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Th2 Immune Response

John Montgomery4 min read

Th2 Immune Response

The Th2 (T-helper type 2) response is the branch of immunity built around the cytokines IL-4, IL-5, IL-13 and IL-31, IgE antibodies, eosinophils and mast cells. In Atopic Dermatitis it is the core immune signature. Acute eczema starts with a Th2 response and IgE sensitisation to environmental allergens. In chronic disease the response widens to include Th1, Th17 and Th22 pathways (Papapostolou et al. 2022; Edslev et al. 2020). Raised Th2 markers are present even in eczema skin that looks normal. About 60–80% of patients have the “extrinsic” (allergic) form, with high IgE, eosinophils and often a personal or family history of atopy (Papapostolou et al. 2022).

Th2 Immune Response [defines] Atopic Dermatitis Th2 Immune Response [relates] Atopic March

How it starts. When the skin barrier is breached, skin cells release alarm cytokines, mainly TSLP, IL-33 and IL-25, together with IL-1 stored in corneocytes. These prime skin dendritic cells. The dendritic cells carry allergen fragments to nearby lymph nodes and steer naive T cells toward the Th2 type. The Th2 cells then make IL-4 and IL-13, which in turn switch B cells to making IgE (Papapostolou et al. 2022; Agrawal & Woodfolk 2014). Other things can also drive this pathway. Staphylococcus aureus superantigens stimulate IgE and Th2 cytokines. The house dust mite allergen Der p 1 can cut tight-junction proteins and so let itself in (Agrawal & Woodfolk 2014; Elias & Wakefield 2011). This same route of sensitisation through the skin is the basis of the Dual-Allergen Exposure Hypothesis for Food Allergy.

Skin Barrier Dysfunction [triggers] Th2 Immune Response Staphylococcus aureus [triggers] Th2 Immune Response House Dust Mites [triggers] Th2 Immune Response Th2 Immune Response [causes] Food Allergy

How it damages the barrier. IL-4 and IL-13 bind the IL-4Rα receptor complex, activate JAK1/JAK2/TYK2 and switch on STAT6 (and STAT3). This lowers production of the barrier proteins Filaggrin, loricrin and involucrin (Furue 2020). IL-4 also cuts ceramide synthesis, and Th2 cytokines suppress the antimicrobial peptides hBD-2 and hBD-3 (Elias & Wakefield 2011; Agrawal & Woodfolk 2014). That reduction in antimicrobial peptides helps S. aureus thrive. IL-31 is the main itch cytokine, and IL-4 increases the IL-31 receptor on dendritic cells (Furue 2020). The result is a vicious cycle: a weak barrier lets in allergens, which drive Th2 inflammation, which weakens the barrier further and causes itch. Scratching then damages the barrier again. Which side of the cycle comes first is the heart of the inside-out vs outside-in debate (see Skin Barrier Dysfunction).

Conflict: [Elias & Wakefield, 2011] argue Th2 inflammation is mostly secondary to a primary barrier defect, so barrier repair should come before immunosuppression. [Furue, 2020] presents IL-4/IL-13 as potent primary suppressors of barrier proteins, and the success of IL-4Rα blockade as evidence of their central role. Unresolved — add to open_questions.

Th2 Immune Response [worsens] Skin Barrier Dysfunction Th2 Immune Response [worsens] Filaggrin Th2 Immune Response [causes] Itch-Scratch Cycle

Treatment implications. Most medical eczema treatments act on this pathway. Topical Corticosteroids and topical calcineurin inhibitors broadly suppress inflammation. Dupilumab, an antibody against IL-4Rα, blocks both IL-4 and IL-13. In trials it restored filaggrin and loricrin expression, and IL-4/IL-13 blockade gives a strong clinical response (Furue 2020). Elias & Wakefield (2011) argue that anti-inflammatory treatment does not fix the underlying barrier defect. They favour adding barrier repair, such as ceramide-dominant Emollient Therapy. For toddlers, the practical meaning is that inflammation control and barrier care work as a pair, not as alternatives.

Dupilumab [treats] Th2 Immune Response Topical Corticosteroids [treats] Th2 Immune Response Emollient Therapy [supports] Skin Barrier Dysfunction

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