Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by chronic abscess formation and development of multiple draining sinus tracts in the groin, axillae, and perineum. Using proteomic and transcriptomic approaches, we characterized the inflammatory responses in HS in depth, revealing immune responses centered on IFN-γ, IL-36, and TNF, with lesser contribution from IL-17A. We further identified B cells and plasma cells, with associated increases in immunoglobulin production and complement activation, as pivotal players in HS pathogenesis, with Bruton’s tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathway activation as a central signal transduction network in HS. These data provide preclinical evidence to accelerate the path toward clinical trials targeting BTK and SYK signaling in moderate-to-severe HS.

Term preeclampsia (tPE), ≥37 weeks, is the most common form of PE and the most difficult to predict. Little is known about its pathogenesis. This study aims to elucidate the pathogenesis and assess early prediction of tPE using serial integrated metabolomic and proteomic systems biology approaches. Serial first- (11–14 weeks) and third-trimester (30–34 weeks) serum samples were analyzed using targeted metabolomic (1H NMR and DI-LC-MS/MS) and proteomic (MALDI-TOF/TOF-MS) platforms. We analyzed 35 tPE cases and 63 controls. Serial first- (sphingomyelin C18:1 and urea) and third-trimester (hexose and citrate) metabolite screening predicted tPE with an area under the receiver operating characteristic curve (AUC) (95% CI) = 0.817 (0.732–0.902) and a sensitivity of 81.6% and specificity of 71.0%. Serial first [TATA box binding protein-associated factor (TBP)] and third-trimester [Testis-expressed sequence 15 protein (TEX15)] protein biomarkers highly accurately predicted tPE with an AUC (95% CI) of 0.987 (0.961–1.000), sensitivity 100% and specificity 98.4%. Integrated pathway over-representation analysis combining metabolomic and proteomic data revealed significant alterations in signal transduction, G protein coupled receptors, serotonin and glycosaminoglycan metabolisms among others. This is the first report of serial integrated and combined metabolomic and proteomic analysis of tPE. High predictive accuracy and potentially important pathogenic information were achieved.

Desmoglein 1 (Dsg1) is a cadherin restricted to stratified tissues of terrestrial vertebrates, which serve as essential physical and immune barriers. Dsg1 loss-of-function mutations in humans result in skin lesions, multiple allergies, and isolated patient keratinocytes exhibit increased pro-allergic cytokine expression. However, the mechanism by which genetic deficiency of Dsg1 causes chronic inflammation is unknown.To determine the systemic response to Dsg1 loss, we deleted the three tandem Dsg1 genes in mice. Whole transcriptome analysis of embryonic Dsg1 -/skin showed a delay in expression of adhesion/differentiation/keratinization genes at E17.5, a subset of which recovered or increased by E18.5.Comparing epidermal transcriptomes from Dsg1-deficient mice and humans revealed a shared IL-17skewed inflammatory signature. Although the impaired intercellular adhesion observed in Dsg1 -/mice resembles that resulting from anti-Dsg1 pemphigus foliaceus antibodies, pemphigus skin lesions exhibit a weaker IL-17 signature. Consistent with the clinical importance of these findings, treatment of two Dsg1deficient patients with an IL-12/IL-23 antagonist originally developed for psoriasis resulted in improvement of skin lesions. Thus, beyond impairing the physical barrier, loss of Dsg1 function through gene mutation results in a psoriatic-like inflammatory signature before birth and treatment with a targeted therapy markedly improved skin lesions in patients.

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The immunopathogenesis of psoriasis, a common chronic inflammatory disease of the skin, is incompletely understood. Here we demonstrate, using a combination of single cell and spatial RNA sequencing, IL-36 dependent amplification of IL-17A and TNF inflammatory responses in the absence of neutrophil proteases, which primarily occur within the supraspinous layer of the psoriatic epidermis. We further show that a subset of SFRP2+ fibroblasts in psoriasis contribute to amplification of the immune network through transition to a pro-inflammatory state. The SFRP2+ fibroblast communication network involves production of CCL13, CCL19 and CXCL12, connected by ligand-receptor interactions to other spatially proximate cell types: CCR2+ myeloid cells, CCR7+LAMP3+ dendritic cells, and CXCR4 expressed on both CD8+ Tc17 cells and keratinocytes, respectively. The SFRP2+ fibroblasts also express cathepsin S, further amplifying inflammatory responses by activating IL-36G in keratinocytes. These data provide an in-depth view of psoriasis pathogenesis, which expands our understanding of the critical cellular participants to include inflammatory fibroblasts and their cellular interactions.