Shifts in the Skin Microbiota after UVB Treatment in Adult Atopic Dermatitis.

BACKGROUND: The pathophysiology in atopic dermatitis (AD) is not fully understood, but immune dysfunction, skin barrier defects, and alterations of the skin microbiota are thought to play important roles. AD skin is frequently colonized with Staphylococcus aureus (S. aureus) and microbial diversity on lesional skin (LS) is reduced compared to on healthy skin. Treatment with narrow-band ultraviolet B (nb-UVB) leads to clinical improvement of the eczema and reduced abundance of S. aureus. However, in-depth knowledge of the temporal dynamics of the skin microbiota in AD in response to nb-UVB treatment is lacking and could provide important clues to decipher whether the microbial changes are primary drivers of the disease, or secondary to the inflammatory process. OBJECTIVES: To map the temporal shifts in the microbiota of the skin, nose, and throat in adult AD patients after nb-UVB treatment. METHODS: Skin swabs were taken from lesional AD skin (n = 16) before and after 3 treatments of nb-UVB, and after 6-8 weeks of full-body treatment. We also obtained samples from non-lesional skin (NLS) and from the nose and throat. All samples were characterized by 16S rRNA gene sequencing. RESULTS: We observed shifts towards higher diversity in the microbiota of lesional AD skin after 6-8 weeks of treatment, while the microbiota of NLS and of the nose/throat remained unchanged. After only 3 treatments with nb-UVB, there were no significant changes in the microbiota. CONCLUSION: Nb-UVB induces changes in the skin microbiota towards higher diversity, but the microbiota of the nose and throat are not altered.

Chromatin interactions in differentiating keratinocytes reveal novel atopic dermatitis- and psoriasis-associated genes.

BACKGROUND: Hundreds of variants associated with atopic dermatitis (AD) and psoriasis, 2 common inflammatory skin disorders, have previously been discovered through genome-wide association studies (GWASs). The majority of these variants are in noncoding regions, and their target genes remain largely unclear. OBJECTIVE: We sought to understand the effects of these noncoding variants on the development of AD and psoriasis by linking them to the genes that they regulate. METHODS: We constructed genomic 3-dimensional maps of human keratinocytes during differentiation by using targeted chromosome conformation capture (Capture Hi-C) targeting more than 20,000 promoters and 214 GWAS variants and combined these data with transcriptome and epigenomic data sets. We validated our results with reporter assays, clustered regularly interspaced short palindromic repeats activation, and examination of patient gene expression from previous studies. RESULTS: We identified 118 target genes of 82 AD and psoriasis GWAS variants. Differential expression of 58 of the 118 target genes (49%) occurred in either AD or psoriatic lesions, many of which were not previously linked to any skin disease. We highlighted the genes AFG1L, CLINT1, ADO, LINC00302, and RP1-140J1.1 and provided further evidence for their potential roles in AD and psoriasis. CONCLUSIONS: Our work focused on skin barrier pathology through investigation of the interaction profile of GWAS variants during keratinocyte differentiation. We have provided a catalogue of candidate genes that could modulate the risk of AD and psoriasis. Given that only 35% of the target genes are the gene nearest to the known GWAS variants, we expect that our work will contribute to the discovery of novel pathways involved in AD and psoriasis.

Early transcriptional changes after UVB treatment in atopic dermatitis include inverse regulation of IL-36γ and IL-37.

Phototherapy with narrow-band Ultraviolet B (nb-UVB) is a major therapeutic option in atopic dermatitis (AD), yet knowledge of the early molecular responses to this treatment is lacking. The objective of this study was to map the early transcriptional changes in AD skin in response to nb-UVB treatment. Adult patients (n = 16) with AD were included in the study and scored with validated scoring tools. AD skin was irradiated with local nb-UVB on day 0, 2 and 4. Skin biopsies were taken before and after treatment (day 0 and 7) and analysed for genome-wide modulation of transcription. When examining the early response after three local UVB treatments, gene expression analysis revealed 77 significantly modulated transcripts (30 down- and 47 upregulated). Among them were transcripts related to the inflammatory response, melanin synthesis, keratinization and epidermal structure. Interestingly, the pro-inflammatory cytokine IL-36γ was reduced after treatment, while the anti-inflammatory cytokine IL-37 increased after treatment with nb-UVB. There was also a modulation of several other mediators involved in inflammation, among them defensins and S100 proteins. This is the first study of early transcriptomic changes in AD skin in response to nb-UVB. We reveal robust modulation of a small group of inflammatory and anti-inflammatory targets, including the IL-1 family members IL36γ and IL-37, which is evident before any detectable changes in skin morphology or immune cell infiltrates. These findings provide important clues to the molecular mechanisms behind the treatment response and shed light on new potential treatment targets.

Prognosis of Preschool Eczema and Factors of Importance for Remission.

