Research Blog

November 15, 2022

Protein Biomarkers: Complement C3

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 levels of the C3 component are associated with cardiovascular disease, obesity, metabolic syndrome, and diabetes. Low levels can be seen with recurrent infections and autoimmune disorders such as lupus and rheumatoid arthritis.

Conventional Lab Range: 82.00 – 185.00 mg/dL (0.82 – 1.85 g/L)

Optimal Dx’s Optimal Range: 82.00 – 112.00 mg/dL (0.82 – 1.12 g/L)

Low levels of complement are associated with congenital or acquired disorders as well as persistently overactivated immunity which can deplete complement. Low complement C3 is associated with recurrent bacterial infections (Pagana 2021), while low levels of both C3 and C4 are seen with lupus (Li 2015).

High levels of complement suggest acute immune system activation and may be seen with cardiovascular disease, insulin resistance, metabolic syndrome, diabetes, kidney disease (Hertle 2012, Hertle 2014), inflammation, obesity (Nilsson 2014), rheumatoid arthritis (Pagana 2021), asthma, ARDS (Sarma 2011), hyperlipidemia, NAFLD, cholestasis, primary biliary cirrhosis, and sclerosing cholangitis. Complement can increase following a meal (Barbu 2015).

Overview

The complement system is an integral part of the immune system. Complement compounds function as cofactors, enzymes, inhibitors, and membrane-integrated proteins that facilitate inflammatory and immunologic reactions. Once activated, portions of the complement system increase vascular permeability and help deliver antibodies and white blood cells to the site of an immune reaction. Complement also enhances phagocytosis and antibody-antigen binding. Levels are assessed in the monitoring of autoimmune or infectious disease. Complement can become depleted with chronic overactivation and low levels of complement component C3 are associated with recurrent bacterial infections (Pagana 2021). However, both overactivation and depletion can contribute to autoimmune disorders (Jia 2022).

Complement is involved in “cleaning up” and clearing soluble immune complexes and cellular debris that may remain after an immune response 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).

The complement system supports both innate and adaptive immunity as part of its host defense role. It can participate in both tissue regeneration and pathology such as tumor growth, hemolytic uremia, and age-related macular degeneration. The most abundant complement protein in circulation is C3. Its activation causes vasodilation, smooth muscle contraction, histamine release, cytokine production, and inflammation…activities that can have persistent negative effects if not kept in check. Causes of C3 elevation include environmental toxins, cigarette smoke, and ozone, and increased levels may be seen with asthma and acute respiratory distress syndrome (ARDS). However, insufficient C3 or its blockage by pathogens can also have negative effects and increase susceptibility to infection (Sarma 2011). C3 supports antiviral activities that help prevent viral replication as well, though some viruses can antagonistically degrade C3 in their defense (Tam 2014).

A review of the literature finds that C3 maintains a linear relationship with serum triglycerides, CRP, waist circumference, and risk of metabolic syndrome, type 2 diabetes, and coronary heart disease. The association of C3 with cardiometabolic disorders may be mediated by its interactions with apolipoprotein E and apoA-1 particles (Onat 2011).

Complement factors can be produced in adipose tissue and appear to contribute to local inflammation, obesity, cardiometabolic disorders, dyslipidemia, endothelial dysfunction, and fatty liver. The positive versus negative effects of complement activation appear to depend on which pathway is activated; the lectin pathway may have favorable cardiometabolic effects while the classic and alternative pathways appear to have unfavorable effects. Elevated C3 in particular is associated with cardiometabolic disorders including insulin resistance, metabolic syndrome, diabetes, liver dysfunction, and cardiovascular disease. Complement can be carried on HDL. Elevated HDL C3 has been observed in individuals with coronary heart disease and is associated with the presence of pro-atherogenic HDLs in lupus patients (Hertle 2012, Hertle 2014).

Elevations in C3 and C3a fragments are associated with obesity, high triglycerides, non-alcoholic fatty liver disease, primary biliary cirrhosis, and sclerosing cholangitis. In obesity, C3 activation fragments from adipose tissue promote release of pro-inflammatory cytokines proportional to the level of adiposity, further increasing systemic inflammation in a vicious cycle. The increase in C3 may also negatively affect fat metabolism, serum triglycerides, and blood pressure. In the PIVUS study of 1,016 70-year-olds, elevated C3 strongly correlated with abdominal fat distribution and BMI, blood pressure, triglycerides, and glucose. A 2-fold increase in metabolic syndrome risk was observed with each standard deviation increase in C3 (Barbu 2015). Mean C3 levels in the study were 0.94 g/L in men and 0.96 g/L in women (Nilsson 2014).

Identification of hypocomplementemia can be used as a tool in the diagnosis of systemic lupus erythematosus. Low levels of both C3 and C4 make the diagnosis of lupus more likely, and both should be tested. 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).

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References

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

Hertle, E et al. “Complement C3: an emerging risk factor in cardiometabolic disease.” Diabetologia vol. 55,4 (2012): 881-4. doi:10.1007/s00125-012-2462-z

Hertle, E et al. “The complement system in human cardiometabolic disease.” Molecular immunology vol. 61,2 (2014): 135-48. doi:10.1016/j.molimm.2014.06.031

Jia, Changhao, Ying Tan, and Minghui Zhao. "The complement system and autoimmune diseases." Chronic Diseases and Translational Medicine (2022).

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

Onat, Altan et al. “Complement C3 and cleavage products in cardiometabolic risk.” Clinica chimica acta; international journal of clinical chemistry vol. 412,13-14 (2011): 1171-9. doi:10.1016/j.cca.2011.03.005

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

Sarma, J Vidya, and Peter A Ward. “The complement system.” Cell and tissue research vol. 343,1 (2011): 227-35. doi:10.1007/s00441-010-1034-0

Tam, Jerry C H et al. “Intracellular sensing of complement C3 activates cell autonomous immunity.” Science (New York, N.Y.) vol. 345,6201 (2014): 1256070. doi:10.1126/science.1256070

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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