Complement proteins C3 and C4: systemic innate immunity and glaucoma progression

Glaucoma is a chronic eye condition in which the optic nerve slowly deteriorates, leading to progressive vision loss (arxiv.org). While high eye pressure is a well-known risk factor, emerging research suggests the immune system – especially the innate immune system – may also influence glaucoma. In particular, scientists are studying complement proteins C3 and C4, which are blood proteins involved in the body’s first-line defense, to see if they play a role in optic nerve damage. This article explains what C3 and C4 do, how complement activation might relate to glaucoma damage, and whether measuring C3/C4 in the blood could help predict disease progression (compared with other inflammation tests like hs-CRP or the systemic immune-inflammation index (SII)). We will also note factors (like autoimmune disease or infection) that can affect complement levels, and mention any known genetic links.

The complement system and innate immunity

The complement system is part of innate immunity – the body’s rapid, non-specific defense against infections or damage. Complement consists of a cascade of proteins in the blood that, when activated, help “tag” invading microbes or dying cells so they can be cleared by immune cells. A key step in all complement pathways is the activation of C3, a protein that splits into fragments that mark targets for destruction. The classical pathway (triggered by antibodies) and lectin pathway both use C4 early on, while the alternative pathway can amplify C3 directly. When complement is active, it helps drive inflammation and cell cleanup. For example, doctors often measure C-reactive protein (CRP) – another inflammation-related protein – to see if patients have systemic inflammation (time.com). In a similar way, unusually high or low levels of complement proteins can indicate immune activation or consumption.

Blood tests for C3 and C4 are widely available through medical labs. These tests report a patient’s C3 and C4 levels (usually in milligrams per deciliter) alongside reference ranges. Under normal conditions, C3 and C4 stay within a standard range. If a test shows low C3/C4, it can mean that complement is being actively used up (for example, in an ongoing autoimmune reaction). If levels are high, it may indicate an acute reaction to infection or injury. In practice, C3/C4 tests are commonly ordered by doctors for autoimmune diseases (like lupus) or certain infections. Patients can obtain these tests through their doctor, or in some regions via direct-to-consumer lab services. The results usually note “high,” “normal,” or “low” relative to normal ranges. For example, CRP (measured by a simple blood test) “can tell doctors how much inflammation” a patient has (time.com), and doctors interpret complement similarly – in context. Because many conditions can affect complement levels, any abnormal result needs professional interpretation.

Complement activation and glaucoma damage

Could complement be involved in glaucoma neurodegeneration? In other words, does stress on the optic nerve trigger the complement cascade, contributing to damage? This is an area of active research. In many neurodegenerative diseases (such as Alzheimer’s), scientists have found that complement proteins can accumulate in the brain and help microglia (brain immune cells) remove synapses and neurons. By analogy, some researchers suspect that in glaucoma, damaged retinal nerve cells might also activate complement. For example, glial cells (support cells in the retina and optic nerve head) under chronic stress could release signals that trigger C3 or C4. Activated complement fragments (like C3b) can bind to nearby cells or debris. This might help clear away waste, but could also accidentally tag healthy nerve fibers for destruction, enhancing inflammation. However, direct evidence in glaucoma is still limited. Animal studies and eye tissue analyses have shown some complement presence in glaucomatous eyes, but it’s not fully proven whether this causes additional damage or is simply a response. In short, scientists suspect complement may play a role in glaucomatous optic nerve injury, but the exact effect is not yet settled in humans.

Most importantly, no large clinical study has yet confirmed that blood levels of C3 or C4 can predict glaucoma progression. Researchers are proposing studies that would measure patients’ serum C3 and C4 over time and see if changes correlate with worsening vision fields or nerve measurements. If complement activation contributes to damage, one might hypothesize that patients with higher or lower C3/C4 (depending on the mechanism) could have faster progression. But to test this properly, a study must control for other factors that influence complement.

Adjusting for other factors affecting C3/C4

Any study of serum C3/C4 must adjust for other conditions that change complement levels. For example:

• Autoimmune diseases. Conditions like systemic lupus erythematosus (SLE) or rheumatoid arthritis can dramatically consume complement. In lupus, immune complexes use up complement components, so doctors often see low C3 and C4 during flares. One news report described a lupus patient whose kidneys failed because “her immune system had been attacking her own body all that time” (apnews.com). In such cases, doctors know to check complement levels. In a glaucoma study, researchers would need to know if a patient has lupus or similar autoimmune diseases, because this could lower C3/C4 independently of anything happening in the eye.

• Infections. Active infections usually raise complement activity (a part of the immune response). For example, a severe infection or inflammation (like pneumonia) can cause a temporary increase in C3/C4 as the body ramps up innate defense. A patient recovering from an infection might have elevated complement unrelated to glaucoma.

• Medications and supplements. Certain drugs can influence complement. For example, eculizumab (a medication for rare blood disorders) directly inhibits complement, lowering C3/C4 levels. Steroids and immunosuppressants used for autoimmune disease can also indirectly alter complement activity. Some supplements (like high-dose niacin) might affect inflammatory proteins in the blood. A proper study would need to record relevant medications and possibly exclude patients on complement-altering drugs.

If researchers find a link between C3/C4 and glaucoma progression, they would have to show that it still holds up after accounting for these factors. In practical terms, a doctor interpreting a patient’s C3/C4 test looks for clues of infection or autoimmune disease first. For the patient: it means you should share your medical history (e.g. lupus, infections, medications) when discussing complement test results with your doctor.

