C3a is used as an inflammatory marker. High levels indicate specific immune- or inflammation-related health problems. C3a levels will be high in Lyme disease but remain low in “mold illnesses”. Keep reading to learn more about high and low C3a levels, their causes and health effects.
What is C3a?
Complement proteins are important for the body’s immune function and inflammatory response. The body needs them to respond to injury, bacterial, and viral infections in a balanced way. Nine main complement proteins exist, labeled C1-C9, of which C3 is most frequently measured [1, 2].
C3a is short for Complement Component 3a. It’s a small fragment of the very large and better-known C3. Since C3a is involved in triggering serious, anaphylactic allergic reactions, it is referred to as an “anaphylatoxin”.
The Good
C3 and C3a are essential for arming the immune system with antibodies to fight microbes. Once the complement system is activated, C3 releases C3a. This small fragment (C3a) knows exactly where the invader is and guides white blood cells to its site (monocytes and macrophages) [3, 4].
C3a may also be important for tissue regeneration. Studies are ongoing about the role of this molecule in muscle regeneration after injury and liver regeneration [5, 6].
The Bad
On the downside, an overactive complement system increases inflammation. By activating white blood cells, C3a sets off the release of inflammatory molecules (IL-1beta, TNF-alpha, IL-6, and PGE2). It can also bind to mast cells and increase the release of histamine. Its constant overactivity in chronic diseases contributes to chronic inflammation [7].
Is C3a Inflammatory or Anti-Inflammatory?
C3a is most commonly seen as inflammatory, alongside its cousin C5a. Indeed, high C3a, in the long run, does worsen chronic inflammation.
But C3a can also act as an anti-inflammatory in acute inflammation and following sudden injuries. For example, it can oppose the effects of C5a and prevent the buildup of neutrophils in tissues, which altogether reduces inflammation and improves recovery [7].
C3a Blood Test
You will need to undergo a standard blood draw for the C3a test. C3a is not usually tested unless a person shows symptoms of lupus, Lyme disease, or another specific inflammatory disease. Some practitioners run C3a tests to rule out mold illnesses, although there is not much research to back this up.
Other blood tests that can help monitor inflammatory conditions include ESR (erythrocyte sedimentation rate), CRP (C-reactive protein), ferritin, IL-6, and TNF-alpha.
Normal Range
C3a normally ranges from 50 to 200 ng/ml [8]. The range may vary among different labs due to differences in techniques, equipment, and chemicals used.
“Mold Illnesses”
C3a levels in people with “mold illness” will typically remain within the normal range. C3a levels will remain normal because mold doesn’t contain the cell membranes (like bacteria do) that usually raise its levels. In an observational study, 1,000 people exposed to water-damaged, moldy buildings and mold had normal C3a levels [9].
However, in an observational study of 15 people, those exposed to mold had increased C3a levels in their tear fluid due to eye inflammation. This indicates that mold exposure can still sometimes result in an increased release of C3a [10].
High C3a Levels
Causes of High C3a Levels
Causes listed below are commonly associated with high C3a levels. Work with your doctor or another health care professional to get an accurate diagnosis. Your doctor will interpret your results, taking into account your medical history, symptoms, and other test results.
1) Inflammation
C3a levels can increase during an inflammatory condition and return back to normal when the inflammation is resolved. But most people with chronic inflammatory conditions will have this marker constantly increased. Their immune systems and inflammatory responses are continuously activated, forcing the complement system to keep releasing C3a [11, 12].
Asthma
Asthma is a chronic inflammatory condition in which C3a levels are high, which worsens the narrowing of the airways and other symptoms.
In one observational study, 50 people with severe asthma had very high C3a levels. After treatment, C3a levels dropped back to normal [13, 14].
In another study of 26 athletes, C3a levels increased after exercise but more so in asthmatic than in healthy athletes. The rise in C3a explains the worsening of asthma some people experience from intense exercise [15].
Some people with asthma are especially sensitive to aspirin (Advil) and similar anti-inflammatory drugs, which worsen their airway inflammation and provoke nose and sinus symptoms. In a study of 54 people with asthma patients, those who suffered from this type of aspirin-induced asthma had higher C3a levels [16].
Hepatitis
In various observational studies, people with chronic hepatitis C had high C3a levels [17, 18].
Pancreas Inflammation
In a study of 34 people, patients with acute pancreas inflammation (pancreatitis) had higher C3a blood levels. C3a levels were also increased during acute pancreatitis attacks in another study of 51 people [19, 20].
2) Autoimmune Diseases
Autoimmune disorders occur when the body mistakenly directs the immune response against its own tissues. It can cause inflammatory injury to various tissues, activate the complement system, and result in high C3a levels [21, 22].
