British Journal of Dermatology最新文献

Background: Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory skin disease associated with significant comorbidities and poor quality of life. Despite uncertainty about pathways driving inflammation in HS lesions, the cytokines interleukin (IL)-17A and IL-17F have been shown to be upregulated in patients with HS. Previous studies have demonstrated that the monoclonal IgG1 antibody bimekizumab selectively inhibits IL-17F in addition to IL-17A.

Objectives: To further investigate the roles of IL-17A and IL-17F in HS pathogenesis.

Methods: RNA sequencing (RNAseq) was conducted on skin biopsies taken at baseline and after treatment at week 12 of a phase II proof-of-concept study of bimekizumab in patients with moderate-to-severe HS. Differentially expressed genes were identified between baseline lesional and nonlesional samples and between lesional samples before and after bimekizumab treatment, to describe molecular disease mechanisms and treatment effect. Human hair follicular keratinocytes (HHFK) were cultured and treated with a supernatant of stimulated T helper (Th)17 cells in combination with anti-IL-17A, anti-IL-17F, anti-IL-17A and anti-IL-17F, or IgG control antibodies. Total mRNA was analysed by RNAseq. Cellular supernatants from the stimulated HHFKs were used as a source of Th17-induced chemoattractants in neutrophil chemotaxis assays.

Results: RNAseq revealed that the most prominently upregulated genes in HS lesions included those associated with neutrophil biology. Bimekizumab treatment resulted in reduced expression of these genes. The extent of reduction in gene expression was dependent on achieving HiSCR50 (≥ 50% reduction from baseline in the total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining tunnel count). In vitro dual inhibition of IL-17A and IL-17F had greater attenuation of Th17-induced HS-associated genes and neutrophil migration in HHFKs vs. IL-17A or IL-17F inhibition alone. In situ hybridization found that IL-17A- and IL-17F-producing cells in HS lesions can lack the IL-23 receptor and IL-1β could induce IL-23-independent IL-17F expression in vitro. Furthermore, mucosal-associated invariant cells in HS tunnels expressed IL-17F and IL-1 receptor type 1. IL-1β-, IL-17A- and IL-17F-expressing cells were found to be co-localized in HS lesions.

Conclusions: These data support the hypothesis that IL-17A and IL-17F play central roles in HS, a neutrophilic dermatosis. The presence of IL-1β may partly explain the high expression of IL-17F in lesional HS tissue.

Background: Taste receptors (TRs) exert many 'non-gustatory' chemosensory functions beyond the sensation of taste. Recently, human keratinocytes were found to express some bitter TRs, whose physiological functions remain unknown. Since we had discovered that human scalp hair follicles (HFs) use olfactory receptors to regulate their growth, we hypothesized that some bitter TRs may exert a similar function.

Objectives: To explore whether human scalp HFs express the bitter TR, TAS2R4, whether its stimulation with cognate agonists or its selective knockdown impacts key human HF functions and, if yes, how.

Methods: TAS2R4 mRNA and protein expression were assessed in situ, and organ-cultured scalp HFs were stimulated with the TAS2R4-agonistic natural sweetener, rebaudioside A (Reb A), in the presence/absence of TAS2R4 siRNA. Subsequently, changes in hair growth, growth factor expression, and HF gene expression were assessed ex vivo.

Results: TAS2R4 mRNA and protein are mainly expressed in the outer root sheath and matrix of human anagen scalp HFs. Stimulating these with Reb-A ex vivo initially inhibits hair matrix keratinocyte proliferation, followed by enhanced intrafollicular production of catagen-promoting TGF-β2. This leads to TGF-β-driven premature catagen entry, which can be antagonized by TGF-β-neutralizing antibodies. Premature catagen induction is also seen with other known TAS2R4 agonists, while TAS2R4 knockdown in the presence of Reb-A promotes hair growth, thus documenting the TAS2R4-dependence of the observed HF effects of Reb-A. Gene expression profiling (RNA-seq) revealed differential transcriptional signatures consistent with TAS2R4-mediated changes in cell cycle control and TGF-β pathway signalling.

Conclusion: Our study uncovers that human scalp HFs engage in chemosensation via bitter TRs to regulate their growth, matrix keratinocyte proliferation, growth factor production, and overall gene expression. Specifically, we demonstrate that a simple tastant like Reb-A can promote the anagen-catagen switch of human scalp HFs, their TGF-β2 production, and modulate both HF keratinocyte proliferation and intrafollicular gene transcription in a TAS2R4-dependent manner. This expands our understanding of bitter TR-mediated chemosensation in human skin and invites a novel, drug-free strategy for inhibiting unwanted hair growth (hirsutism, hypertrichosis) by targeting TAS2R4, e.g. via topical Reb-A.

