When the Body’s Tempo Breaks: Food Allergy, DAMPs, and the Rhythm of Immunity

Healing_ Passion
2 days ago
3 min read

A recent review in Nature Reviews Immunology by Nicholas Lukacs and Simon Hogan, “Food allergy: begin at the skin, end at the mast cell?”, reframes how we think about food allergy. It highlights that what begins as a breach in the skin barrier can end as a violent allergic reaction in the gut and beyond.

From Barrier to Breakdown

Ordinarily, the gut is a place of peace. When we eat, proteins are digested into small fragments and sampled by dendritic cells (CD103⁺ DCs) in the intestine. These cells present the proteins to naïve T cells in the lymph nodes, in the presence of retinoic acid, TGF-β, and IL-10. The outcome is FOXP3⁺ regulatory T cells (Tregs), which home back to the gut and promote IgA production. IgA coats incoming antigens, while commensal-derived short-chain fatty acids (butyrate, acetate, propionate) further strengthen the barrier. This process — oral tolerance — is the immune equivalent of restoring rhythm after each meal.

But when the skin barrier is broken, a different melody plays. Damaged keratinocytes release alarmins — TSLP, IL-25, IL-33 — along with ATP and other DAMPs. These signals activate skin dendritic cells and bias them toward a TH2 program (via OX40L, CD80/86 engagement). B cells are instructed to switch to IgE, and the systemic immune system is set to “allergic mode.”

Allergic Gut Tropism

Once the body is sensitized through the skin, the gut environment changes. The Lukacs & Hogan review calls this allergic gut tropism — a reshaping of the intestinal immune landscape.

Tuft cells and ILC2s expand, secreting IL-4 and IL-13.
IL-9 drives the proliferation of mast cells, which line the gut mucosa like loaded tripwires.
Secretory antigen passages (SAPs) form in the epithelium, ferrying intact food antigens directly to mast cells beneath.

The result: the gut is primed not for tolerance, but for overreaction.

Mast Cells: The Final Crescendo

On re-exposure to the food, IgE crosslinks FcεRI on mast cells, triggering degranulation. Mast cells unleash a storm of mediators:

Histamine → vascular leak, hives, hypotension.
Leukotrienes (LTC₄, LTD₄, LTE₄) → smooth muscle contraction, airway narrowing.
Serotonin and PAF → diarrhea and abdominal pain via CFTR-dependent chloride secretion.
Proteases (tryptase, chymase) → degradation of tight junction proteins (claudins, occludin, E-cadherin), increasing gut permeability.

The reaction ripples beyond the gut — fluid shifts, cardiovascular collapse, hypothermia — the full picture of anaphylaxis.

Our Perspective: Tempo and CACH

This molecular story fits within a broader framework we call the CACH cycle — Catabolic–Anabolic Cycling of Hormesis.

Tolerance = restoration of tempo.
- PAMPs (from food, commensals) without DAMPs generate small “catabolic” cues: antigen sampling, mild activation.
- These are followed by “anabolic” repair cues: Treg expansion, IgA, barrier reinforcement.
- The cycle restores rhythm — a hormetic balance that strengthens resilience.
Barrier break = distortion of tempo.
- DAMPs flip the script. The cycle is biased toward prolonged catabolism (alarmins, TH2 cytokines, mast cell priming).
- Anabolism (repair, tolerance) cannot catch up. The rhythm accelerates and destabilizes.
- The result is maladaptation: allergic sensitization and systemic vulnerability.

Why It Matters

This review reinforces a broader principle: mucosal immunity works as one network. A break in the skin does not stay local; its DAMP signals reverberate through the gut, airway, and beyond.

For prevention and therapy, this points to two parallel strategies:

Protect the barriers. Support skin and gut integrity through nutrition, microbiome care, and avoidance of unnecessary irritants.
Restore the tempo. Shift immune responses back toward tolerance — interventions that reduce DAMP signaling, strengthen Tregs, or stabilize mast cells can help bring the rhythm back.

Closing Note

Food allergy is not just an overreaction to a peanut. It is the sound of a broken rhythm — where tolerance is lost, barriers fail, and mast cells strike the final note. Healing means more than blocking the reaction; it means restoring the body’s tempo of adaptation.

Lukacs, N. W., & Hogan, S. P. (2025). Food allergy: Begin at the skin, end at the mast cell? Nature Reviews Immunology. Advance online publication. https://doi.org/10.1038/s41577-025-01185-y

#Food allergy, #Mucosal immunity, #Damage-associated molecular patterns (DAMPs), #Mast cells, #Barrier dysfunction