By Eben van Tonder, 7 Oct 2025
Introduction
On 6 October 2025, the Nobel Prize in Physiology or Medicine was awarded to Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi “for their fundamental discoveries relating to peripheral immune tolerance.” Their work revealed how the immune system maintains balance through regulatory T cells (Tregs) and the master transcription factor FOXP3, preventing the body from turning on itself.
This year’s award is not just a story about immunology. It gives us a metaphor for understanding how the body handles other potentially dangerous yet essential processes. One striking parallel comes from nitrite and nitric oxide (NO) chemistry in human physiology. Both involve vital agents that, if left unchecked, can cause harm, yet evolution has provided regulatory mechanisms that actively maintain balance.
Peripheral Tolerance: The Nobel Discovery
Shimon Sakaguchi’s work in the 1990s provided the first clear evidence that a subset of T cells, later called regulatory T cells, suppress excessive immune responses and prevent autoimmunity. His findings explained how the immune system maintains what is known as peripheral tolerance and showed that without these cells, the body can turn its defences against itself.
To understand this, it helps to know about the thymus. The thymus is a small gland in the upper chest, just behind the breastbone, that is especially active in children. It works like a school for T cells, which are white blood cells that direct the body’s defences. In the thymus, immature T cells are “trained” to recognise what belongs to the body and what does not. Those that mistakenly react strongly against the body’s own tissues are eliminated, while the useful ones graduate and move into the bloodstream. This process is called central tolerance.
However, not all self-reactive T cells are removed in the thymus. Some escape into circulation. Peripheral tolerance is the second layer of protection that takes over once T cells leave the thymus. It ensures that potentially dangerous T cells are kept in check in the body’s tissues and lymph nodes, preventing them from attacking the body’s own cells. Sakaguchi demonstrated that when the regulatory T cells responsible for this control were removed, autoimmune disease followed, proving their central role in keeping the immune system balanced. This is where the parallel lies with our interest in nitrite and nitrate: the body survives by keeping its systems in balance.
Mary Brunkow and Fred Ramsdell, the other Nobel Prize recipients, identified FOXP3 as the gene required for the development and function of regulatory T cells. Without this gene, mice developed a lethal autoimmune disease known as the “scurfy” phenotype, while humans developed IPEX syndrome, a severe autoimmune disorder. Their discoveries showed that the immune system avoids self-destruction not by removing all danger, but by establishing regulatory brakes that keep it under constant control.
Nitrite and Nitric Oxide: A Parallel Balancing Act
Just as autoreactive T cells can turn destructive, nitrite and nitric oxide present a paradox.
Nitric oxide is indispensable: it regulates blood vessel dilation, neurotransmission, and immune defence. Nitrite acts as a reservoir of NO, especially under hypoxia, helping sustain life-critical signalling. Yet both nitrite and NO can produce harmful byproducts. In acidic conditions, nitrite can generate nitrosating agents that react with amines to form nitrosamines, many of which are carcinogenic.
Here again, biology does not ban nitrite or NO. They are too valuable. Instead, it builds a regulatory network to control their risks while keeping their benefits.
The Role of Ascorbic Acid in Gastric Protection and the Essential Nature of Nitrate-Nitrite-NO
One of the clearest examples of this regulation occurs in the stomach.
Gastric juice contains significant levels of ascorbic acid, actively secreted by the gastric mucosa and salivary glands. When dietary nitrite enters the stomach, ascorbic acid intercepts nitrosating intermediates, diverting the chemistry away from nitrosamines and toward harmless NO. This is not random. It is a targeted protective mechanism: the body actively sends ascorbate to the stomach to neutralise risk.
The body does not leave the stomach unprotected when it comes to nitrite chemistry. Vitamin C (ascorbic acid) is not only absorbed from the diet but actively mobilised to sites where it is most needed. One such site is the gastric lumen, where dietary nitrite from saliva encounters acidic conditions and amines from food. The gastric mucosa is equipped with sodium-dependent vitamin C transporters (SVCT1 and SVCT2), which move ascorbate from blood plasma into gastric juice. This results in concentrations of ascorbic acid in gastric juice that are often higher than in plasma, showing that the body deliberately prioritises this interface as a defensive stronghold.
