C3

Complement C3 (C3) plays a central role in the complement system, a critical component of innate immunity. As the convergence point of all three complement pathways, C3 is implicated in several inflammatory and immune-mediated diseases, making it an attractive drug target. In recent years, therapeutic strategies targeting C3 have been developed to attenuate excessive complement activation in diseases such as paroxysmal nocturnal hemoglobinuria (PNH), age-related macular degeneration (AMD), and atypical hemolytic uremic syndrome (aHUS).

NCBI Gene ID: 718

UniProtKB ID: P01024

Function of C3

C3 is primarily synthesized in the liver and circulates as an inactive precursor. Upon activation by C3 convertases (C4b2a in the classical/lectin pathway and C3bBb in the alternative pathway), C3 is cleaved into C3a and C3b. C3a functions as an anaphylatoxin, promoting inflammation through mast cell degranulation and leukocyte recruitment, whereas C3b functions as an opsonin, facilitating phagocytosis and clearance of immune complexes. In addition, C3b amplifies complement activation by forming additional C3 convertases, resulting in a positive feedback loop that enhances the immune response.

The importance of C3 in immune defense is further emphasized by its ability to interact with complement receptors, which mediate various immunoregulatory functions. CR1 aids in the clearance of immune complexes and inhibits complement activation, while CR2 plays a role in B cell activation and adaptive immunity. CR3 and CR4 contribute to phagocytosis and immune cell adhesion, further emphasizing the role of C3 in orchestrating immune responses. In addition, C3 degradation products such as iC3b and C3dg contribute to immune modulation by dampening excessive inflammation and promoting immune tolerance.

Figure 1. Three extracellular complement initiation pathways culminate in a common terminal pathway. (Girardi et al., 2020)

Role of C3 in Disease Pathogenesis

Due to its central role in complement activation, C3 dysregulation is implicated in numerous pathological conditions:

Autoimmune Diseases

• Systemic Lupus Erythematosus (SLE): In SLE, defective clearance of apoptotic cells and immune complexes results in excessive complement activation. C3 cleavage products contribute to the formation of immune deposits in tissues, leading to chronic inflammation, glomerulonephritis, and multi-organ damage. Hypocomplementemia (low C3 levels) is often observed in active SLE flares, indicating persistent complement consumption.
• Rheumatoid Arthritis (RA): In RA, synovial inflammation is exacerbated by complement activation, with C3 fragments contributing to the recruitment of inflammatory cells. The formation of immune complexes in joint tissues leads to persistent complement activation, synovial hyperplasia, and cartilage destruction. Elevated C3a levels correlate with disease severity and joint damage.

Renal Diseases

• Atypical Hemolytic Uremic Syndrome (aHUS): Mutations in complement regulatory proteins (e.g., Factor H, Factor I, MCP/CD46) result in uncontrolled C3 activation, leading to thrombotic microangiopathy. This manifests as endothelial damage, platelet activation, and kidney failure due to microvascular thrombosis.
• C3 Glomerulopathy (C3G): Persistent activation of the alternative pathway leads to deposition of C3 fragments in the glomeruli, triggering chronic inflammation and fibrosis. C3G includes dense deposition disease (DDD) and C3 glomerulonephritis (C3GN), both of which are characterized by complement dysregulation leading to progressive renal failure.

Hematologic Disorders

• Paroxysmal Nocturnal Hemoglobinuria (PNH): PNH results from mutations in the PIGA gene, leading to a deficiency of GPI-anchored complement regulators (CD55 and CD59) on erythrocytes. This leads to uncontrolled C3 activation and subsequent intravascular hemolysis, anemia, and thrombotic complications. C3 inhibitors such as pegcetacoplan have shown efficacy in reducing hemolysis and transfusion dependency in PNH patients.

Neurological and Ocular Disorders

• Age-related Macular Degeneration (AMD): Excessive alternative pathway activation contributes to retinal inflammation and drusen formation, a hallmark of AMD. Genetic polymorphisms in complement regulators (e.g., Factor H) increase susceptibility to C3-mediated retinal damage, leading to progressive vision loss.
• Alzheimer's Disease: Neuroinflammation driven by C3 activation has been implicated in the pathogenesis of Alzheimer's disease. C3a and C3b promote microglial activation, synaptic pruning, and neuronal injury. Elevated cerebrospinal fluid (CSF) C3 levels correlate with amyloid plaque accumulation and disease progression in Alzheimer's disease patients.

Therapeutic Strategies Targeting C3

Targeting C3 Given its central role in complement activation, C3 inhibition represents a promising therapeutic approach. Several strategies have been developed to target C3 directly or modulate its activation pathways.

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Reference

1. Girardi G, Lingo JJ, Fleming SD, Regal JF. Essential role of complement in pregnancy: from implantation to parturition and beyond. Front Immunol. 2020;11. doi:10.3389/fimmu.2020.01681