Complement C4 is a protein that is important for your immune function. It helps clear infections and protects against autoimmunity. Low levels increase the risk of various autoimmune disease, including lupus. High levels, on the other hand, mean that there is more inflammation in the body. They increase your risk of developing metabolic syndrome and heart disease. Read on to find out more about this protein.

What is Complement C4?

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

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 [R].

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 [R].

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

Complement C4 and Autoimmunity

C4 has an important role in suppressing autoimmunity. One of the ways it does this is by promoting the production of treg cells [R, R].

When C4 is absent, cell debris is not cleared effectively. This increases the number of self-reactive (autoimmune) white blood cells [R].

Scientists have shown that C4 protects mice from developing lupus. Mice deficient in C4 spontaneously develop a lupus-like autoimmune disease [R, R].

People with lupus often have low C4 (and other complement) levels [R].

Complement C4 Normal Range

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

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.

Low Complement C4 Levels

Low C4 levels are often found in autoimmune conditions or when there are issues that interfere with C4 production (e.g. liver disease) [R].

Factors That Decrease Complement C4 Levels

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 [R, R].

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

Low C4 levels are also found in:

  • Sjögren’s syndrome [R]
  • Celiac disease [R]
  • Juvenile dermatomyositis [R]
  • Juvenile idiopathic arthritis [R]
  • Autoimmune hepatitis [R]
  • IgA nephropathy (IgAN) [R]
  • Cold agglutinin disease [R, R]
  • Hereditary angioedema [R]

However, in another autoimmune disease, rheumatoid arthritis, C4 levels can be either low, normal, or high [R].

2) High Fat Diets

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

Although the mechanism here is unknown, one possible explanation is that overfeeding and excess fat reduce the liver’s ability to produce complement proteins [R].

3) Liver Diseases

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

Chronic liver disease patients 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 [R].

4) Beta Thalassemia

Low C4 levels were found in 60 patients with beta thalassemia [R].

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 [R].

5) Malaria

Complement C4 levels can fall during acute malaria [R, R].

6) Complement Deficiency

Complement deficiency is a genetic disorder that causes low complement levels [R].

While complete C4 deficiency is very rare (there are less than a 100 recorded cases to date), partial C4 deficiency is pretty common. It occurs in up to 30 – 40 % of populations of European descent [R, R, R].

Health Effects of Low Complement C4 Levels

Low C4 Levels Increase the Risk of Infections

C4 helps clear microbes. When C4 levels are low, the immune system can’t fight invading bacteria and viruses efficiently. That is why having low complement C4 levels increases your risk of infections [R, R, R, R, R, R]

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

Low C4 Levels Increase the Risk of Autoimmune Disease

C4 is important for immune tolerance. When there is a lack of C4, your immune system can start reacting against the body’s own cells. Low C4 levels increase the risk of developing autoimmune disease, such as lupus and juvenile idiopathic arthritis [R].

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

Partial C4 deficiencies also predisposes people to different autoimmune disease, including:

  • Lupus [R, R, R, R]
  • Type 1 diabetes [R]
  • Celiac disease [R]
  • Autoimmune hepatitis [R]
  • Vitiligo [R]
  • Juvenile idiopathic arthritis [R]
  • Vogt-Koyanagi-Harada (VKH) syndrome [R]

High Complement C4 Levels

Factors That Increase Complement C4 Levels

1) Inflammatory Conditions

Complement C4 rises with inflammation [R, R].

C4 levels can increase with other inflammatory proteins, such as CRP and homocysteine [R, R].

Inflammatory conditions that increase C4 levels include:

  • Obesity [R] – C4 levels increase with BMI (body mass index) [R]
  • Crohn’s disease and ulcerative colitis (IBD) [R, R]
  • Skin conditions, such as psoriasis, dermatitis, and hives (urticaria) [R, R]
  • Psoriatic arthritis [R]
  • Rheumatoid arthritis [R, R, R]
  • Rheumatic fever, an inflammatory disease that may result from untreated strep throat [R]
  • Inflammation and kidney failure in IgA nephropathy [R]
  • Various cancers [R, R]

2) Pregnancy

Complement C4 levels normally rise during pregnancy [R].

3) Drugs

Drugs such as cimetidine (Tagamet) can increase complement C4 levels [R].

Health Effects of High Complement C4 Levels

1) High C4 Levels Increase the Risk of 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 3000 people, higher complement C4 levels were associated with a higher risk of metabolic syndrome after a four-year follow-up [R].

2) High C4 Levels Increase the Risk of Heart Disease

In an observational study of 5,850 initially healthy men, higher complement C4 were 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 [R].

Ways to Change Your Complement C4 Levels

How to Increase Complement C4 Levels

Refrain from overeating and reduce your intake of fatty foods. Eating a high-fat diet may reduce your complement C4 levels [R].

Supplements such as mangosteen can help boost C4 levels [R].

Avoid:

  • Cannabis — it inhibits the immune system, including C4 (shown in 60 users and 30 controls) [R]
  • Exposure to heavy metals such as lead [R]
  • Exposure to allergens such as cotton dust and cereal grain [R, R, R+]

How to Decrease Complement C4 Levels

Make life choices that will help reduce any chronic inflammation:

  • Lose weight if you are overweight [R]
  • Switch to an anti-inflammatory diet
  • Exercise
  • Get enough sleep
  • Reduce stress

Supplements that can help:

Avoid exposure to toxins such as styrene [R]

Complement C4 Genetics

C4 is highly variable. There are two genes that encode this protein: C4A and C4B [R].

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 [R, R, R].

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 [R].

The copy number and the size of C4 genes determine the blood C4 protein concentrations. Blood levels increase in a linear fashion with 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 [R].

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

C4 Genes and Lifespan

Several studies have linked low C4B copy number with shorter life span [R, R, R]. This would make sense, because lower C4 levels increase the risk of infections. However, these studies included only a couple dozen to a couple hundred subjects. Furthermore, other studies failed to support this link [R].

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

C4 Genes and Disease

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

Low number of C4B copies has been associated with a higher risk of infections [R].

Also, low C4B copy number has been linked to heart disease (heart attack, stroke) [R, R, R].

On the other hand, multiple copies of the C4B gene can aggravate IBD, through escalated complement reactivity towards the microbiota [R].

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