Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-γ-expressing Th1 cells and IL-17A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment

Background We analysed incidence, predictors, histological features and specific treatment options of anti-tumour necrosis factor alpha (TNF-alpha) antibody-induced psoriasiform skin lesions in patients with inflammatory bowel diseases (IBD).

Design Patients with IBD were prospectively screened for anti-TNF-induced psoriasiform skin lesions. Patients were genotyped for IL23R and IL12B variants. Skin lesions were examined for infiltrating Th1 and Th17 cells. Patients with severe lesions were treated with the anti-interleukin (IL)-12/IL-23 p40 antibody ustekinumab.

Results Among 434 anti-TNF-treated patients with IBD, 21 (4.8%) developed psoriasiform skin lesions. Multiple logistic regression revealed smoking (p=0.007; OR 4.24, 95% CI 1.55 to 13.60) and an increased body mass index (p=0.029; OR 1.12, 95% CI 1.01 to 1.24) as main predictors for these lesions. Nine patients with Crohn's disease and with severe psoriasiform lesions and/or anti-TNF antibody-induced alopecia were successfully treated with the anti-p40-IL-12/IL-23 antibody ustekinumab (response rate 100%). Skin lesions were histologically characterised by infiltrates of IL-17A/IL-22-secreting T helper 17 (Th17) cells and interferon (IFN)-gamma-secreting Th1 cells and IFN-alpha-expressing cells. IL-17A expression was significantly stronger in patients requiring ustekinumab than in patients responding to topical therapy (p=0.001). IL23R genotyping suggests disease-modifying effects of rs11209026 (p.Arg381Gln) and rs7530511 (p.Leu310Pro) in patients requiring ustekinumab.

Conclusions New onset psoriasiform skin lesions develop in nearly 5% of anti-TNF-treated patients with IBD. We identified smoking as a main risk factor for developing these lesions. Anti-TNF-induced psoriasiform skin lesions are characterised by Th17 and Th1 cell infiltrates. The number of IL-17A-expressing T cells correlates with the severity of skin lesions. Anti-IL-12/IL23 antibody therapy is a highly effective therapy for these lesions.

Cytosolic DNA triggers inflammasome activation in keratinocytes in psoriatic lesions

The proinflammatory cytokine interleukin-1β (IL-1β) plays a central role in the pathogenesis and the course of inflammatory skin diseases, including psoriasis. Posttranscriptional activation of IL-1β is mediated by inflammasomes; however, the mechanisms triggering IL-1β processing remain unknown. Recently, cytosolic DNA has been identified as a danger signal that activates inflammasomes containing the DNA sensor AIM2. In this study, we detected abundant cytosolic DNA and increased AIM2 expression in keratinocytes in psoriatic lesions but not in healthy skin. In cultured keratinocytes, interferon-γ induced AIM2, and cytosolic DNA triggered the release of IL-1β via the AIM2 inflammasome. Moreover, the antimicrobial cathelicidin peptide LL-37, which can interact with DNA in psoriatic skin, neutralized cytosolic DNA in keratinocytes and blocked AIM2 inflammasome activation. Together, these data suggest that cytosolic DNA is an important disease-associated molecular pattern that can trigger AIM2 inflammasome and IL-1β activation in psoriasis. Furthermore, cathelicidin LL-37 interfered with DNA-sensing inflammasomes, which thereby suggests an anti-inflammatory function for this peptide. Thus, our data reveal a link between the AIM2 inflammasome, cathelicidin LL-37, and autoinflammation in psoriasis, providing new potential targets for the treatment of this chronic skin disease.

Impact of vitamin D3 on cutaneous immunity and antimicrobial peptide expression

Antimicrobial peptides (AMPs) are effectors of cutaneous innate immunity and protect primarily against microbial infections. An array of AMPs can be found in and on the skin. Those include peptides that were first discovered for their antimicrobial properties but also proteins with antimicrobial activity first characterized for their activity as chemokines, enzymes, enzyme inhibitors and neuropeptides. Cathelicidins were among the first families of AMPs discovered in skin. They are now known to exert a dual role in innate immune defense: they have direct antimicrobial activity and will also initiate a host cellular response resulting in cytokine release, inflammation and angiogenesis. Altered cathelicidin expression and function was observed in several common inflammatory skin diseases such as atopic dermatitis, rosacea and psoriasis. Until recently the molecular mechanisms underlying cathelicidin regulation were not known. Lately, vitamin D3 was identified as the major regulator of cathelicidin expression and entered the spotlight as an immune modulator with impact on both, innate and adaptive immunity. Therapies targeting vitamin D3 signalling may provide novel approaches for the treatment of infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions through AMP regulation.

