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Microbial elements as the initial triggers in the pathogenesis of polymorphic light eruption?

ABSTRACT: The primary trigger of polymorphic light eruption (PLE) remains to be uncovered. We hypothesize that PLE may be initiated by elements resulting from UV-induced damage to microbial communities of the skin, leading to a cascade of events eventually resulting in the skin rash of the disease. One mechanism by which epidermal injury by UV radiation could trigger PLE are danger signals such as damage or pathogen associated molecular patterns DAMP/PAMPs or commensal-associated molecular patterns (CAMPs). Such triggers could be produced due to UV-induced stress on microbial communities of the skin and exacerbate inflammatory responses by inducing the innate immune system through antimicrobial peptides (AMPs) such as psoriasin, RNase7, HBD-2 and LL-37. These AMPs also actively take part in initiating adaptive immunity. That signals derived from microbial rather than human elements may initiate PLE is supported by series of observations, including the PLE-protective effect of topically applied microbial-derived DNA repair enzymes.

SUBMITTER: Patra V

PROVIDER: S-EPMC5396279 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Microbial elements as the initial triggers in the pathogenesis of polymorphic light eruption?

Patra VijayKumar V Wolf Peter P

Experimental dermatology 20161201 12

The primary trigger of polymorphic light eruption (PLE) remains to be uncovered. We hypothesize that PLE may be initiated by elements resulting from UV-induced damage to microbial communities of the skin, leading to a cascade of events eventually resulting in the skin rash of the disease. One mechanism by which epidermal injury by UV radiation could trigger PLE are danger signals such as damage or pathogen associated molecular patterns DAMP/PAMPs or commensal-associated molecular patterns (CAMPs ...[more]

PMID: 27514020

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Project description:IntroductionPolymorphic light eruption (PLE) is the most common idiopathic, acquired photodermatosis. The pathophysiology of PLE is not yet fully understood but seems to involve immunological mechanisms, UVA-induced oxidative stress, and the subsequent elicitation of a cellular stress response affecting keratinocyte gene expression and skin immune function. In the present study, a high broad-spectrum sunscreen medical device (MD), containing a very high protection complex of UVB and UVA filters and ectoin, was investigated for its ability to protect against UVA-induced PLE.MethodsThe study was carried out as a monocentric, double-blinded, randomized, untreated controlled design. The test MD was applied (2 mg/cm2) on one side of the chest according to a randomization list of 15 patients with a typical history of PLE, and the contralateral area remained untreated. After product application, the test areas were exposed daily to increasing doses of UVA radiation (from 40 to 60 J/cm2) until a PLE reaction was detected or for a maximum of five consecutive days. Evaluations of induced PLE included clinical scoring and chromametry for erythema and pigmentation.ResultsOverall, no positive PLE reaction was observed on the side of the chest treated by the test MD, whereas positive PLE reactions were triggered on the untreated side of 13 subjects. Subjective sensations were very rare on the MD-treated side but were numerous and more severe on the untreated side. Chromametry and clinical visual inspection indicated that the skin color was unchanged on the MD-protected side, whereas high increased values of erythema and pigmentation were observed on the untreated chest side.ConclusionThis MD sunscreen based on a complex of UVA-UVB filters and 1% of ectoin may be effective in preventing UVA-induced PLE. New studies comparing this MD sunscreen versus the same product without ectoin should be conducted.Clinicaltrialsgov identifier: NCT05320315 (retrospectively registered 09/17/2021).

