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Complement C4 Test, Autoimmunity, Infections & Inflammation

Written by Puya Yazdi, MD | Last updated:
Jonathan Ritter
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology) | Written by Puya Yazdi, MD | Last updated:

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Complement C4 is a protein that is important for your immune function. It helps clear infections and protects against autoimmunity. Low levels may point to autoimmune disease, including lupus. High levels are rare, poorly understood, and may signal inflammation. Read on to find out more about the C4 test.

What is Complement C4?

Overview

C4 is one of over 30 small proteins of the complement system, which is an important part of the immune system [1].

Scientists think that the complement system improves the function of antibodies and phagocytes — cells that ingest harmful particles, bacteria, and dead or dying cells. In other words, it “complements” antibodies and phagocytes, helping them clear microbes and damaged cells more effectively [1].

Complement C4, in particular, marks targets that need to be cleared, such as microbes, immune complexes, and dying cells. It also activates other complement proteins and promotes immune tolerance [2].

C4 is produced by some white blood cells (macrophages) and the liver [3]. It circulates in the blood as inactive and becomes activated by specific immune signals [1, 4].

Test & Normal Range

Lab results are commonly shown as a set of values known as a “reference range”, which is sometimes referred to as a “normal range”. A reference range includes the upper and lower limits of a lab test based on a group of otherwise healthy people.

Your healthcare provider will compare your lab test results with reference values to see if any of your results fall outside the range of expected values. By doing so, you and your healthcare provider can gain clues to help identify possible conditions or diseases.

Doctors will usually order a complement C4 blood test if they suspect that you have lupus or another autoimmune disease.

C4 levels will be decreased in these non-hereditary autoimmune disorders. For example, people with lupus often have low C4 (and other complement) levels [5].

Other rare conditions that may also lower C4 levels include hereditary angioedema and congenital C4 deficiency.

Normal complement C4 levels in the blood are between 16 and 47 mg/dL (milligrams per deciliter), or 0.16 to 0.47 g/L (grams per liter). Levels may vary slightly between laboratories.

Your healthcare provider will recommend follow-up testing or treatment based on your results.

Some lab-to-lab variability occurs due to differences in equipment, techniques, and chemicals used. Don’t panic if your result is slightly out of range – as long as it’s in the normal range based on the laboratory that did the testing, your value is normal.

However, it’s important to remember that a normal test doesn’t mean a particular medical condition is absent. Your doctor will interpret your results in conjunction with your medical history and other test results.

Have in mind that a single test isn’t enough to make a diagnosis. Your doctor will interpret this test, taking into account your medical history and other tests. A result that is slightly low/high may not be of medical significance, as this test often varies from day to day and from person to person.

Autoimmunity

C4 is implicated in suppressing autoimmunity. Researchers suspect that one of the ways it does this is by promoting the production of Treg cells [6, 7].

When C4 is absent, cell debris is not cleared effectively. This increases the number of self-reactive (autoimmune) white blood cells, although bacterial infections will still be cleared normally [3].

Scientists hypothesize that C4 protects mice from developing lupus. Mice deficient in C4 spontaneously develop a lupus-like autoimmune disease. We can’t apply these findings directly to humans, though [6, 8].

Low Complement C4 Levels

Factors shown here are commonly associated with low complement C4 levels. Low levels are often found in autoimmune conditions or when there are issues that interfere with C4 production (e.g. liver disease) [3].

Work with your doctor or other health care professional for an accurate diagnosis.

Associated Factors

1) Autoimmune Disease

Low complement C4 levels are most commonly found in lupus (systemic lupus erythematosus), an autoimmune disease where the immune system attacks the body’s own tissues [9, 10].

Patients with lupus can have persistently low C4 levels (< 10 mg/dL). Alternatively, they can have fluctuating levels, with low levels corresponding to disease flare-ups [11].

Low C4 levels are also found in:

  • Sjögren’s syndrome [12]
  • Celiac disease [13]
  • Juvenile dermatomyositis [14]
  • Juvenile idiopathic arthritis [15]
  • Autoimmune hepatitis [16]
  • IgA nephropathy (IgAN) [17]
  • Cold agglutinin disease [18, 19]
  • Hereditary angioedema [20]

However, in another autoimmune disease, rheumatoid arthritis, C4 levels can be either low, normal, or high. Blood levels may also differ from joint levels [21].

2) Complement Deficiency

Complement deficiency is a genetic disorder that causes low complement levels. Undetectable levels usually point to congenital (inborn) C4 deficiency [22].

While complete C4 deficiency is very rare (there are less than 100 recorded cases to date), partial C4 deficiency is pretty common. It’s estimated to occur in up to 30 – 40 % of populations of European descent [22, 23, 24].

3) Liver Disease

In an observational study, 66 patients with hepatitis C had low complement C4 levels compared to 50 healthy people [25].

