The Inflammatory Prequel 

 

The inflammatory prequel: a foundational driver of immune imbalance in atopic dermatitis (AD)

Understanding the role of the inflammatory prequel underscores the importance of shifting the immune system from overactivity towards homeostasis.^1,2 

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A foundational driver of immune imbalance

OX40 ligand: a key costimulatory signal

Looking beyond near‑term management

A foundational driver of immune imbalance

The inflammatory prequel is a foundational driver of immune imbalance that plays a key role in activating and maintaining type 2 and non–type 2 inflammatory responses in AD.^1,2

Even when AD symptoms appear controlled, the inflammatory prequel can promote^2,3:

1. Activation, proliferation, and survival of effector T cells → Drives persistent inflammation and contributes to flare activity

2. Potential reduced induction of regulatory T cells → Allows inflammation to remain unchecked

3. Generation of tissue‑resident memory T cells → Fuels the chronic, recurrent nature of AD 

OX40 ligand: a key costimulatory signal

During the inflammatory prequel, the OX40L/OX40R interaction acts as an important secondary costimulatory signal across immune pathways, contributing to inflammatory overactivity in AD. This signaling helps shape early T‑cell activity and reinforces the imbalance between effector and regulatory responses.^1,2

By supporting effector T‑cell activation, proliferation, and survival, OX40 ligand signaling can amplify immune activity. At the same time, reductions in regulatory T‑cell activity may allow inflammatory signals to persist. Together, these dynamics support the development and persistence of tissue‑resident memory T cells, extending the impact of OX40 ligand signaling over time.^1-3

Through its influence on effector activity, regulatory restraint, and memory formation, OX40 ligand signaling contributes to immune dysregulation across multiple inflammatory pathways. By reinforcing effector T‑cell activation across type 2 and non–type 2 pathways, OX40 ligand signaling helps explain the multi‑pathway immune dysregulation that underlies AD’s heterogeneity, chronicity, and relapsing patterns.^1-3

Looking beyond near‑term management

Understanding the T cell-driven imbalance may reveal new possibilities in how we approach AD.^1,2,4-6

Recognizing the interconnected roles of effector, regulatory, and memory T‑cell subsets can help shift perspectives toward broader immune health. These insights also underscore the importance of the preservation of T cells, since in AD, all T cells have a role to play.^1,2,4-6