RESUMEN
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.
Asunto(s)
Alopecia/congénito , Sitios Genéticos , Predisposición Genética a la Enfermedad , Antígeno HLA-B7/genética , Transcriptoma/inmunología , Inmunidad Adaptativa , Alopecia/diagnóstico , Alopecia/genética , Alopecia/fisiopatología , Estudios de Casos y Controles , Estudios de Cohortes , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/inmunología , Femenino , Expresión Génica , Genoma Humano , Estudio de Asociación del Genoma Completo , Antígeno HLA-B7/inmunología , Humanos , Inmunidad Innata , Polimorfismo de Nucleótido SimpleRESUMEN
A 68-year-old woman, with a 75-pack-year smoking history and a history of chronic excess alcohol intake, presented with a 5-week history of worsening perianal pain and ulceration. She recently had an inpatient admission with back pain and urinary tract infection during which she developed diarrhea and fecal incontinence. Initially, the perianal ulceration was diagnosed as severe irritant contact dermatitis and treated with barrier creams and topical clobetasone 17-butyrate 0.05% weight for weight, oxytetracycline 3.0% weight for weight and nystatin cream (Trimovate®). Despite this, the ulceration progressed, resulting in hospital readmission 1 month later. There was no history of consumption of nicorandil (an antianginal therapy), of recurrent oral ulcers, or of inflammatory bowel disease. On examination, there were multiple areas of deep, sloughy ulceration bilaterally around the perianal and buttock regions with erythematous and violaceous edges (Figure 1). Complete blood count, blood film, rheumatoid factor, autoimmune and vasculitic profile, hepatitis screen, immunoglobulins and plasma protein electrophoresis were all normal. Punch biopsy revealed scanty dermal perivascular inflammatory cell infiltrate and occasional neutrophils (Figure 2). No evidence of granulomata, dysplasia, malignancy, or Langerhans histiocytes was identified, and periodic acid-Schiff staining was negative.
Asunto(s)
Isquemia/etiología , Enfermedad Arterial Periférica/complicaciones , Piodermia Gangrenosa/diagnóstico , Úlcera Cutánea/diagnóstico , Úlcera Cutánea/etiología , Anciano , Canal Anal , Aorta Abdominal , Nalgas , Diagnóstico Diferencial , Femenino , Arteria Femoral , Humanos , Arteria Ilíaca , Enfermedad Arterial Periférica/cirugíaRESUMEN
The incidence of allergy and asthma in developed countries is on the increase and this trend looks likely to continue. CD4(+) T helper 2 (Th2) cells are major drivers of these diseases and their commitment is controlled by cytokines such as interleukin 4, which are in turn regulated by the suppressor of cytokine signaling (SOCS) proteins. We report that SOCS2(-/-) CD4(+) T cells show markedly enhanced Th2 differentiation. SOCS2(-/-) mice, as well as RAG-1(-/-) mice transferred with SOCS2(-/-) CD4(+) T cells, exhibit elevated type 2 responses after helminth antigen challenge. Moreover, in in vivo models of atopic dermatitis and allergen-induced airway inflammation, SOCS2(-/-) mice show significantly elevated IgE, eosinophilia, type 2 responses, and inflammatory pathology relative to wild-type mice. Finally, after T cell activation, markedly enhanced STAT6 and STAT5 phosphorylation is observed in SOCS2(-/-) T cells, whereas STAT3 phosphorylation is blunted. Thus, we provide the first evidence that SOCS2 plays an important role in regulating Th2 cell expansion and development of the type 2 allergic responses.