Vitamin C: Layers of Immune Function

by Michael Stanclift, ND

Vitamin C helps with immune system function, but due to its ubiquity, it is often underappreciated clinically. With the current COVID-19 pandemic clinicians are in search of clinical tools that are relatively easy to acquire, safe, and effective. Vitamin C (AKA ascorbic acid/ascorbate) plays an important role in immune function with Swiss Army knife-like utility.

We are one of the rare animals that lack the ability to make vitamin C within our body, so we must acquire it through food or supplementation.¹ Though scurvy from extreme deficiency is rare in industrialized countries, low vitamin C status is surprisingly common.¹ This is likely due to our relatively low storage capacity and high demand. Exposure to oxidative stress from diseases, environmental pollutants, and even the activities of our own body like physical or psychological challenges can utilize the antioxidant capacity of vitamin C, requiring more than many of us obtain in our diets.¹

 Highlighted functions of vitamin C

Vitamin C helps us with many layers of protection. Vitamin C’s job starts with maintaining our epithelial barriers—those delicate layers of cells that protect our bodies from the outside world.¹ Some infections, such as SARS-CoV-2 (the virus that causes COVID-19), enter through epithelial cells, while other pathogens create or exploit weaknesses in these barriers to gain entry to the rest of the body.²

Once a pathogen such as a virus enters our body and is initially detected, our innate immune system is the first to respond. While vitamin C is most famous for being a water-soluble antioxidant with the ability to protect important molecules like proteins, lipids, and nucleic acids, it also has some pro-oxidative capacity.¹ Our innate immunity, the broad-spectrum defenses involving neutrophils, macrophages, and natural killer cells,* relies heavily on vitamin C for producing reactive oxygen species (ROS) and the movement of these cells to sites of injury and infection.¹ Neutrophils and macrophages are the first to respond to infections, and research shows neutrophils from people with low serum vitamin C can increase their ROS fire-power by 20% and improve phagocytosis with supplementation.¹ Macrophages usually follow the neutrophils and clear the cellular debris as neutrophils undergo a programmed cell death—these processes also require vitamin C.¹ The clearance of this debris is part of the normal and healthy immune response, and a dysfunction in it results in an inflammatory response that is more damaging to the surrounding tissues and is longer lasting.¹

Inside cells there are proteins that sense danger, like a viral infection, and trigger inflammatory signals.³  The stronger the signal, the more inflammatory cytokines are released from the cell, which tells the immune system how strongly to respond.³ In the SARS outbreak of 2003, these signals were extremely strong, causing a “cytokine storm,” and we believe this caused the high death rate from that coronavirus (SARS-CoV).⁴ The specific intracellular sensor responsible was called NOD-like receptor family, pyrin domain-containing 3 (NLRP3) and was involved in the onset of acute respiratory distress syndrome (ARDS), a critical illness with lethal potential.⁴ The portion of the virus that caused the intense triggering of NLRP3 in SARS-CoV has changed in current SARS-CoV-2, warranting further investigation and comparison of their individual properties.⁴ Nonetheless, this may be an important checkpoint for the COVID-19 illness, and there is some preclinical evidence (in vitro/vivo) that vitamin C may inhibit activation of NLRP3 by acting as an antioxidant of mitochondrial ROS.^5,6 This has theoretical potential to decrease the strong inflammatory signal of cytokines such as IL-1B, which is associated with the onset of ARDS, though vitamin C’s potential to influence cytokine signaling varies by cell type.^1,4,5

Vitamin C also appears to be involved in our adaptive or acquired immune response, the more specific targeted microbial killing that comes from production of antibodies.¹ This response is carried out by lymphocytes—both B and T-cells.¹ In vitro studies with lymphocytes suggests vitamin C can promote lymphocyte proliferation, but there is conflicting data on whether it can enhance antibody production.¹

Studies of vitamin C in infection and ICU situations

Vitamin C has far-ranging activity across a variety of cell types (epithelial and immune) and is safe to administer in gram dosages, making it an attractive agent for prevention of many viral conditions such as the common cold. We must keep in mind to date there are no known published clinical trials using vitamin C for the prevention, treatment, or cure of COVID-19, though there is one currently in phase 2 in China, with the trial slated to end in September 2020.⁷ With that said, we urge you to familiarize yourself with the following studies/articles before making decisions on using vitamin C.

