Twenty-eight-day follow-up of patch test reactions to p-phenylenediamine and p-phenylenediamine dihydrochloride: A multicentre study on behalf of the European Environmental and Contact Dermatitis Research Group.

BACKGROUND: There is an ongoing discussion on whether routinely patch testing with p-phenylenediamine (PPD) 1.0% pet. is safe, owing to the risk of patch test sensitization. Late-appearing patch test reactions may reflect patch test sensitization, but may also be attributable to a low degree of pre-existing sensitization. OBJECTIVES: To follow the positive patch test reactions to PPD and its salt PPD dihydrochloride (PPD-DHC) in order to characterize reaction patterns concerning time and dose in PPD-sensitized individuals. METHODS: Volunteers with previous reactions to PPD 1.0% were included and patch tested with PPD and PPD-DHC in equimolar dilution series. There were then seven follow-up visits over a period of 28 days. RESULTS: Twenty-six volunteers completed the study, of whom 23 of 26 (88%) reacted to PPD 1.0%, and 69% reacted to PPD 0.32%. Altogether, 42% and 27% reacted to the corresponding equimolar concentrations of PPD-DHC. After day 7, no new reactions were observed to any concentration tested, either of PPD or of PPD-DHC. CONCLUSION: No late-appearing reactions to PPD or PPD-DHC were observed at any dose. There is a risk of missing contact allergy when the dose is decreased.

The nickel dose-response relationship by filaggrin genotype (FLG).

BACKGROUND: On skin contact, nickel accumulates in the stratum corneum, where it is probably bound to proteins and amino acids. One probable contributor is filaggrin, which binds nickel avidly. Filaggrin gene (FLG) null mutations lead to a complete lack of filaggrin production from the affected allele, and have been associated with an increased risk of nickel contact sensitization in German and Danish adults. OBJECTIVES: To investigate whether the experimental nickel elicitation threshold level differed between heterozygous FLG mutation and non-mutation carriers. METHOD: Thirteen nickel-sensitized female patients, seven heterozygous mutation carriers and six non-mutation carriers (genotyped for R501X, 2282del4, or R2447X), were patch tested and performed a repeated open application test (ROAT) with a nickel sulfate dilution series. Logistic threshold dose-response analyses were used to test for differences between the two groups. RESULTS: No difference was found in the dose-response relationship between FLG mutation and non-mutation carriers. CONCLUSIONS: On the basis of this small patient study, it appears that the elicitation threshold level for nickel is independent of FLG null mutation single-allele carrier status.

Carriers of filaggrin gene (FLG) mutations avoid professional exposure to irritants in adulthood.

BACKGROUND: Loss-of-function mutations in the filaggrin gene (FLG) are associated with xerosis, atopic dermatitis, and early onset of hand eczema. Irritant exposure is a risk factor for occupational hand eczema, and FLG mutations increase the risk of occupational irritant contact dermatitis on the hands in hospital cohorts. It is unknown whether FLG mutations affect the level of irritant exposure. OBJECTIVES: To evaluate whether exposure to occupational irritants was dependent on FLG mutations, atopic dermatitis, and age at hand eczema onset. METHODS: Randomly chosen Danish adults completed a questionnaire on general health and occupational exposures. Genotyping for FLG mutations (R501X, 2282del4, and R2447X) and patch testing were performed. RESULTS: Overall, 38.7% of subjects reported present or previous occupational exposure to irritants. Among individuals who reported hand eczema onset before entering their work life, 50.6% (45/89) of FLG non-mutation carriers became exposed to irritants, as compared with 28.6% (4/14) of heterozygous and 0% (0/6) of homozygous mutation carriers (p = 0.006). Avoidance was conspicuous among mutation carriers reporting childhood hand eczema and atopic dermatitis (odds ratio 0.08, 95% confidence interval 0.01-0.65). CONCLUSIONS: Carriers of FLG mutations who have had hand eczema onset in childhood avoid occupational exposure to irritants; the association is most marked with homozygous mutation status combined with atopic dermatitis.

Filaggrin mutations are strongly associated with contact sensitization in individuals with dermatitis.

BACKGROUND: Although heterozygous filaggrin gene (FLG) mutation carriers seem to have an increased risk of atopic, irritant and allergic nickel dermatitis, it remains unclear whether the risk of contact sensitization to allergens other than nickel is also elevated in FLG mutation carriers. OBJECTIVES: We hypothesized that heterozygous FLG mutation carriers who suffer from dermatitis will have strongly reduced or even absent filaggrin levels during episodes of inflammation, potentially increasing the penetration of contact allergens, and hence the risk of becoming sensitized. MATERIALS AND METHODS: During 2006-2008, 3335 randomly invited 18-69-year-old adult Danes participated in a general health examination, filled out a questionnaire, and were genotyped for the R501X and 2282del4 mutations in FLG. RESULTS: A logistic regression analysis restricted to individuals who reported atopic dermatitis and frequent episodes of hand eczema showed a strong association between FLG mutations and contact sensitization to allergens other than nickel (odds ratio 5.71; 95% confidence interval 1.31-24.94). In participants without dermatitis, no association was found between contact sensitization and FLG mutations. CONCLUSION: FLG mutation carriers with self-reported dermatitis have an increased risk of contact sensitization to substances other than nickel, whereas FLG mutations alone may not, or may only slightly, increase the risk of sensitization.

U20 is responsible for human herpesvirus 6B inhibition of tumor necrosis factor receptor-dependent signaling and apoptosis.