Project description:BackgroundWe hypothesized that regulatory T cells (Tregs) are involved in the immunological abnormalities seen in patients with polymorphic light eruption (PLE).ObjectivesTo investigate the number and suppressive function of peripheral Tregs in patients with PLE compared with healthy controls.MethodsBlood sampling was done in 30 patients with PLE [seeking or not seeking 311-nm ultraviolet (UV)B photohardening] as well as 19 healthy controls at two time points: TP1, March to June (before phototherapy); and TP2, May to August (after phototherapy). We compared the number of CD4(+) CD25(high) CD127(-) FoxP3(+) Tregs by flow cytometry and their function by assessing FoxP3 mRNA levels and effector T cell/Treg suppression assays.ResultsTregs isolated from healthy controls significantly suppressed the proliferation of effector T cells at TP1 by 68% (P = 0·0156). In contrast, Tregs from patients with PLE entirely lacked the capacity to suppress effector T-cell proliferation at that time point. The medical photohardening seen in 23 patients with PLE resulted in a significant increase in the median percentage of circulating Tregs [both as a proportion of all lymphocytes; 65 6% increase (P = 0·0049), and as a proportion of CD4(+) T cells; 32.5% increase (P = 0·0049)]. This was accompanied by an increase in the expression of FoxP3 mRNA (P = 0·0083) and relative immunosuppressive function of Tregs (P = 0·083) comparing the two time points in representative subsets of patients with healthy controls tested. Seven patients with PLE not receiving 311-nm UVB also exhibited an increase in the number of Tregs but this was not statistically significant. No significant differences in Treg numbers were observed in healthy subjects between the two time points.ConclusionsAn impaired Treg function is likely to play a role in PLE pathogenesis. A UV-induced increase in the number of Tregs (either naturally or therapeutically) may be a compensatory mechanism by which the immune system counteracts the susceptibility to PLE.

Project description:Transcriptional profiling provides global snapshots of virus-mediated cellular reprogramming, which can simultaneously encompass pro- and antiviral components. To determine early transcriptional signatures associated with HCV infection of authentic target cells, we performed ex vivo infections of adult primary human hepatocytes (PHHs) from seven donors. Longitudinal sampling identified minimal gene dysregulation at six hours post infection (hpi). In contrast, at 72 hpi, massive increases in the breadth and magnitude of HCV-induced gene dysregulation were apparent, affecting gene classes associated with diverse biological processes. Comparison with HCV-induced transcriptional dysregulation in Huh-7.5 cells identified limited overlap between the two systems. Of note, in PHHs, HCV infection initiated broad upregulation of canonical interferon (IFN)-mediated defense programs, limiting viral RNA replication and abrogating virion release. We further find that constitutive expression of IRF1 in PHHs maintains a steady-state antiviral program in the absence of infection, which can additionally reduce HCV RNA translation and replication. We also detected infection-induced downregulation of ∼90 genes encoding components of the EIF2 translation initiation complex and ribosomal subunits in PHHs, consistent with a signature of translational shutoff. As HCV polyprotein translation occurs independently of the EIF2 complex, this process is likely pro-viral: only translation initiation of host transcripts is arrested. The combination of antiviral intrinsic and inducible immunity, balanced against pro-viral programs, including translational arrest, maintains HCV replication at a low-level in PHHs. This may ultimately keep HCV under the radar of extra-hepatocyte immune surveillance while initial infection is established, promoting tolerance, preventing clearance and facilitating progression to chronicity.IMPORTANCEAcute HCV infections are often asymptomatic and therefore frequently undiagnosed. We endeavored to recreate this understudied phase of HCV infection using explanted PHHs and monitored host responses to initial infection. We detected temporally distinct virus-induced perturbations in the transcriptional landscape, which were initially narrow but massively amplified in breadth and magnitude over time. At 72 hpi, we detected dysregulation of diverse gene programs, concurrently promoting both virus clearance and virus persistence. On the one hand, baseline expression of IRF1 combined with infection-induced upregulation of IFN-mediated effector genes suppresses virus propagation. On the other, we detect transcriptional signatures of host translational inhibition, which likely reduces processing of IFN-regulated gene transcripts and facilitates virus survival. Together, our data provide important insights into constitutive and virus-induced transcriptional programs in PHHs, and identifies simultaneous antagonistic dysregulation of pro-and anti-viral programs which may facilitate host tolerance and promote viral persistence.

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Microbial elements as the initial triggers in the pathogenesis of polymorphic light eruption?

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Microbial elements as the initial triggers in the pathogenesis of polymorphic light eruption?

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