Genetic variants in complement pathways

Some people have genetic differences (variants) in complement genes that affect how much C3 or C4 they make. For example, complement factor H (CFH) gene variants are famous risk factors for age-related macular degeneration (a different eye disease) – they lead to higher complement activation in the retina. In glaucoma, a few studies have looked for genetic links in the complement system, but nothing is definitive yet. No common C3 or C4 gene mutation has been confirmed as a major glaucoma risk factor. That said, if a patient did carry a known complement-related variant (from experimental genome testing), it would be another reason to pay attention to their complement levels. At present, genetic testing for complement variants is not a standard part of glaucoma care.

Comparing C3/C4 to hs-CRP and SII

High-sensitivity C-reactive protein (hs-CRP) and the Systemic Immune-Inflammation Index (SII) are two other blood-based inflammation markers. Unlike C3/C4 which are specific to the complement cascade, CRP is a general acute-phase protein made by the liver, and SII is a calculation based on blood cell counts. Here’s how they compare:

• hs-CRP: This blood test measures tiny amounts of CRP. It is widely used in heart disease and other fields to gauge low-level chronic inflammation. A doctor can order hs-CRP easily, and it reports a number (e.g. mg/L) with risk categories. Higher CRP generally means more inflammation. Studies have looked at CRP in glaucoma with mixed results; some found no clear link. However, CRP is not specific to the eye – many factors (like obesity, smoking, infection) can raise it. As one source noted, CRP testing tells doctors “how much inflammation their patients have” (time.com), which is useful in general but not glaucoma-specific.

• Systemic Immune-Inflammation Index (SII): This is a newer marker calculated from your complete blood count:

  SII = (Platelet count) × (Neutrophil count) / (Lymphocyte count).
  

  All three values come from a standard blood test. The idea is that high neutrophils and platelets (with low lymphocytes) indicate an active inflammatory state. SII has been studied as a prognostic marker in cancers and cardiovascular diseases, but it is not yet standard in glaucoma research. Calculating SII yourself requires no special lab – you just need a CBC results sheet – but interpreting it is not straightforward for patients.

To compare predictive values: currently no study says “hs-CRP is better” or “C3 is better” at predicting glaucoma outcomes. One would have to measure all of them in a large group of glaucoma patients over time. Each marker has pros and cons: hs-CRP is easy and cheap but non-specific; SII needs a CBC and combines several cell types; C3/C4 directly reflect the complement system. If a study were done, researchers would say, for example, “After adjusting for factors like age and treatment, does C3 level at baseline predict vision loss better than CRP or SII?” Until such data exist, we can only say that all these markers might carry some information about systemic inflammation, but none is a proven glaucoma progression test.

Practical blood tests and interpretation

For patients who want to know their complement status: C3 and C4 levels are typically ordered through a blood test by a physician. Many routine labs (like Quest or LabCorp in the U.S.) offer “Complement C3, C4” panels. The blood draw is the same as for other tests. Results are reported with reference ranges (which can vary by lab). For example, a normal C3 range might be ~90–180 mg/dL and C4 ~10–40 mg/dL. If your results fall outside the normal range, you would discuss it with your doctor. Interpretation:

• Low C3 or C4: This often suggests active consumption. In practice, low complement may be seen in lupus, certain kidney diseases, or severe infections. It means your immune system is likely “using up” complement as part of an intense immune response. Alone this finding doesn’t diagnose glaucoma, but it could point to another health issue.
• High C3 or C4: Higher-than-normal levels can occur with general inflammation, but isolated high values are less common. They are sometimes interpreted as an acute-phase reaction (similar to how CRP goes up). Again, context matters – for example, pregnancy can raise C3/C4, as can obesity or metabolic syndrome.

Example: If a glaucoma patient without any known autoimmune disease has a normal eye pressure but unexpectedly low C3/C4 on a blood test, the doctor might look for an occult lupus flare or infection. If they find none, it would be unclear what that means for the glaucoma – it would need further study to say if low complement in that case predicts faster vision loss.

In summary, the complement tests are accessible, but complex. Patients can ask their eye doctor or primary care doctor about getting C3/C4 measured (and also hs-CRP or a full blood count if interested). However, getting a result is just the first step – understanding it requires medical context. For example, CRP testing (as one source explained) is guided by medical guidelines because it tells doctors about inflammation in general (time.com). Similarly, your doctor would interpret your C3/C4 in light of your whole health picture.

Conclusion

In glaucoma research, scientists are keen to understand all the factors that drive optic nerve damage. The complement system (including proteins C3 and C4) is a natural candidate because it links immunity to neurodegeneration in other diseases. So far, evidence directly tying serum C3/C4 to glaucoma progression is limited or anecdotal. To determine if these blood levels predict vision loss, future studies need to measure them in patients while carefully accounting for autoimmune diseases, infections, medications, and genetics. At present, common blood markers like hs-CRP are easier to test but are very non-specific, so it’s not clear if complement proteins would offer any advantage in predicting glaucoma.

Patients interested in this topic should know that C3 and C4 blood tests exist and can be ordered by doctors. However, even if a test shows abnormal levels, it does not give a definitive answer about glaucoma – it could simply indicate another immune process at work. Always discuss your full medical history (other conditions and medications) when looking at immune-related blood tests. In sum, complement proteins C3 and C4 are part of the body’s innate defense system, and researchers are exploring whether they might one day help us understand or monitor glaucoma better. For now, they remain an intriguing area of study rather than a clinically proven tool.