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C4
C4 Full Name
C4
C4 Introduction
Complement component C4 is a core protein in the complement cascade of the human immune system, playing an indispensable role in innate immune defense. As a central node shared by both the Classical Pathway and the Lectin Pathway of the complement system, the activation of C4 is a critical step in initiating a series of downstream immune effects. When antibody‑antigen complexes or specific carbohydrate structures on pathogen surfaces are recognized, C4 is cleaved by the corresponding proteases (such as C1s), producing two functionally distinct fragments: C4a and C4b. The C4b fragment, via an exposed thioester bond, can covalently bind to pathogen surfaces or immune complexes, acting as a "tag". This process, known as opsonization, greatly enhances the recognition and clearance of foreign particles by phagocytes. Simultaneously, C4b is a key component of the C3 convertase (C4b2a), which catalyzes the cleavage of the more abundant downstream complement component C3, thereby amplifying the signal and ultimately leading to pathogen lysis (through formation of the membrane attack complex, MAC) or more efficient clearance. The smaller C4a fragment is released into surrounding tissues as an anaphylatoxin, exhibiting relatively weak pro‑inflammatory activity that helps recruit immune cells and modulate local inflammatory responses.
Figure 1. Schematic illustration of fragmentation of complement C4 activation. (Source: Wang H, et al. 2021)
Under normal conditions, C4 (especially the C4A isotype) plays a vital role in binding and clearing immune complexes from circulation. When C4 function is deficient, these complexes—which often contain self‑antigens—cannot be effectively removed. They then deposit in various tissues and organs such as the kidneys, skin, joints, and blood vessels, where they persistently activate immune responses, leading to widespread inflammation and tissue damage. This forms the pathophysiological basis for the multi‑system involvement seen in systemic lupus erythematosus (SLE). Furthermore, studies confirm significant genetic overlap between SLE and other autoimmune diseases, such as rheumatoid arthritis, type 1 diabetes, and autoimmune thyroid disease, meaning these conditions may share certain susceptibility genes or pathways. This suggests that dysfunction of the complement system—epitomized by C4—may represent a common upstream pathogenic link across multiple autoimmune disorders.
Large‑scale genome‑wide association studies (GWAS) have strikingly revealed a significant and robust genetic correlation between immune‑mediated diseases like SLE and schizophrenia. Fine‑mapping studies further pointed to the C4 gene within the major histocompatibility complex (MHC) region. Research indicates that structural variation in the human C4 gene—specifically, different alleles leading to varying expression levels of C4A and C4B proteins—is strongly associated with the risk of schizophrenia. A higher copy number of the C4A gene correlates with increased C4A expression in the brain and a correspondingly elevated risk of developing schizophrenia. The mechanism behind this breakthrough finding points to a key role of C4 in synaptic pruning. During adolescent brain maturation, the complement system (including C4) participates in tagging and removing redundant or weaker synaptic connections—a physiological process essential for shaping refined and efficient neural circuits. However, excessive C4A expression may lead to exaggerated synaptic pruning during adolescence, excessively weakening neuronal connectivity and impairing normal brain function, ultimately manifesting as the positive, negative, and cognitive symptoms of schizophrenia.
Alternate Names for C4
acidic C4; Acidic complement C4; basic C4; basic complement C4; C3 and PZP-like alpha-2-macroglobulin domain-containing protein 2; C3 and PZP-like alpha-2-macroglobulin domain-containing protein 3; C4; C4, chido form; C4, Rodgers form; C4-1
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