Immune Signatures Outperform Clinical Appearance in Treatment Guidance

At the 2025 Inflammatory Skin Disease Summit, Kilian Eyerich, MD, PhD, chair and professor at the Department of Dermatology and Venerology of the University of Freiburg, Germany, delivered a compelling and forward-looking talk on how dermatology can evolve from a morphology-based discipline to a mechanism-based one. “It’s a big pleasure to talk for the third time, actually, in 12 years… at this magnificent meeting, especially today, which is outstanding quality,” Eyerich said. That continuity set the stage for examining how far the field has come—and where it must go next.¹

Why Morphology Is No Longer Enough

Eyerich revisited the origins of dermatologic classification, noting that “it actually all started in Vienna… where classification was based on pure morphology.” For over 2 centuries, clinicians have relied on how lesions look under the eye and microscope. But today’s therapies, often exquisitely targeted, require a more specific understanding of disease biology. As he put it, “The best that we can actually do is a compromise… to classify inflammatory skin diseases according to their immune response.”

Rather than abandoning morphology, Eyerich argued for complementing it with immunologic profiling. The goal is practical: improve diagnostic accuracy and select therapies that align with the dominant immune driver.²

Methods

Eyerich illustrated how the same antigen can produce entirely different skin diseases depending on the T-cell subset that responds to it. Using desmoglein-3, he showed:

• TH2 responses → blistering autoimmune disease resembling pemphigus
• TH1 responses → interface dermatitis
• TH17 responses → psoriasiform inflammation with pustules and parakeratosis

This model demonstrates a key principle: phenotype depends more on the immune response than on the antigen itself.

A 2-Gene Molecular Classifier

To bring this concept into everyday practice, Eyerich described a rapid, point-of-care test based on 2 genes with opposite expression patterns: NOS2 and CCL27. This classifier reliably distinguishes type-2 from type-3 inflammation and can be run on paraffin tissue, scrapings, or even tape strips. Results are available within an hour, making immune typing clinically feasible rather than theoretical.

Findings

Type 2 (TH2) Pattern: Atopic Dermatitis as the Prototype

Using house-dust-mite–specific atopy patch testing, Eyerich showed that restimulating infiltrating T cells with antigen and autologous dendritic cells produces an “almost exclusive type-2 immune response.” The downstream effects—itch, barrier dysfunction, dysbiosis, diminished antimicrobial peptides—reinforce why targeted type-2 therapies are so effective.

Type 3 (TH17) Pattern: Psoriasis and Neutrophil-Driven Inflammation

Even minimal IL-17A expression can trigger massive downstream gene activation. Psoriasis exemplifies this module, but Eyerich highlighted new nuances, such as SirPβ3, recently identified as an antigen driving mixed TH17/TH2 inflammation in patients with eczematized psoriasis. This helps explain why some psoriatic patients present with overlapping features and respond differently to therapy.

Type 1 (Cytotoxic / IFN-γ) Pattern: Interface Dermatitis

Diseases such as lichen planus are driven by IFN-γ–mediated cytotoxicity, which enhances keratinocyte HLA and adhesion molecule expression, enabling T-cell–mediated basal keratinocyte injury. JAK inhibitors remain the most effective targeted therapy for this pattern.

Real-World Complexity

A central theme of the talk was that real patients rarely fit neatly into one category. For example:

• Nummular eczema shows mixed type-2 and type-3 features clinically and histologically. Yet molecular profiling reveals that >90% of cases are type-2 dominant, supporting the use of type-2 biologics rather than psoriasis-directed therapies.
• Paradoxical reactions under biologics—psoriasis on type-2 blockade, eczema on type-17 blockade—reflect shifts in immune dominance rather than misdiagnosis.
• Chronic conditions evolve over time. Diseases like frontal fibrosing alopecia and morphea begin with inflammatory immune patterns but later transition to T-reg–driven fibrotic pathways, requiring different treatment strategies at different disease stages.

Therapeutic Impact

One of the most clinically relevant findings came from a study showing that when the immune signature matched the clinician’s impression (e.g., psoriasis phenotype and psoriatic immune module), patients had >80% likelihood of responding to the targeted therapy. However, when the clinical and immune phenotypes disagreed, none of the patients responded until therapy was adjusted.

This strongly supports Eyerich’s argument that immune-pattern classification is not just academic, it is predictive, and therefore clinically valuable.

Conclusion

Eyerich’s closing message was both practical and forward-looking. “The question is, can’t we do better? And, of course, we need to do better.” Immune response patterns provide the most actionable framework available today for understanding, diagnosing, and treating inflammatory skin disease. While imperfect and still evolving, they offer clarity in complex, overlapping, and dynamic conditions where morphology alone falls short.

As molecular tools become faster and more accessible, immune-pattern–guided care may soon become routine, helping clinicians deliver more precise, biologically grounded treatment to every patient.

References

1. Eyerich K. Immune response patterns in inflammatory skin diseases. Oral presentation. Presented at: Inflammatory Skin Disease Summit 2025; November 12-15, 2025; New York, New York.
2. Garzorz-Stark N, Weidinger S, Sticherling M, Ghoreschi K, Enk A, Eyerich K. Inflammatory skin diseases: the importance of immunological signatures. Dtsch Arztebl Int. 2025. 122(10):277-282. doi: 10.3238/arztebl.m2025.0045