Chronic liver disease patients may also have lower complement C4 levels. In an observational study of over 120 people, liver disease patients (primary biliary cirrhosis, chronic active hepatitis, and cirrhosis) had significantly lower complement C4 levels [26].

Larger studies are needed to determine if measuring C4 levels is relevant in people with liver disease.

4) Beta Thalassemia

Low C4 levels were found in 60 patients with beta-thalassemia in one study [27].

It’s possible that multiple blood transfusions, which represent the only treatment for this disease, lead to continuous contact with various infection factors, causing overuse of the complement factors. Changes in the immune system due to iron overload may also be a contributing factor, but this is still just a hypothesis [27].

More research is needed.

5) Malaria

Limited research suggests that complement C4 levels may fall during acute malaria, but more studies are needed to confirm the link [28, 29].

6) High-Fat Diets

A high-fat diet decreased blood C4 levels in a study of 46 healthy people. This decrease was linked to an increase in insulin resistance [30].

Although the mechanism here is unknown, one possible explanation is that overeating and excess fat reduce the liver’s ability to produce complement proteins. This has yet to be properly verified in large human studies [30].

Potential Health Effects

Risk of Infections

C4 helps clear microbes. Some evidence suggests that when C4 levels are low, the immune system can’t fight invading bacteria and viruses efficiently. That is why low complement C4 levels are thought to increase the risk of infections. However, there’s still an alternate pathway that can clear bacteria from the body [31, 32, 33, 34, 35, 36].

People with C4 gene deficiencies are more likely to suffer from gum and sinus inflammation (chronic periodontitis and chronic or recurrent rhinosinusitis) [37, 24].

Autoimmune Disease Risk

C4 is involved in immune tolerance. When there is a lack of C4, the immune system may start reacting against the body’s own cells. Researchers think that low C4 levels increase the risk of developing an autoimmune disease, such as lupus and juvenile idiopathic arthritis [35].

More than 75% of people who are completely deficient in C4 proteins develop lupus or lupus-like disease [2].

Partial C4 deficiencies are also hypothesized to predispose people to different autoimmune disease, including:

  • Lupus [38, 10, 2]
  • Type 1 diabetes [39]
  • Celiac disease [13]
  • Autoimmune hepatitis [16]
  • Vitiligo [40]
  • Juvenile idiopathic arthritis [15]
  • Vogt-Koyanagi-Harada (VKH) syndrome [41]

A causal relationship has yet to be determined, though. Have in mind that many other factors can also contribute to autoimmune disease risk.

High Complement C4 Levels

Factors shown here are commonly associated with high complement C4 levels. Work with your doctor or other health care professional for an accurate diagnosis.

Additionally, the potential causes and health effects of high complement C4 levels are still poorly understood. We know more about high complement C4 levels.

Associated Factors

1) Inflammatory Conditions

Research suggests that complement C4 may rise with some types of low-grade inflammation [42, 43].

C4 levels sometimes increase with other inflammatory proteins, such as CRP and homocysteine [44, 45].

Inflammatory conditions that have been associated with increased C4 levels include:

  • Obesity [46] – C4 levels appear to increase with BMI (body mass index) [47]
  • Crohn’s disease and ulcerative colitis (IBD) [48, 49]
  • Skin conditions, such as psoriasis, dermatitis, and hives (urticaria) [50, 51]
  • Psoriatic arthritis [52]
  • Rheumatoid arthritis [53, 54, 55]
  • Rheumatic fever, an inflammatory disease that may result from untreated strep throat [56]
  • Inflammation and kidney failure in IgA nephropathy [57]
  • Some types of cancers [58, 59]

However, some of the mentioned studies had mixed findings. Plus, complement C4 levels can vary throughout the body and levels in a certain tissue (e.g. joints) may not correspond to blood levels. More research is needed to understand the relevance of complement C4 levels in these diseases.

2) Pregnancy

Complement C4 levels normally rise during pregnancy [60].

3) Drugs

Drugs such as cimetidine (Tagamet) may increase complement C4 levels, but more research is needed [61].

Potential Health Effects

Metabolic Syndrome

Metabolic syndrome is a condition characterized by three or more of the following symptoms: high blood pressure, high blood sugar, abnormal cholesterol, abnormal triglyceride levels, and increased stomach fat.

In an observational study of over 3,000 people, higher complement C4 levels were associated with a higher risk of metabolic syndrome after a four-year follow-up. These findings need to be replicated in multi-center studies [42].

Heart Disease

In an observational study of 5,850 initially healthy men, higher complement C4 was associated with an increased risk of stroke or heart attack over the following 18 months. C4 was correlated with other heart risk factors, such as cholesterol, blood pressure, and BMI [43].

Since this study dealt with associations, we don’t know whether complement C4 levels were the cause, consequence, or a random association with heart disease risk. More research is needed.

Factors that May Affect Complement C4 Levels

Precautions & Limitations

Remember that complex autoimmune disorders always involve multiple possible factors – including biochemistry, environment, health status, and genetics – that may vary from one person to another.