Control of cutaneous antimicrobial peptides by vitamin D3

Constant exposure to a wide variety of microbial pathogens represents a major challenge for our skin. Antimicrobial peptides (AMPs) are mediators of cutaneous innate immunity and protect primarily against microbial infections. Cathelicidins were among the first AMPs identified in human skin and recent evidence suggests that they exert a dual role in innate immune defense: At first, due to their antimicrobial activity they kill pathogens directly. In addition, these peptides initiate a potent host response to infection resulting in cytokine release, inflammation and a cellular response. Disturbed cathelicidin expression and function was observed in several common inflammatory skin diseases, such as psoriasis where cathelicidin peptide converts inert self-DNA and self-RNA into an autoimmune stimulus. In atopic dermatitis decreased levels of cathelicidin facilitating microbial superinfections have been discussed. Furthermore, abnormally processed cathelicidin peptides induce inflammation and a vascular response in rosacea. Until recently, the molecular mechanisms underlying cathelicidin regulation were unknown. Recently, the vitamin D3 pathway was identified as the major regulator of cathelicidin expression. Consequently, vitamin D3 entered the spotlight as an immune modulator with impact on both innate and adaptive immunity. Therapies targeting vitamin D3 signaling may provide new approaches for infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions.

Photosensitisers - the progression from photodynamic therapy to anti-infective surfaces

Introduction: The application of light as a stimulus in pharmaceutical systems and the associated ability to provide precise spatiotemporal control over location, wavelength and intensity, allowing ease of external control independent of environmental conditionals, has led to its increased use. Of particular note is the use of light with photosensitisers.

Areas covered: Photosensitisers are widely used in photodynamic therapy to cause a cidal effect towards cells on irradiation due to the generation of reactive oxygen species. These cidal effects have also been used to treat infectious diseases. The effects and benefits of photosensitisers in the treatment of such conditions are still being developed and further realised, with the design of novel delivery strategies. This review provides an overview of the realisation of the pharmaceutically relevant uses of photosensitisers, both in the context of current research and in terms of current clinical application, and looks to the future direction of research.

Expert opinion: Substantial advances have been and are being made in the use of photosensitisers. Of particular note are their antimicrobial applications, due to absence of resistance that is so frequently associated with conventional treatments. Their potency of action and the ability to immobilise to polymeric supports is opening a wide range of possibilities with great potential for use in healthcare infection prevention strategies.

Effect of polyethylenimine, a cell permeabilizer, on the photosensitized destruction of algae by methylene blue and nuclear fast red

The present study reports the effect a cell permeabilizer, polyethylenimine (PEI) has on the photodynamic effect of methylene blue (MB) and nuclear fast red (NFR) in the presence of hydrogen peroxide (H₂O₂). The photosensitized destruction of the algae Chlorella vulgaris under irradiation with visible light is examined. The photodynamic effect was investigated under aerobic and anaerobic conditions. The presence of a permeabilizer during the photosensitized destruction of C. vulgaris does not enhance the activity of the MB, MB/H₂O₂ system or the NFR, NFR/H₂O ₂ system under aerobic conditions. However under anaerobic conditions we have determined that when a cell permeabilizer was added to the MB/H ₂O₂ system, the photosensitized destruction of C. vulgaris proceeded via a combination of Type I and Type II mechanisms. The presence of PEI enforces MB/H₂O₂ to be active toward the destruction of C. vulgaris whether oxygen is present or absent. Under aerobic and anaerobic conditions the activity of NFR was suppressed in the presence of PEI as a result of electrostatic interactions between the photosensitizer and the cell permeabilizer. The decrease in fluorescence recorded is indicative of destruction of the chlorophyll a pigment. 

Climatic signals in the life histories of insects:the distribution and abundance of heather psyllids (Strophingia spp.) in the UK

1. The population density and age structure of two species of heather psyllid Strophingia ericae and Strophingia cinereae, feeding on Calluna vulgaris and Erica cinerea, respectively, were sampled using standardized methods at locations throughout Britain. Locations were chosen to represent the full latitudinal and altitudinal range of the host plants.

2. The paper explains how spatial variation in thermal environment, insect life-history characteristics and physiology, and plant distribution, interact to provide the mechanisms that determine the range and abundance of Strophingia spp.

3. Strophingia ericae and S. cinereae, despite the similarity in the spatial distribution patterns of their host plants within Britain, display strongly contrasting geographical ranges and corresponding life-history strategies. Strophingia ericae is found on its host plant throughout Britain but S. cinereae is restricted to low elevation sites south of the Mersey-Humber line and occupies only part of the latitudinal and altitudinal range of its host plant. There is no evidence to suggest that S. ericae has reached its potential altitudinal or latitudinal limit in the UK, even though its host plant appears to reach its altitudinal limit.

4. There was little difference in the ability of the two Strophingia spp. to survive shortterm exposure to temperatures as low as - 15 degrees C and low winter temperatures probably do not limit distribution in S. cinereae.

5. Population density of S. ericae was not related to altitude but showed a weak correlation with latitude. The spread of larval instars present at a site, measured as an index of instar homogeneity, was significantly correlated with a range of temperature related variables, of which May mean temperature and length of growing season above 3 degrees C (calculated using the Lennon and Turner climatic model) were the most significant. Factor analysis did not improve the level of correlation significantly above those obtained for single climatic variables. The data confirmed that S. ericae has a I year life cycle at the lowest elevations and a 2 year life cycle at the higher elevations. However, there was no evidence, as previously suggested, for an abrupt change from a one to a 2 year life cycle in S. ericae with increasing altitudes or latitudes.