People with active lupus have high C3a levels, which further increase as the disease worsens [23].
A similar pattern follows most autoimmune diseases, even the rare ones. For example, primary antiphospholipid syndrome is an autoimmune disorder in which the immune system attacks normal proteins in the blood. As the complement system is activated, C3a levels also increase [8].
3) Lyme Disease
People with acute Lyme Disease (caused by a Borrelia burgdorferi infection) have higher C3a levels than healthy people. It’s unknown exactly how long C3a remains high [24].
4) Smoking
Smoking significantly increases C3a levels, which may worsen the narrowing of airways in smokers [25].
5) Stroke
C3a levels are increased in people who suffered from a stroke, regardless of what caused the stroke (unknown origin or due to a blockage of large vessels in the brain) [26].
6) Cancer
Colon (colorectal) cancer patients have higher C3a levels than healthy people. Cancer treatment significantly reduced C3a levels in several studies [27, 28, 3].
C3a is also increased in patients with liver and esophageal cancer [17, 18, 29].
C3a can contribute to cancer development by maintaining chronic inflammation, suppressing the immune response, promoting new blood vessel growth, and increasing the mobility and metastatic potential of cancer cells [30].
7) Pregnancy
Normal, healthy pregnancies are associated with increased C3a levels. During pregnancy, C3a and complement proteins are activated to protect the body from microbes. In pregnancy, a more active complement system compensates for a less active adaptive immune system [31].
Health Effects of High C3a Levels
Airway Inflammation and Breathing Problems
As an anaphylatoxin, C3a can provoke all the symptoms of an anaphylactic reaction, in milder or more severe form depending on its levels and other inflammatory markers. A lot of these symptoms affect the lungs and airways, such as throat or tongue swelling, coughing, and shortness of breath.
Higher C3a levels were associated with a worsening of severe asthma. C3a triggers inflammation and narrows the airways, which causes coughing and shortness of breath during asthma attacks [13].
Hardening of the Arteries and Heart Disease
In a study of 545 people, higher C3a was linked to the hardening of the arteries. C3a was also associated with heart disease, but only in smokers [32].
How to Lower C3a Levels
C3a levels are usually due to underlying health issues. That’s why the most important thing is to work with your doctor to find out what’s causing your high C3a levels and to treat any underlying conditions!
The additional lifestyle changes listed below are other things you may want to discuss with your doctor. None of these strategies should ever be done in place of what your doctor recommends or prescribes!
Lower Inflammation
Lowering inflammation can prevent C3 activation and C3a levels from increasing. Some ways to lower inflammation include [33, 34]:
- Mapping out and addressing any underlying inflammatory condition
- Regular exercise
- Stress reduction
- Anti-inflammatory supplements such as omega-3s and curcumin
Remember, always speak to your doctor before taking any supplements, because they may interfere with your health condition or your treatment/medications!
Quit Smoking
Since smoking activates the complement system, quitting smoking will prevent C3a levels from increasing [25].
Avoid Allergens
Avoid known allergens, such as peanuts. They can trigger C3a production [35].
Low C3a Levels
Causes of Low C3a Levels
Causes listed below are commonly associated with low C3a levels. Work with your doctor or another health care professional to get an accurate diagnosis. Your doctor will interpret your results, taking into account your medical history, symptoms, and other test results.
Hereditary C3 Deficiency
C3a levels are low in hereditary C3 deficiency. People with this rare disorder suffer frequent bacterial infections [36].
Gestational Diabetes
Gestational diabetes occurs when previously healthy women develop high blood sugar during pregnancy. Normally, C3a levels rise during pregnancy. But one study suggests that women who develop diabetes during pregnancy may have significantly lower C3a levels than healthy pregnant women [37].
C3a Genetics: Obesity and Brain Inflammation
The complement system is a crucial part of the immune response. C3a binds to the C3a receptor (C3aR). Fat and immune cells contain a large number of these receptors. In animal studies, an increased number of C3aRs, due to a high activity of genes that produce them, is linked to insulin resistance and obesity [38, 39].
For example, mice lacking these receptors were completely resistant to obesity, had improved insulin sensitivity, and lower inflammation despite being on a harmful high-fat diet [38].
Mice without C3aR also had less brain inflammation and a lower risk of neurodegenerative diseases in another study. C3a can cross the blood-brain barrier, especially if it is “leaky“, triggering brain inflammation and potentially triggering a cascade that causes further brain damage [40].
However, research has yet to confirm whether this also holds true in humans. It’s important to stress that what’s found in animal studies, doesn’t always match what’s later found in humans. We will update the article as soon as new findings from human studies become available.
