Research Blog

November 16, 2022

Protein Biomarkers: Complement C4

Optimal Takeaways

The complement system is fundamentally involved in immunity and can promote inflammation, vascular permeability, histamine release, vasodilation, and smooth muscle contraction upon activation. The system is complex and is involved with resolution of the immune response and promotion of tissue repair as well.

Elevated C4 is associated with cardiovascular disease, obesity, metabolic syndrome, diabetes, and gut dysbiosis. Low levels can be seen with recurrent infections and autoimmune disorders such as lupus and rheumatoid arthritis.

Conventional Lab Range: 15.00 – 57.00 mg/dL (0.15 – 0.57 g/L)

Optimal Dx’s Optimal Range: 16.00 – 34.00 mg/dL (0.16 – 0.34 g/L)

Low levels of C4 are associated with microbial infections, autoimmune disorders (Wang 2021), lupus (Pagana 2021) especially lupus nephritis (Martin 2017), and chronic hepatitis B and C (Wang 2021). A low ratio of C4 to C3 is associated with immune complex diseases and increased risk of ischemic vascular events in coronary syndrome (Barbu 2015).

High levels of C4 are seen with obesity, CVD, metabolic syndrome, and diabetes (Nilsson 2014, Barbu 2015), and may be seen with gut dysbiosis (Severance 2021).


Complement compounds function as cofactors, enzymes, inhibitors, and membrane-integrated proteins that facilitate inflammatory and immunologic reactions. Once activated, the complement system contributes to increased vascular permeability and helps deliver antibodies and white blood cells to the site of an immune reaction. Complement also enhances phagocytosis and antibody-antigen binding. Low levels of complement component C4, along with low C3, are associated with systemic lupus erythematosus (Pagana 2021, Li 2015).

Following an immune response, the complement system is involved in “cleaning up” and clearing soluble immune complexes and cellular debris that may remain and trigger an autoimmune reaction. Without removal of these elements, an individual is more susceptible to autoimmune disorders including lupus, systemic sclerosis, and rheumatoid arthritis. Activation pathways and complement component cleavage fragments appear to ultimately determine the effect of complement on immunity and homeostasis (Wang 2021).

Similar to elevated C3, elevated C4 is associated with higher BMI, adiposity, cardiovascular disease, metabolic syndrome. Weight loss in obese subjects is associated with a significant decline in both C4 and C3 following gastric bypass. The ratio of C4 to C3 may be an important factor as well. A low ratio of C4 to C3 may reflect consumption and depletion of C4 during complement activation, a phenomenon seen with immune complex disease. A low C4 to C3 ratio is also considered a risk factor for ischemic vascular events in coronary syndrome (Nilsson 2014, Barbu 2015).

Complement C4 is considered a chief component of innate immunity and is charged with recognizing and eliminating invading microorganisms. Deficiency of C4 is associated with increased susceptibility to infection and autoimmunity (Wang 2021). Identification of hypocomplementemia can be used as a tool in the diagnosis of systemic lupus erythematosus. Low levels of both complement C3 and C4 make the diagnosis of lupus more likely, and both should be tested during a comprehensive evaluation. Researchers found that using a cut-off of C3 below 78.5 mg/dL (0.785 g/L) with a C4 below 14.5 mg/dL (0.145 g/L) had the greatest diagnostic value for lupus (Li 2015).

Complement C4 can be activated by gut dysbiosis as well as conventional infection and this interaction may play a role in schizophrenia. In one study, specific C4 polymorphisms, combined with dysbiosis and elevated microbial plasma biomarkers, were associated with increased susceptibility to schizophrenia. Certain polymorphisms were associated with alterations in cognitive functioning in both subjects with schizophrenia and controls (Severance 2021).

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Barbu, Andreea et al. “The role of complement factor C3 in lipid metabolism.” Molecular immunology vol. 67,1 (2015): 101-7. doi:10.1016/j.molimm.2015.02.027

Li, Hejun et al. “Diagnostic value of serum complement C3 and C4 levels in Chinese patients with systemic lupus erythematosus.” Clinical rheumatology vol. 34,3 (2015): 471-7. doi:10.1007/s10067-014-2843-4

Nilsson, Bo et al. “C3 and C4 are strongly related to adipose tissue variables and cardiovascular risk factors.” European journal of clinical investigation vol. 44,6 (2014): 587-96. doi:10.1111/eci.12275

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Severance, Emily G et al. “Complement C4 associations with altered microbial biomarkers exemplify gene-by-environment interactions in schizophrenia.” Schizophrenia research vol. 234 (2021): 87-93. doi:10.1016/j.schres.2021.02.001

Wang, Hongbin, and Mengyao Liu. “Complement C4, Infections, and Autoimmune Diseases.” Frontiers in immunology vol. 12 694928. 14 Jul. 2021, doi:10.3389/fimmu.2021.694928

Tag(s): Biomarkers

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