Psoriasis and atopic dermatitis (AD) are two of the most common cutaneous immune disorders affecting 3% and 10% of the population, respectively. These two diseases classically are generally mutually exclusive as they constitute opposite ends of the immune spectrum. Thus, while psoriasis is driven by the activation of the Th17 axis, AD, in stark contrast, is characterized by the activation of the Th2 axis. Remarkably, and unexpectedly, when patients with psoriasis are treated with anti-Th17 therapeutics (anti-IL-23/anti-IL-17/ anti TNF α) agents, up to 10% of patients with psoriasis switch their phenotype to AD-like disease, while in contrast, up to 4% of AD patients treated with an anti-Th2 treatment, develop a psoriatic-like eruption. While being an interesting and challenging clinical dilemma, these paradoxical reactions provide a unique model to investigate the mechanisms and plasticity of the immunological circuits of these diseases and their specific immunological switches, which remain obscure. These shifts in disease behavior with targeted biologics can help shed novel and important insights into the mechanisms of these diseases, particularly those relating to disease heterogeneity and likely also treatment failure. The central hypothesis of our proposal is that paradoxical reactions are due to shifts toward “alternative” inflammatory signaling pathways and promote treatment resistance and failure. Based on our preliminary results, we characterized the transcriptomic profile of skin samples, obtained from patients with anti-Th17-induced AD compared to skin samples of healthy individuals, classic psoriasis, and AD. In this study, we will elucidate the mechanisms underlying this paradoxical reaction.