Salivary glands also secrete vitamin C, adding another layer of protection. As food and saliva enter the stomach, nitrite is accompanied by ascorbate, which intercepts nitrosating intermediates and reduces them to harmless nitric oxide. This is not a passive coincidence but an evolved system of balance: where the risk of nitrosamine formation is greatest, the body ensures that a protective molecule is present.
In effect, if vitamin C is not already abundant in the stomach, the body draws from its circulating reserves and delivers it there. This mobilisation illustrates a wider principle also visible in the immune system: regulation is active and targeted, not random. Just as regulatory T cells patrol to suppress autoimmunity, ascorbate is secreted into gastric juice to suppress harmful chemistry, ensuring that vital but potentially dangerous processes are channelled into safe physiological outcomes.
If, however, gastric ascorbate is depleted through poor diet, Helicobacter pylori infection, or atrophic gastritis, nitrosamine formation risk increases. The system is protective, but not invincible, much like immune regulation can fail, leading to autoimmunity.
Cured meats also need to be understood in terms of their social and nutritional function. Many such products emerged historically not only as a means of preservation but also as practical foods for people “on the go.” Sausages such as frankfurters, Krainerwurst, and their relatives could be eaten quickly, carried easily, and were already cooked or partially cooked, making them ideal for labourers and urban workers. In South Africa, Russian sausages became a national favourite. Consumed both across the board from low- to high-income earners, the Russian with chips replaced the English fish and chips as one of the country’s most popular fast-food dishes.
In Zambia, Russians are sold widely, but here they are called Hungarians. As in South Africa, they are consumed by people from all walks of life as everyday street food. In Australia, the equivalent product is known as the kransky, a Slovenian-origin sausage that became popular in Australian and New Zealand cuisine.
In Austria and Germany, it is called Krainerwurst. All these sausages likely come from the Slovenian prototype, the “Kranjska klobasa” (Carniolan sausage), protected under EU designation and often simply called kranjska or kranjska klobasa.
These cooked, cured sausages are typically consumed by populations that also have access to a balanced diet. The same applies to bacon, which in many cultures is not eaten in isolation but paired with vegetables, eggs, or bread. In South Africa, cured pork belly ribs and corned beef are consumed as part of larger meals, often accompanied by fresh produce. Around the world, bacon or ham served at breakfast or lunch almost always appears alongside vegetables, fruit, or wholegrain bread. Thus, nitrite-cured products are not “nutritional isolates” but components of broader meals, eaten by people who do not suffer from scurvy—that is, who have sufficient ascorbate to protect against any potentially harmful effects of nitrite and NO, which is physiologically essential to human health.
The nutritional balance is borne out in dietary surveys. In Europe and North America, where cured meat consumption is higher, overt vitamin C deficiency is rare, typically below 5–10% of the population. In the U.S. NHANES data, mean plasma vitamin C levels generally fall in the adequate range, ensuring gastric ascorbate secretion is intact. In low-income settings where vitamin C deficiency may reach 30–50%, cured meat intake remains minimal. Thus, the populations most likely to consume bacon, ham, Russians, or kransky are often those who can maintain sufficient vitamin C status to counteract the risk of nitrosamine chemistry.
Let us be clear: you have to ingest nitrates and nitrites for optimal physical health. This is without question. The only real issue is whether the protective mechanisms that prevent these compounds from turning against the body and creating undesirable byproducts are intact, and these mechanisms depend heavily on the essential intake of vitamin C. Vitamin C, in turn, is itself indispensable for a wide range of physiological processes. Limiting vitamin C, nitrite, or nitrate intake is ultimately to one’s detriment.
It is, of course, possible to have too much vitamin C, although the risks are relatively mild compared to many other nutrients. Vitamin C is water-soluble, which means that excess is usually excreted in urine rather than stored in the body. Still, very high intakes can overwhelm the body’s handling systems and lead to negative effects. The U.S. National Academies of Sciences, Engineering, and Medicine set the Tolerable Upper Intake Level (UL) for adults at 2,000 mg per day. This is considered the safe maximum daily intake for most healthy people.
The most common side effects of exceeding this threshold are gastrointestinal. High doses of vitamin C create an osmotic effect in the gut, drawing water into the intestines and causing diarrhoea, cramping, and nausea. Another concern is kidney stones. Excess vitamin C is broken down into oxalate, which can crystallise and increase the risk of calcium oxalate kidney stones, especially in men. Very high doses may also interfere with laboratory tests, such as blood glucose measurements, giving false results.
