C3a is usually an inflammatory marker, although it can even reduce inflammation in rare cases. High levels indicate specific immune- or inflammation-related health problems. Your C3a levels will be high if you have Lyme disease but remain low if you suffer from 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 your body’s immune function and inflammatory response. Your 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 [R, R].

C3a is short for Complement Component 3a. It’s a small peptide fragment of the very large and better-known sugar-bound protein (glycoprotein) 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) [R, R].

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 [R, R].

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 [R].

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 [R].

c3a
Image taken from Liam G. Coulthard et al www.jimmunol.org/content/194/8/3542

C3a Blood Test

You will need to undergo a standard blood draw for the C3a test. It is analyzed through a method known as radioimmunoassay (RIA). 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, TNF-alpha, and fibrinogen.

Normal Range

C3a normally ranges from 50 to 200 ng/ml [R].

The reference range may vary among different labs.

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 [R].

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 [R].

Low C3a Levels

Causes of Low C3a Levels

Gestational Diabetes

Gestational diabetes occurs when previously healthy women develop high blood sugar during pregnancy. Normally, C3a levels rise during pregnancy. But women who develop diabetes during pregnancy have significantly lower C3a levels than healthy pregnant women. Low C3a levels may increase the risk of infections [R].

Hereditary C3 Deficiency

C3a levels are low in hereditary C3 deficiency. People with this rare disorder suffer frequent bacterial infections [R].

High C3a Levels

Causes of High C3a Levels

1) Inflammation

C3a levels can increase during any inflammatory condition and return back to normal if 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 [R, R].

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 [R, R].

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 [R].

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 [R].

Hepatitis

In various observational studies, people with chronic hepatitis C had high C3a levels [R, R].

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 [R, R].

2) 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 [R].

3) Smoking

Smoking significantly increases C3a levels, which may worsen the narrowing of airways in smokers [R].

4) 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) [R].

5) Lyme Disease

People with acute Lyme Disease (caused by a Borrelia burgdorferi infection) have higher C3a levels than healthy people. It’s unknown for exactly how long C3a remains high, as in chronic Lyme Disease [R].

6) 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 [R, R].

People with active lupus have high C3a levels, which further increase as the disease worsens [R].

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 [R].

7) Cancer

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 [R].

Colon (colorectal) cancer patients have higher C3a levels than healthy people. Cancer treatment significantly reduced C3a levels in several studies [R, R, R].

C3a is also increased in patients with liver and esophageal cancer [R, R, R].

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 [R].

Acute respiratory distress syndrome (ARDS) occurs when fluids leak into the lungs and block oxygen flow. In a study of 24 critically-ill patients, those who developed this syndrome had higher C3a levels than those who did not [R].

Hardening of the Arteries and Heart Disease

In a study of 545 people, higher C3a was linked to hardening of the arteries. C3a was also associated with heart disease, but only in smokers [R].

Increased Risk of Death after a Stroke or Blood Poisoning

In a study of 150 people, high C3a levels 3 months and up to 2 years after a stroke were linked to an increased risk of death. This was true only for those who experienced a stroke due to a blockage in large vessels of the brain [R].

In a study of 48 patients with life-threatening blood poisoning known as sepsis, the risk of dying was proportionally higher as C3a levels increased [R].

How to Lower C3a Levels

Lower Inflammation

Lowering inflammation can prevent C3 activation and C3a levels from increasing. Some ways to lower inflammation include [R, R]:

Quit Smoking

Since smoking activates the complement system, quitting smoking will prevent C3a levels from increasing [R].

Avoid Allergens

Avoid known allergens, such as peanuts. They can trigger C3a production [R].

Supplements

The following supplements help block the conversion of C3 into C3a:

C3a Genetics: Obesity and Brain Inflammation

The complement system is a crucial part of the immune response. C3a controls its signaling by binding to the C3a receptor (C3aR). Fat and immune cells contain a large number of these receptors. An increased number of C3aRs, due to a high activity of genes that produce them, is linked to insulin resistance and obesity [R, R].

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 [R].

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”, trigger brain inflammation and potentially trigger a cascade that causes further brain damage [R].

Blocking C3aR naturally, especially in people prone to inflammation and obesity may be a useful strategy. Curcumin had been researched for its ability to block the complement cascade, including C3a. Although useful in most cases of chronic inflammation, one animal study suggests it may be harmful to the brain in lupus [R].

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