Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02.

Frontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence the aetiopathogenesis of FFA remains unknown. We undertake genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and perform statistical meta-analysis. We observe genome-wide significant association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22 and 15q2.1. Within the 6p21.1 locus, fine-mapping indicates that the association is driven by the HLA-B*07:02 allele. At 2p22.1, we implicate a putative causal missense variant in CYP1B1, encoding the homonymous xenobiotic- and hormone-processing enzyme. Transcriptomic analysis of affected scalp tissue highlights overrepresentation of transcripts encoding components of innate and adaptive immune response pathways. These findings provide insight into disease pathogenesis and characterise FFA as a genetically predisposed immuno-inflammatory disorder driven by HLA-B*07:02.

Enzyme-independent NO stores in human skin: quantification and influence of UV radiation.

Nitric oxide (NO) has many functions in the skin, including the mediation of inflammation and antimicrobial defense, wound healing, regulation of keratinocyte homeostasis, and regulation of apoptosis following UV radiation. NO is synthesized by a family of NO synthase enzymes, but its rapid release following UV exposure suggests the existence of preformed stores. NO can be converted into nitrite or nitrosothiols that are stable until cleaved by UV to release NO. Using dermal microdialysis, suction blister epidermal samples, and sweat collection, we demonstrated cutaneous concentrations of total NO-related products of 12+/-5.97 microM, 0.03+/-0.03 micromol mg(-1) epidermal protein, and 22+/-9.34 microM, respectively. The predominant oxyanion was nitrate (60-75%) followed by nitrite. S-Nitrosothiols were barely detectable. Serum total NO-related products correlated directly with those of the upper dermis and sweat (R(2)=0.62 and 0.3, respectively). UVA irradiation (10 mW cm(-2)) increased the yield of NO-related products by microdialysis, peaking after 30 minutes. Dialysis with noradrenaline abrogated this rise. Both the skin and the dermal vasculature contain biologically significant stores of NO, particularly nitrite, which can be directly mobilized by UVA irradiation. The level of circulating NO-related products probably determines skin-bound stores.

Topically applied nitric oxide induces T-lymphocyte infiltration in human skin, but minimal inflammation.

Nitric oxide (NO) plays an important role in the cutaneous response to UV radiation and in cutaneous inflammation. The presence of inducible NO synthase protein in a number of inflammatory dermatoses, coupled with the induction of an intense cutaneous inflammatory infiltrate following topical application of the NO donor-acidified nitrite (NO2(-)), has set the paradigm of NO being an inflammatory mediator in human skin. Using zeolite NO (Ze-NO), a chemically inert, pure NO donor, we have shown that NO per se produces little inflammation. Biologically, relevant doses of Ze-NO induce a dermal CD4-positive T-cell infiltrate and IFN-gamma secretion. In contrast acidified nitrite, releasing equal quantities of NO (measured by dermal microdialysis and cutaneous erythema), induces an intense epidermal infiltrate of macrophages with a similar dermal infiltrate of CD3-, CD4-, CD8-, and CD68-positive cells and neutrophils. Suction blisters were created in Ze-NO-treated and control skin. IFN-gamma, but not IL-4, was detected in Ze-NO-treated skin (mean control 0.1+/-0.07 pg mg(-1) protein, mean IFN-gamma 0.6+/-0.4 pg mg(-1) protein). We suggest that the potent inflammation induced by acidified NO2(-) is secondary to the release of additional mediators.