The CITRIS-ALI study reported in JAMA used IV vitamin C for the treatment of ARDS due to sepsis.⁸ While the primary outcome of the study, end organ damage, reported negative findings, the secondary outcome of mortality showed a robust effect, suggesting possible “survivor bias.”⁸ In the first 96 hours (4 days) of ARDS, placebo recipients had a 23% mortality, while the vitamin C recipients had a 4% mortality—almost 6x the chance of surviving. Because of this, it’s possible sicker patients lived with vitamin C, albeit coming away with significant end organ damage, which portrayed the treatment in a negative light given the primary endpoints.⁸

Oral vitamin C at an average of 2g/day significantly reduced intensive care unit stays by 8.6% and the same meta-analysis found patients needing over 24 hours of mechanical ventilation shortened that need by 18.2% when administered vitamin C.⁹ Another systematic review and meta-analysis looking at a very small patient population (142 critically ill patients) had similar findings, with decreased vasopressor and ventilation need.¹⁰ This paper noted a 24% reduction in mortality; however, the p-value (p = 0.6) of this finding was far from reaching clinical significance.¹⁰

Conclusion

Vitamin C is an important molecule for our immune health that acts on many tiers. It maintains our epithelial barriers and is critical for our innate immune response and much of the cytokine signaling that follows. Our body’s vitamin C demand can change based on conditions, and inadequate intake is common, even in industrialized countries. These factors make vitamin C a meaningful nutrient across a spectrum from the healthy to the critically ill. Ongoing studies will shed more light in the utility of vitamin C for the treatment of serious illnesses such as ARDS and the infections that can precede them.

*Natural killer cells do not clearly fit into definitions of innate/adaptive immunity.¹¹

Citations

1. Carr AC et al. Vitamin C and immune function. Nutrients. 2017;9(11):1211.
2. Hoffmann et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:1–10.
3. Swanson KV et al. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19:477–489.
4. Yuen KS et al. SARS-CoV-2 and COVID-19: The most important research questions. Cell Biosci. 2020;10:40.
5. Sang X et al. Vitamin C inhibits the activation of NLRP3 inflammasome by scavenging mitochondrial ROS. Inflammasome. 2016;2(1):13-19.
6. Choe JY et al. Quercetin and ascorbic acid suppress fructose-induced NLRP3 inflammasome activation by blocking intracellular shuttling of TXNIP in human macrophage cell lines. Inflammation. 2017;40(3):980-994.
7. https://clinicaltrials.gov/ct2/show/NCT04264533. Accessed March 31, 2020.
8. Fowler AA et al. Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: The CITRIS-ALI Randomized Clinical Trial. 2019;322(13):1261-1270. JAMA. 2019;322(13):1261-1270.
9. Hemilä H et al. Vitamin C can shorten the length of stay in the ICU: A meta-analysis. Nutrients. 2019;11;
10. Zhang M et al. Vitamin C supplementation in the critically ill: A systematic review and meta-analysis. SAGE Open Med. 2018;6:2050312118807615.
11. Vivier E et al. Innate or adaptive immunity? The example of natural killer cells. Science. 2011;331(6013):44–49.

Michael Stanclift, ND is a naturopathic doctor and senior medical writer at Metagenics. He graduated from Bastyr University’s school of naturopathic medicine and practiced in Edinburgh, Scotland, and Southern California. He enjoys educating other healthcare providers and impacting the lives of their many patients. When he’s not working, he spends his hours with his wife and two children.