Information on factors of importance for remission of eczema is scarce. This study explored factors related to the remission and course of preschool eczema (PSE) (eczema at 1, 2 and/or 4 years of age) to 16 years of age (n = 889) in a Swedish cohort. Half of the children were in complete remission by school age (at age 8, 12, and 16 years). In multivariate prognostic models, persistent PSE (eczema at 1, 2 and 4 years of age) (odds ratio 0.27 (95% confidence interval 0.18-0.41)), PSE with sleep disturbance (due to itch at least once a week at 1, 2 and/or 4 years of age) (0.59 (0.43-0.81)), parental allergy (0.73 (0.55-0.96)), parental smoking at child's birth (0.70 (0.50-0.99)) and filaggrin mutation (R501X, R2447X, 2282del4) (0.47 (0.26-0.85)) were inversely associated with complete remission by school age. Male sex (1.37 (1.03-1.82)) and exclusive breastfeeding ≥4 months (1.44 (1.01-2.05)) were positively associated with complete remission by school age. In conclusion, half of the children with PSE were in complete remission by school age. The most important prognostic factors were persistent PSE and PSE with sleep disturbance due to itch.

Intragenic Copy Number Variation in the Filaggrin Gene in Ethiopian Patients with Atopic Dermatitis.

Genetic variants in filaggrin (FLG) involving truncating mutations or intragenic copy number variation are strongly associated with the risk of developing atopic dermatitis (AD) in European and Asian populations. Few loss-of-function mutations have been identified in Africans, although an association between FLG copy number variation and AD severity in a small African American cohort has been proposed. We studied the association between FLG copy number and AD in 132 Ethiopians and found no association between AD severity and FLG copy number, suggesting that other, still unidentified genetic factors are of more importance in predisposing Ethiopians to AD.

Uncommon Variants in FLG2 and NOD2 Are Associated with Atopic Dermatitis in the Ethiopian Population.

Loss-of-function variants in the FLG gene have been identified as the strongest cause of susceptibility to atopic dermatitis (AD) in Europeans and Asians. However, very little is known about the genetic etiology behind AD in African populations, where the prevalence of AD is notably high. We sought to investigate the genetic origins of AD by performing whole-genome sequencing in an Ethiopian family with 12 individuals and several affected in different generations. We identified 2 variants within FLG2 (p.D13Y) and NOD2 (p.A918S) genes cosegregating with AD in the affected individuals. Further genotyping analyses in both Ethiopian and Swedish AD cases and controls revealed a significant association with the FLG2 variant (p.D13Y, P < .0013) only in the Ethiopian cohort. However, the NOD2 variant (p.A918S) did not show any association in our Ethiopian cohort. Instead, 2 previously recognized NOD2 variants (p.A849V, P < .0085 and p.G908R, P < .0036) were significantly associated with AD in our Ethiopian cohort. Our study indicates that the FLG2 and NOD2 genes might be important in the etiology of AD in Ethiopians. Additional genetic and functional studies are needed to confirm the role of these genes and the associated variants into the development of AD.

HTR1A a novel type 1 diabetes susceptibility gene on chromosome 5p13-q13.

BACKGROUND: We have previously performed a genome-wide linkage study in Scandinavian Type 1 diabetes (T1D) families. In the Swedish families, we detected suggestive linkage (LOD≤2.2) to the chromosome 5p13-q13 region. The aim of our study was to investigate the linked region in search for possible T1D susceptibility genes. METHODOLOGY/PRINCIPAL FINDINGS: Microsatellites were genotyped in the Scandinavian families to fine-map the previously linked region. Further, SNPs were genotyped in Swedish and Danish families as well as Swedish sporadic cases. In the Swedish families we detected genome-wide significant linkage to the 5-hydroxytryptamine receptor 1A (HTR1A) gene (LOD 3.98, p<9.8×10(-6)). Markers tagging two separate genes; the ring finger protein 180 (RNF180) and HTR1A showed association to T1D in the Swedish and Danish families (p<0.002, p<0.001 respectively). The association was not confirmed in sporadic cases. Conditional analysis indicates that the primary association was to HTR1A. Quantitative PCR show that transcripts of both HTR1A and RNF180 are present in human islets of Langerhans. Moreover, immunohistochemical analysis confirmed the presence of the 5-HTR1A protein in isolated human islets of Langerhans as well as in sections of human pancreas. CONCLUSIONS: We have identified and confirmed the association of both HTR1A and RFN180, two genes in high linkage disequilibrium (LD) to T1D in two separate family materials. As both HTR1A and RFN180 were expressed at the mRNA level and HTR1A as protein in human islets of Langerhans, we suggest that HTR1A may affect T1D susceptibility by modulating the initial autoimmune attack or either islet regeneration, insulin release, or both.