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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. 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. 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. Overall, we report targeting CD38 may be worth pursuing in clinical trials.

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.

Mucosal-associated invariant T (MAIT) cells primarily reside in mucosal tissues and tissues exposed to the environment to act as a defense against microbial threats. Additionally, they are also involved in a broad spectrum of diseases, including infection, cancer, allergy, and autoimmunity. Although some transcriptional factors and micro-RNA have been recently identified to regulate MAIT cell development and differentiation, a significant gap in our knowledge of MAIT cell regulation still exists. The core binding factor subunit beta (Cbf-β) is a non-DNA binding protein forming a heterodimer with RUNX family proteins to regulate diverse signaling pathways which maintain homeostasis of a wide range of immune cells. To understand the role of Cbf-β in MAIT cell development and function, we generated T cell lineage specific Cbf-β knockout mice (CD4cre+Cbf-β KO) and inducible Cbf-β knockdown mice (UBCcre+Cbf-β KO). We found that Cbf-β deficiency impaired thymic MAIT cell development and interrupted MAIT1 and MAIT17 differentiation. Additionally, inducible knockdown of Cbf-β reduced activation and cytotoxicity in peripheral MAIT cells. Our work suggests that Cbf-β is required for thymic MAIT cell development and MAIT1 and MAIT17 commitment in addition to playing a role in MAIT cell activation and cytotoxicity. Overall, Cbf-β may serve as a novel target to modulate MAIT cells in MAIT cell-based immunotherapies. This study was supported by Henry Ford Immunology Program grants (T71016 and T71017) to QSM and LZ, by the National Institutes of Health (NIH) grants R61AR076803, R01AR063611, and R01AR069681 to QSM, RO1AR072046 to LZ.