Atypical MCAS manifestations could be explained by the IL-33 route

This is a personal hypothesis, reshaped and organised with the help of AI. It is not a finding, not a consensus view, and not something a doctor can act on today. The individual pieces below are well documented, but the way they are assembled here is speculation, and much more research is needed before anyone can say whether it holds up.

The problem this tries to explain

A person has flushing, palpitations, gut trouble, brain fog and reactions to food that come and go for no clear reason. It looks like mast cell activation. Then the tests come back normal, the tryptase is unremarkable, antihistamines help a little but not much, and they are told it is probably not MCAS.

This happens often enough to be worth asking a simple question: what if the mast cells really are activated, but by a different switch than the one the tests are built around?

Two ways to switch a mast cell on

Mast cells are immune cells that sit in the skin, gut, lungs and around blood vessels. The classical way to set one off is an allergy: an allergen meets an antibody stuck to the cell surface, the cell dumps its granules, and histamine and tryptase flood out within seconds. That is the version everything is designed to detect. (There is more on the classical picture in the histamine and MCAS post.)

There is a second switch. Mast cells also carry a receptor called ST2, which responds to a signal called IL-33.

IL-33 is not an allergy signal. It is an alarm. Cells lining the lungs and gut keep it stored and ready, and release it when they are damaged. No allergy, no prior sensitisation and no antibodies are needed — damaged tissue is enough.

Why the tests would miss it

The two switches produce different results.

Formal MCAS criteria ask for a measured rise in a mast cell mediator, usually tryptase. A mast cell driven by IL-33 leans towards releasing inflammatory messengers rather than emptying its granules, so tryptase can stay flat while the person is genuinely unwell.

They fail the test and are sent away. The mast cells were busy the whole time, just not in the way the test looks for.

It also explains a familiar frustration: if the problem is not mostly histamine, antihistamines will only take the edge off. Partial relief is what you would expect, not evidence that mast cells are innocent.

Why lungs and gut keep coming up

The lining of the lungs and the lining of the gut are where IL-33 is most abundant, and a large share of the body’s mast cells live in the gut wall. Damage there releases the alarm signal exactly where the mast cells are waiting.

This is where COVID enters the picture. The virus damages those linings, and fragments of it have been found in gut tissue more than a year after the infection. If something keeps irritating the lining, the alarm never fully switches off.

There is a detail that makes this more than a one-off event. The enzymes mast cells release sharpen IL-33 into a much more potent form. More IL-33 activates more mast cells, which release more enzymes, which sharpen more IL-33. Once that loop starts, it does not obviously need the original trigger to keep going.

This is not a made-up loop. A version of it has already been demonstrated in the stomach with H. pylori infection. The open question is whether a persistent viral remnant can play the same role.

What is solid and what is not

Solid: IL-33 is an alarm released by damaged tissue, it activates mast cells without any allergy involved, it pushes them towards inflammatory messengers instead of a histamine dump, and mast cell enzymes amplify it. The self-feeding loop is proven in the stomach with a different trigger. Viral material really does persist in gut tissue.

Not solid, and this is the important part:

• Nobody has shown this chain actually running in people with long COVID or with atypical mast cell symptoms.
• At least one study found IL-33 lower, not higher, in long COVID. It was small, but it points the other way.
• IL-33 acts locally in tissue and is cleared quickly, so a normal blood level proves very little. That makes the idea hard to test with a simple blood draw — a real weakness, not just an inconvenience.
• The most cited laboratory work supporting it comes from one group with a declared commercial interest.
• No drug that blocks IL-33 has ever been tried in this population. Such drugs now exist and have succeeded in large trials for a chronic lung condition, but that is a different illness, and borrowing a result across diseases is not evidence.

Why it is worth writing down anyway

If this turns out to be right, it changes something practical. It would mean a group of people are being told they do not have a mast cell problem on the basis of a test that was never built to detect their version of it. It would explain the normal tryptase, the partial response to antihistamines, and why symptoms began after an infection in someone who was previously fine.

It would also suggest that the useful measurements are in tissue rather than blood, and that the pattern to look for is inflammation with a stubbornly normal tryptase.

None of that is established. It is a hypothesis, and it is written here as one.

References:

• Tsilioni I, Theoharides TC. “Recombinant SARS-CoV-2 spike protein stimulates secretion of chymase, tryptase, and IL-1beta from human mast cells, augmented by IL-33.” International Journal of Molecular Sciences, 2023;24(11):9487.
• Zizzo G, Cohen PL. “Imperfect storm: is interleukin-33 the Achilles heel of COVID-19?” The Lancet Rheumatology, 2020;2(12):e779-e790.
• Liang Y, Ge Y, Sun J. “IL-33 in COVID-19: friend or foe?” Cellular & Molecular Immunology, 2021;18:1602-1604.
• Tan J, Anderson DE, Rathore APS, et al. “Signatures of mast cell activation are associated with severe COVID-19.” Journal of Clinical Investigation, 2023;133(19):e149834.
• Weinstock LB, Brook JB, Walters AS, Goris A, Afrin LB, Molderings GJ. “Mast cell activation symptoms are prevalent in Long-COVID.” International Journal of Infectious Diseases, 2021;112:217-226.
• Buzzelli JN, Chalinor HV, Pavlic DI, et al. “IL33 is a stomach alarmin that initiates a skewed Th2 response to injury and infection.” Cellular and Molecular Gastroenterology and Hepatology, 2015;1(2):203-221.
• Zhao Y, Zhang J, Cheng ASL, et al. “Helicobacter pylori-induced IL-33 modulates mast cell responses, benefits bacterial growth, and contributes to gastritis.” Cell Death & Disease, 2018;9:1092.
• Zollner A, Koch R, Jukic A, et al. “Postacute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases.” Gastroenterology, 2022;163(2):495-506.
• England E, Rees DG, Scott IC, et al. “Tozorakimab (MEDI3506): an anti-IL-33 antibody that inhibits IL-33 signalling via ST2 and RAGE/EGFR.” Scientific Reports, 2023;13:9825.
• Strickson S, Houslay KF, Negri VA, et al. “Oxidised IL-33 drives COPD epithelial pathogenesis via ST2-independent RAGE/EGFR signalling complex.” European Respiratory Journal, 2023;62:2202210.
• Manolov V, Petrova J, Vasilev V, et al. “High free IgE and mast cell activation in long COVID.” Life, 2025;15(10):1538.