It is important to note that the body’s tissues are already saturated at relatively modest intakes. This happens at around 100–200 mg per day, which can be easily achieved from fruits and vegetables. At this level, the protective role of ascorbate in the stomach against nitrosamine formation is fully supported. Supplement doses of 500–1,000 mg per day are generally considered safe, but amounts above 2,000 mg per day provide no extra benefit and increase the chance of side effects.
In practical terms, the amounts needed for optimal health, antioxidant activity, and gastric protection are well below the levels associated with risk. Regular intake from diet ensures sufficiency, and while supplements can be helpful in some cases, megadoses far above the recommended range are unnecessary and may be counterproductive. The balance, as with so many aspects of nutrition, is in meeting physiological needs without overwhelming the system.
Let’s now look at cured meats again.
Health authorities set conservative “acceptable daily intakes” (ADIs) of 3.7 mg/kg body weight/day for nitrate (about 260 mg/day for a 70 kg adult) and 0.07 mg/kg/day for nitrite (about 5 mg/day). These thresholds are designed as safety limits, but actual physiology shows that humans typically consume more nitrate — mostly from vegetables — without harm. The critical question is not whether we ingest nitrate and nitrite, but whether protective systems like ascorbic acid are in place to keep their chemistry beneficial.
In practice, vegetables provide the vast majority of nitrate intake. A single serving of spinach or beetroot can deliver 250–400 mg nitrate, often more than the entire regulatory ADI. Cured meats, by contrast, contribute very little. While regulations may allow 100–150 ppm nitrite ingoing, the combination of ascorbate and heat treatment during bacon and ham processing causes nitrite to react quickly, leaving residual levels typically in the 5–15 ppm range, and sometimes even lower.
Translating this into actual food, a rasher of bacon weighing 25 g at 10 ppm residual nitrite contains about 0.25 mg nitrite. To reach the 5 mg/day ADI purely from bacon, one would need to eat 20 rashers in a day, which is far beyond normal consumption. Ham, eaten in slices of 30–40 g, contributes similarly small amounts. This makes it clear that even frequent consumption of cured meats does not come close to providing the nitrate/nitrite levels the body actually uses in physiology.
The real supply comes from vegetables, which can provide ten times more nitrate in a single meal than cured meat does in a week. And this nitrate is not just safe — it is essential for the nitrate–nitrite–NO pathway that regulates blood flow, blood pressure, and exercise performance. Nitrite from cured meats is simply a minor contributor to an already necessary physiological system.
The conclusion is straightforward: nitrate and nitrite are required for optimal health, and no diet can be sufficient without them. Cured meats contribute modestly, but vegetables remain the main source. What matters most is that the protective partner — vitamin C — is present, as it prevents nitrosamine formation and directs nitrite chemistry toward producing beneficial nitric oxide. Limiting nitrite, nitrate, or vitamin C is not protective; it is detrimental to human health.
Shared Principles: Immune Tolerance and Nitrite/NO Homeostasis
What Brunkow, Ramsdell, and Sakaguchi uncovered in immune regulation mirrors what we see in nitrite and NO biology.
Autoreactive T cells can destroy tissues, and nitrite and NO can form toxins. Yet both are vital.
Regulation is active, not passive. Tregs, via FOXP3, suppress destructive immunity, while ascorbic acid and antioxidants suppress nitrosamine chemistry.
Homeostasis is achieved through balance, not elimination.
Failure of regulation leads to disease. Loss of Tregs results in autoimmunity, while loss of nitrite and NO regulation results in cancer or vascular dysfunction.
Both systems embody the principle that biology sustains itself not by removing danger, but by embedding danger within controlled networks of regulation.
Conclusion
The 2025 Nobel Prize in Physiology or Medicine highlights a universal biological principle: life sustains itself not by removing danger, but by regulating it.
Regulatory T cells prevent the immune system from destroying its host.
Ascorbic acid and antioxidant systems prevent nitrosamines from forming in the stomach, steering nitrite and NO chemistry toward useful ends.
Both cases illustrate that homeostasis is not passive balance, but an active and layered defence. Things sometimes go wrong — autoimmunity flares, nitrosamines slip through — yet overwhelmingly, the system works, allowing us to live in harmony with biochemical forces that, if unrestrained, would consume us.
In that sense, nitrite and NO physiology and immune tolerance are twin parables of biology’s wisdom: danger transformed into life through the art of regulation.
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