Work with your doctor to treat any underlying conditions causing your abnormal complement C4 levels.

You may try the strategies listed above if you and your doctor determine that they could be appropriate. Read through the approaches we bring up and discuss them with your doctor before trying them out. This is particularly important if you plan to take any dietary supplements.

Most of the lifestyle, dietary, and supplement factors listed in this article rely on animal and cellular data. These findings can’t be applied to humans. Clinical research is needed before the safety and effectiveness of any approach listed in this post is determined.

Additionally, supplements have not been approved by the FDA for medical use. Supplements generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective.

Thus, we’re providing a summary of the existing research, which should guide further investigational efforts. However, the studies listed should not be interpreted as supportive of any health benefit.

Proposed to Increase Complement C4

Refrain from overeating and reduce your intake of fatty foods. Eating a high-fat diet may reduce complement C4 levels. Plus, diets high in unhealthy fats may have other detrimental health effects [30].

Supplements such as mangosteen help boost C4 levels in animals [62].

It might be a good idea to avoid:

  • Cannabis, which tends to inhibit the immune system, including C4 (shown in 60 users and 30 controls) [63]
  • Exposure to heavy metals such as lead [64]
  • Exposure to allergens such as cotton dust and cereal grain [65, 66, 67]

Proposed to Decrease Complement C4 Levels

Some life choices that help reduce chronic inflammation may be helpful, such as:

The following supplements are being researched for lowering inflammation and complement C4 levels:

Human data are lacking.

Cannabis is also being investigated for reducing inflammation and complement C4. But remember that the use of cannabis is illegal under federal law in the US. Its use remains controversial because of a risk of addiction and side effects [63].

Avoiding exposure to toxins such as styrene may also be a good idea [71].

Complement C4 & Genetics

C4 seems to be highly variable. There are two genes that encode this protein: C4A and C4B [72].

Both genes have varying copy numbers, ranging between 2 and 8. In a study of over 500 healthy Americans of European descent, about 60% of people had 4 copies of C4 genes, 27% had less, and 12% had more than 4 copies [23, 2, 73].

In addition, both C4A and C4B differ in size; they can be short or long (longer variants are due to a retrovirus). In Whites, about 76% of the C4 genes belong to the long form and 24% to the short form [23].

The copy number and the size of C4 genes might determine the blood C4 protein concentrations. Blood levels increase in a linear fashion with the total C4 gene copy number. Further, those with one or more short C4 genes have higher blood C4 levels than those with long C4 genes only [23].

Partial deficiency of C4A or C4B has been described in up to 30 – 40% of populations of European descent [23, 24].

C4 Genes and Lifespan

Several studies have linked low C4B copy number with a shorter life span, but this association is still highly controversial [74, 75, 76].

Some scientists try to explain it by saying that since lower C4 levels tend to increase the risk of infections, they might shorten lifespan. No solid data back them up. The existing studies included only a couple dozen to a couple of hundred subjects. Furthermore, other studies failed to support this link [23].

Another study found that people without long C4 variants were less likely to be long-lived [23].

More research is needed.

C4 Genes and Disease

The following associations are mostly based on small-scale or lower-quality studies. More research is needed to determine their relevance.

Low C4 and C4A copy numbers are related to an earlier onset and a more severe course of lupus [77].

A low number of C4B copies has been associated with a higher risk of infections [78].

Also, a low C4B copy number has been linked to heart disease (heart attack, stroke) [79, 80, 81].

On the other hand, multiple copies of the C4B gene were associated with IBD worsening, through escalated complement reactivity towards the microbiota. This has yet to be confirmed in future studies [82].

About the Author

Puya Yazdi

Puya Yazdi

MD
Dr. Puya Yazdi is a physician-scientist with 14+ years of experience in clinical medicine, life sciences, biotechnology, and nutraceuticals.
As a physician-scientist with expertise in genomics, biotechnology, and nutraceuticals, he has made it his mission to bring precision medicine to the bedside and help transform healthcare in the 21st century.He received his undergraduate education at the University of California at Irvine, a Medical Doctorate from the University of Southern California, and was a Resident Physician at Stanford University. He then proceeded to serve as a Clinical Fellow of The California Institute of Regenerative Medicine at The University of California at Irvine, where he conducted research of stem cells, epigenetics, and genomics. He was also a Medical Director for Cyvex Nutrition before serving as president of Systomic Health, a biotechnology consulting agency, where he served as an expert on genomics and other high-throughput technologies. His previous clients include Allergan, Caladrius Biosciences, and Omega Protein. He has a history of peer-reviewed publications, intellectual property discoveries (patents, etc.), clinical trial design, and a thorough knowledge of the regulatory landscape in biotechnology.He is leading our entire scientific and medical team in order to ensure accuracy and scientific validity of our content and products.

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