophrenia. C4 protein is found in human neurons and at synapses (the junctions between nerve cells).
In brain development, C4 plays a role in synaptic pruning, a process where excess synaptic connections are eliminated during adolescence. Studies suggest that excessive C4 activity can lead to over-pruning of synapses, contributing to the reduced number of synapses and thinner cerebral cortex observed in individuals with schizophrenia. While exact mechanisms are still being explored, this excessive pruning, particularly during adolescence when schizophrenia symptoms often emerge, may disrupt neural connections and contribute to the disorder’s cognitive symptoms.
Assessing C4 Levels
C4 levels are typically measured through a blood test in a clinical setting. This test, often referred to as a complement C4 test, quantifies the amount of C4 protein circulating in the bloodstream. The normal range for C4 generally falls between 10 to 48 milligrams per deciliter (mg/dL), though values can vary slightly between different laboratories.
Abnormal C4 levels can provide insights into a person’s immune system activity. Low C4 levels, often below 10-15 mg/dL, might suggest an underlying complement deficiency, an active autoimmune disease like lupus, liver diseases such as hepatitis or cirrhosis, or kidney problems. In autoimmune conditions, low C4 levels may indicate disease activity, and an increase towards the normal range might suggest a positive response to treatment.
Conversely, high C4 levels, typically above 45 mg/dL, can indicate inflammatory conditions or recent infections, as the body produces more complement proteins during an active immune response. Elevated C4 levels can also be associated with conditions such as cancer, ulcerative colitis, obesity, metabolic syndrome, and diabetes. It is important to note that C4 test results are part of a broader diagnostic process and require interpretation by a healthcare professional, who will consider them alongside other clinical findings and patient history.