The immune system targets virus-infected cells by different means. One of the essential antiviral mechanisms is apoptosis induced by ligation of tumor necrosis factor receptor 1 (TNFR1). This receptor can be activated by tumor necrosis factor alpha (TNF-α), which upon binding to TNFR1 induces the assembly of first an inflammatory and later a proapoptotic signaling complex. Here, we report that infection by human herpesvirus 6B (HHV-6B) inhibited poly(ADP-ribose) polymerase (PARP) cleavage, caspase 3 and 8 activation, and IκBα Ser-32 phosphorylation downstream of TNFR1, indicating inhibition of both the inflammatory and apoptotic signaling pathways. We identified a hitherto uncharacterized viral protein, U20, as sufficient for mediating this inhibition. U20 was shown to locate to the cell membrane, and overexpression inhibited PARP cleavage, caspase 3 and 8 activation, IκBα Ser-32 phosphorylation, and NF-κB transcriptional activity. Moreover, small interfering RNA (siRNA) knockdown of U20 demonstrated that the protein is necessary for HHV-6B-mediated inhibition of TNFR signaling during infection. These results suggest an important novel function of U20 as a viral immune evasion protein during HHV-6B infection.

Nickel reactivity and filaggrin null mutations--evaluation of the filaggrin bypass theory in a general population.

BACKGROUND: It was recently shown that filaggrin null mutation carrier status was associated with nickel allergy and self-reported intolerance to costume jewellery. Because of the biochemical characteristics of filaggrin, it may show nickel barrier properties in the stratum corneum. OBJECTIVES: To investigate whether subjects with filaggrin null mutations report nickel dermatitis at an earlier age than wild-type individuals, and to analyse whether null mutation carriers have stronger patch test reactivity to nickel sulfate than do wild-type individuals. MATERIALS: A total of 3471 Danes (18-69 years of age) answered a questionnaire about general health, and underwent patch testing and filaggrin genotyping. RESULTS: The mean number of years at risk of developing nickel dermatitis was significantly lower for the filaggrin null genotype than for the wild-type genotype when ear piercing status was considered. In positive patch test readings, the proportion of null mutants increased with increasing reaction strength. CONCLUSIONS: Filaggrin null mutations may lower the age of onset of nickel dermatitis. The hypothesis that ear piercings obscure the effect of filaggrin null mutations on the development of nickel allergy in statistical analyses was supported. An association between the null genotype and increased nickel sensitivity was indicated by patch test reading and questionnaire data.

Patch test reactivity to metal allergens following regulatory interventions: a 33-year retrospective study.

BACKGROUND: Contact allergy epidemics to chromate and nickel were addressed in Denmark in 1983 and 1990 by regulatory interventions. OBJECTIVES: To evaluate whether regulatory interventions on nickel and chromate exposure have reduced the proportion of strong patch test reactions. METHODS: 22 506 patients with dermatitis aged 4-99 years were patch tested with nickel sulfate, potassium dichromate, or cobalt chloride between 1977 and 2009. RESULTS: The proportion of 3+ reactions to nickel sulfate was reduced and almost disappeared after the mid- and late 1980s (P-trend = 0.001). Today, 1+ and 2+ nickel reactions occur equally frequent. Cobalt chloride patch test reactivity reflected the nickel development to some degree. The proportion of 3+ reactions to potassium dichromate was reduced during the 1980s (P-trend = 0.13), whereas the proportion of 2+ reactions to potassium dichromate have increased in recent years. CONCLUSIONS: The decrease in nickel sulfate and cobalt chloride 3+ patch test reactivity began long before the Danish nickel regulation came into effect. This could be because of research activity at the time as well as political attention in Northern Europe. The chromate content in cement regulation may have changed the epidemiology of patch test reactivity; however, in recent years, 2+ reactions to chromate have increased markedly, a development that should be carefully followed.

Human herpesvirus 6B U19 protein is a PML-regulated transcriptional activator that localizes to nuclear foci in a PML-independent manner.

Human herpesvirus 6B (HHV-6B) contains an IE-B domain spanning open reading frames U16/17-U19, based on homology with human cytomegalovirus. Here, the protein product, U19, of the HHV-6B U19 gene is identified as a 47 kDa transcriptional activator. HHV-6B infection or overexpression of U19 transactivated the RANTES promoter. Mutational analysis of the promoter indicated that transactivation was not critically dependent on the promoter sites CRE, NF-kappaB, ISRE or NF-IL6. ND10 are nuclear substructures that are involved in several cellular regulatory pathways, including those controlling gene expression. HHV-6B infection resulted in a reduced number of ND10 structures, but with a concomitantly increased level of promyelocytic leukaemia (PML) protein expression and mRNA induction. The U19 protein co-located to ND10 with PML and heterochromatin protein 1 (HP1), but whilst PML formed a ring structure, U19 also localized to the centre of ND10. Knockdown of PML by small interfering RNA did not prevent U19 localization to ND10-like foci, but instead led to a fourfold increase in U19-induced transcription from the RANTES promoter. Generation of four truncated U19 proteins indicated that the N-terminal portion of the protein contains a sequence responsible for nuclear localization; a domain in the N-terminal half of U19 is responsible for its ND10 localization, whereas the C-terminal portion contains the transactivation domain. None of the truncated proteins retained full transactivating ability on the RANTES promoter. Thus, U19 is a transcriptional activator that co-localizes with PML and localizes to ND10-like foci independently of PML, yet is regulated negatively by PML or its associated proteins.