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2.ABSTRACTBackgroundHidradenitis suppurativa (HS) is a multifactorial, inflammatory skin disease. Increased systemic inflammatory comorbidities and serum cytokines highlight systemic inflammation as a feature of HS. However, the specific immune cell subsets contributing to systemic and cutaneous inflammation have not been resolved.ObjectiveIdentify features of peripheral and cutaneous immune dysregulation.MethodsHere, we generated whole-blood immunomes by mass cytometry. We performed a meta-analysis of RNA-seq data, immunohistochemistry, and imaging mass cytometry to characterize the immunological landscape of skin lesions and perilesions from patients with HS.ResultsBlood from patients with HS exhibited lower frequencies of natural killer cells, dendritic cells, and classical (CD14+CD16-) and nonclassical (CD14-CD16+) monocytes, as well as higher frequencies of Th17 cells and intermediate (CD14+CD16+) monocytes than blood from healthy controls. Classical and intermediate monocytes from patients with HS had increased expression of skin-homing chemokine receptors. Furthermore, we identified a CD38+ intermediate monocyte subpopulation that was more abundant in the immunome of blood from patients with HS. Meta-analysis of RNA-seq data found higher CD38 expression in lesional HS skin than in perilesional skin, and markers of classical monocyte infiltration. Imaging mass cytometry showed that CD38+ classical monocytes and CD38+ monocyte-derived macrophages were more abundant in lesional HS skin.ConclusionOverall, we report targeting CD38 may be worth pursuing in clinical trials.3.Key MessagesMonocyte subsets express markers of activation in circulation and HS lesionsTargeting CD38 may be a viable strategy for treating systemic and cutaneous inflammation in patients with HS4.Capsule SummaryDysregulated immune cells in patients with HS express CD38 and may be targeting by anti-CD38 immunotherapy.