Mutations in NCSTN gene (encoding for nicastrin protein) are associated with hidradenitis suppurativa (HS), a chronic inflammatory disease involving hair follicles.
Therefore, we conclude that haploinsufficiency of the NCSTN gene caused by the nonsense mutation c.1258C>T (p.Q420X) contributes to the occurrence of HS in this family.
Altered signalling pathways were further confirmed by real-time polymerase chain reaction, Western blotting and immunohistochemistry in both HaCaT cells and lesions of a patient with AI with NCSTN mutation.
In skin keratinocytes, lymphocytes, and monocytes, but not in neutrophils, P2X7R and NLRP3 protein expression was significantly increased in HS versus the HC group.
Furthermore, in HS, there is dysregulated function of other immune players closely associated with macrophage function including: matrix metalloproteases (MMP) 2 and 9 overexpression, toll-like receptor upregulation, impaired Notch signalling, NLRP3 inflammasome upregulation, and dysregulated keratinocyte function.
Peripheral blood mononuclear cells (PBMCs) were isolated from seven patients with Hurley stage III HS and seven healthy volunteers and stimulated in the presence of 25% of plasma for the production of tumour necrosis factor-α (TNF-α).
The levels of IL-1<i>β</i>, IL-6, IL-8, IL-10, IL-12p70, IL-17A, sTNF-RII, CRP, and ESR were significantly elevated according to inflammatory activity based on HS-PGA scores (<i>r</i> > 0.25, <i>P</i> < 0.05).
Adalimumab is a fully human, immunoglobulin G1 monoclonal antibody specific for tumor necrosis factor-alpha recently approved for use in patients with HS.
In vitro, these cells upregulated LCN2 production in response to tumour necrosis factor (TNF)-α, and a positive relationship between systemic TNF-α and LCN2 levels (r<sub>s</sub> = 0·55, P = 0·011; n = 20) was evident for AI.
These data suggest that inhibition of pathogenic IL-17 via tumor necrosis factor blockade is associated with improvement in immune dysregulation in HS and may provide a rationale for targeting IL-17 in the disease.
Lesional skin samples from 10 patients with HS and skin samples from five healthy controls were cultured ex vivo and exposed to prednisolone or biologics targeting tumour necrosis factor (TNF)-α, interleukin (IL)-17A, IL-12/23p40 or CD20 (adalimumab, infliximab, secukinumab, ustekinumab and rituximab, respectively).