The ability to grow long scalp hair is a distinct human characteristic. It probably originally evolved to aid in cooling the sun-exposed head, although the genetic determinants of long hair are largely unknown. Despite ancestral variations in hair growth, long scalp hair is common to all extant human populations, which suggests its emergence before or concurrently with the emergence of anatomically modern humans (AMHs), approximately 300 000 years ago. Long scalp hair in AMHs was also a trait that was selected because it conveyed essential signals related to an individual's age, sexual maturity, health and social status. Biologically, hair length is primarily determined by the amount of time that a hair follicle spends in the active growth phase (anagen). While anagen duration is typically tightly regulated in most mammals, the inherent ability of a hair follicle to continuously recruit new dividing progenitors to its base, where hair fibre is generated, theoretically removes limits on maximal anagen duration. We propose a model wherein hair cycle progression into and out of anagen is regulated by evolutionary malleable molecular checkpoints. Several animal species and domesticated animal breeds display long body hair, which suggests that extremely long scalp hair in humans emerged via attenuation of an existing out-of-anagen checkpoint mechanism rather than via a newly evolved molecular programme. Studying congenital and somatic mosaicism conditions featuring altered hair length could potentially unveil the currently unknown molecular basis underlying this human trait.

Background: The SUNSHINE and SUNRISE phase III trials demonstrated sustained clinical efficacy of secukinumab in patients with moderate-to-severe hidradenitis suppurativa (HS) through 52 weeks. Patients completing the core trials could enter a 4-year extension trial.

Objectives: To evaluate the long-term efficacy, safety/tolerability and maintenance of clinical response to secukinumab through week 104 in the extension trial.

Methods: Patients with a hidradenitis suppurativa (HS) clinical response (HiSCR) at week 52 of the core trials (extension trial baseline visit) entered a randomized withdrawal period. HiSCR responders receiving subcutaneous secukinumab 300 mg every 2 or 4 weeks (SECQ2W/SECQ4W) through week 52 in the core trials were randomized 2 : 1 to continue secukinumab (SECQ2W-R-Q2W or SECQ4W-R-Q4W) or receive placebo (SECQ2W-R-PBO or SECQ4W-R-PBO) through week 104. The primary endpoint was time to loss of response (LOR; newly defined for this trial) through week 104 in week 52 HiSCR responders (SECQ2W-R-Q2W vs. SECQ2W-R-PBO and SECQ4W-R-Q4W vs. SECQ4W-R-PBO). Time to LOR was tested at 1.25% (one-sided) for each comparison (one-sided familywise alpha of 2.5%) through week 104. If LOR was met, patients could remain in the trial on open-label secukinumab treatment. Additional endpoints included safety and HiSCR. The trial was registered with ClinicalTrials.gov (NCT04179175).

Results: Overall, 84.3% of patients who completed the core trials entered the extension trial; 55.9% were week 52 HiSCR responders. The primary endpoint was not met for either secukinumab dosing regimen. The estimated risk reduction for LOR was 13% (SECQ2W-R-Q2W vs. SECQ2W-R-PBO; one-sided P = 0.25) and 30% (SECQ4W-R-Q4W vs. SECQ4W-R-PBO; one-sided P = 0.04). The median time to LOR was numerically longer in the secukinumab arms vs. placebo {SECQ2W-R-Q2W [283 days; 95% confidence interval (CI) 176, -] vs. SECQ2W-R-PBO [239 days; 95% CI 120, -]; SECQ4W-R-Q4W [365 days 95% CI 225, -] vs. SECQ4W-R-PBO [171 days; 95% CI 113-337]}. In week 52 HiSCR responders reporting LOR, 44% (SECQ2W-R-Q2W), 58% (SECQ2W-R-PBO), 40% (SECQ4W-R-Q4W) and 34% (SECQ4W-R-PBO) were achieving HiSCR at the time of LOR. Overall, the safety of secukinumab was consistent with the core trials.

Conclusions: The primary endpoint of this trial was not met. HiSCR was maintained in many patients at the time of LOR. The safety of secukinumab was consistent with the previously characterized safety profile in the core trials.