Dysregulated CD38 expression in blood and skin immune cells of patients with hidradenitis suppurativa

Background Hidradenitis 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. Objective Identify features of peripheral and cutaneous immune dysregulation. Methods Here, 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. Results Blood 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. Conclusion Overall, we report targeting CD38 may be worth pursuing in clinical trials. Key Messages 1. Monocyte subsets express markers of activation in circulation and HS lesions 2. Targeting CD38 may be a viable strategy for treating systemic and cutaneous inflammation in patients with HS Capsule Summary Dysregulated immune cells in patients with HS express CD38 and may be targeting by anti-CD38 immunotherapy. ### Competing Interest Statement Dr Hamzavi has served as an investigator (grant to institution) for Pfizer Inc, Bayer, Lenicura, and Incyte, Estee Lauder, L'Oreal, Unigen, Avita, Arcutis Biotherapeutics, and Ferndale Laboratories, Inc; as an Advisory Board member for AbbVie; and as a Consultant to Galderma Laboratories, LP, Incyte, Pfizer, UCB, Boehringer Ingelheim, Beiersdorf, and Clarify Medical. Dr. Huggins is a principal investigator for Pfizer, Incyte, Arcutis and the Immune Tolerance Network. Dr Liao has received research grant funding from Abbvie, Amgen, Janssen, Leo, Novartis, Pfizer, Regeneron, and TRex Bio. Dr Lim is an investigator for Incyte, L'Oreal, Pfizer, and PCORI, has served as consultant for Pierre Fabre, ISDIN, Ferndale, La Roche-Posay, Cantabria, and Beiersdorf, and has participated as a speaker in general educational sessions for La Roche-Posay and Cantabria Labs. All other authors have no conflict of interests to report. * HC : healthy control HS : hidradenitis suppurativa CM : central memory DC : dendritic cells EM : effector memory MAIT : mucosal-associated invariant T cells NK : natural killer NKT : natural killer T cells TE : Terminal Effector Treg : T regulatory cells PL : Perilesion L : Lesion CyTOF : Cytomertry by time-of-flight IMC : imaging mass cytometry