Integrating the skin and blood transcriptomes and serum proteome in hidradenitis suppurativa reveals complement dysregulation and a plasma cell signature

Abstract

Hidradenitis suppurativa (HS) is a chronic skin disease of the pilo-sebaceous apocrine unit characterized by significant inflammation and an impaired quality of life. The pathogenesis of HS remains unclear. To determine the HS skin and blood transcriptomes and HS blood proteome, patient data from previously published studies were analysed and integrated from a cohort of patients with moderate to severe HS (n = 17) compared to healthy volunteers (n = 10). The analysis utilized empirical Bayes methods to determine differentially expressed genes (DEGs) (fold change (FCH) >2.0 and false discovery rate (FDR) <0.05), and differentially expressed proteins (DEPs) (FCH>1.5, FDR<0.05). In the HS skin transcriptome (lesional skin compared to non-lesional skin), there was an abundance of immunoglobulins, antimicrobial peptides, and an interferon signature. Gene-sets related to Notch signalling and Interferon pathways were differentially activated in lesional compared to non-lesional skin. CIBERSORT analysis of the HS skin transcriptome revealed a significantly increased proportion of plasma cells in lesional skin. In the HS skin and blood transcriptomes and HS blood proteome, gene-sets related to the complement system changed significantly (FDR<0.05), with dysregulation of complement-specific DEGs and DEPs. These data point towards an exaggerated immune response in lesional skin that may be responding to commensal cutaneous bacterial presence and raise the possibility that this may be an important driver of HS disease progression.

Fig 1. CIBERSORT analysis of HS skin transcriptome.

(A) Heatmap showing normalized absolute abundance for each cell type in individual samples, mean abundance for each cell type is also displayed (left, green); (B) bar graph showing absolute abundance of each cell type in non-lesional (NL) and lesional (LS) samples; and (C) mean abundance of each cell type in all NL samples (left) and LS samples (right). Data from S4 Table. The abundance of plasma cells was significantly higher in LS versus NL skin (*FDR <0.05).

Fig 2. Dysregulation of complement pathway components.

Fold change of skin DEGs (S4 Table) (blue arrows) and blood DEPs (Table 1) (red arrows) in the context of the complement cascade. It is not entirely clear which of the three complement activation pathways is engaged in HS, classical, lectin or alternative pathways. However, the classical pathway may be primarily implicated because of the involvement of C4 and the presence of immunoglobulins in the skin and blood. Additionally, lectin pathway activators, such as MBL and MASP, were not identified as DEGs in the skin or DEPs in the serum. Reprinted from Springe Nature under a CC BY license, with permission from Springe Nature, original copyright 2008. Modified by permission from Springer Customer Service Center GmbH: Springer Nature, Clinical and Basic Immunodermatology by Gaspari and Tyring, COPYRIGHT (2008).

Fig 3. Proposed pathogenesis of hidradenitis suppurativa.

Pathogenesis of hidradenitis suppurativa (HS) can be considered in two phases, initiation and progression. Our analysis of advanced HS showed immunoglobulin (Igs) transcripts, antimicrobial peptides (AMPs), an interferon signature, plasma cells in lesional skin, and an association with complement dysregulation. Considered in the context of prior findings in HS such as numerous neutrophils, B cells, plasma cells, TLR2, and IL-32, there appears to be a concerted immune response (IR) to eradicate bacteria in HS. These efforts may drive HS disease progression. There are also data supporting general cutaneous immune responses such as abundant AMPs, pro-inflammatory cytokines including IL-1, IL-6, IL-17, IL-12/23, and a dysregulated Th17/T-reg cell axis (often seen in other chronic skin diseases such as psoriasis or atopic dermatitis).