6. By contrast with S. ericae, S. cinereae had an obligatory 1 year life cycle, its population decreased with altitude and the index of instar homogeneity showed little correlation with single temperature variables. Moreover, it occupied only part of the range of its host plant and its spatial distribution in the UK could be predicted with 96% accuracy using selected variables in discriminant analysis.

7. The life histories of the congeneric heather psyllids reflect adaptations that allow them to exploit host plants with different distributions in climatic and thereby geographical space. Strophingia ericae has the flexible life history that enables it to exploit C. vulgaris throughout its European boreal temperate range. Strophingia cinereae has a less flexible life history and is adapted for living on an oceanic temperate host. While the geographic ranges of the two Strophingia spp. overlap within the UK, the psyllids appear to respond differently to variation in their thermal environment.

A novel recovery process for lipids from microalgæ for biodiesel production using a hydrated phosphonium ionic liquid

The use of a hydrated phosphonium ionic liquid, [P(CH<inf>2</inf>OH)<inf>4</inf>]Cl, for the extraction of microalgæ lipids for biodiesel production, was evaluated using two microalgæ species, Chlorella vulgaris and Nannochloropsis oculata. The ionic liquid extraction was compared to the conventional Soxhlet, and Bligh & Dyer, methods, giving the highest extraction efficiency in the case of C. vulgaris, at 8.1%. The extraction from N. oculata achieved the highest lipid yield for Bligh & Dyer (17.3%), while the ionic liquid extracted 12.8%. Nevertheless, the ionic liquid extraction showed high affinity to neutral/saponifiable lipids, resulting in the highest fatty acid methyl esters (FAMEs)-biodiesel yield (4.5%) for C. vulgaris. For N. oculata, the FAMEs yield of the ionic liquid and Bligh & Dyer extraction methods were similar (>8%), and much higher than for Soxhlet (<5%). The ionic liquid extraction proved especially suitable for lipid extraction from wet biomass, giving even higher extraction yields than from dry biomass, 14.9% and 12.8%, respectively (N. oculata). Remarkably, the overall yield of FAMEs was almost unchanged, 8.1% and 8.0%, for dry and wet biomass. The ionic liquid extraction process was also studied at ambient temperature, varying the extraction time, giving 75% of lipid and 93% of FAMEs recovery after thirty minutes, as compared to the extraction at 100 °C for one day. The recyclability study demonstrated that the ionic liquid was unchanged after treatment, and was successfully reused. The ionic liquid used is best described as [P(CH<inf>2</inf>OH)<inf>4</inf>]Cl·2H<inf>2</inf>O, where the water is not free, but strongly bound to the ions.

Effects of Parasitism and Morphology on Squirrelpox Virus Seroprevalence in Grey Squirrels (Sciurus carolinensis)

Invasive species have been cited as major causes of population extinctions in several animal and plant classes worldwide. The North American grey squirrel (Sciurus carolinensis) has a major detrimental effect on native red squirrel (Sciurus vulgaris) populations across Britain and Ireland, in part because it can be a reservoir host for the deadly squirrelpox virus (SQPV). Whilst various researchers have investigated the epizootiology of SQPV disease in grey squirrels and have modelled the consequent effects on red squirrel populations, less work has examined morphological and physiological characteristics that might make individual grey squirrels more susceptible to contracting SQPV. The current study investigated the putative relationships between morphology, parasitism, and SQPV exposure in grey squirrels. We found geographical, sex, and morphological differences in SQPV seroprevalence. In particular, larger animals, those with wide zygomatic arch widths (ZAW), males with large testes, and individuals with concurrent nematode and/or coccidial infections had an increased seroprevalence of SQPV. In addition, males with larger spleens, particularly those with narrow ZAW, were more likely to be exposed to SQPV. Overall these results show that there is variation in SQPV seroprevalence in grey squirrels and that, consequently, certain individual, or populations of, grey squirrels might be more responsible for transmitting SQPV to native red squirrel populations.

Arsenate resistance in the ericoid mycorrhizal fungus Hymenoscyphus ericae

• Differential resistance to arsenate (AsO₄ ^3-) is demonstrated here among populations of the ericoid mycorrhizal fungus Hymenoscyphus ericae isolated from Calluna vulgaris in natural heathland soils and soils contaminated with AsO₄ ^3-. • Isolates (c. 25) of the fungus from each of two As and Cu mine sites, and a natural heathland site, were screened for AsO₄ ^3- and Cu²⁺ resistance by growing isolates in media containing a range of AsO₄ ^3- and Cu²⁺ concentrations. • H. ericae populations from the mine sites demonstrated resistance to AsO₄ ^3- compared with the heathland population; the mine-site populations producing significant growth at the highest AsO₄ ^3- concentration (4.67 mol m^-3), whereas growth of the heathland population was almost completely inhibited. EC₅₀ values for mine-site isolates were estimated to be 5-41-times higher than the heathland population. All isolates produced identical responses to increasing Cu²⁺ concentrations, with no differences observed between mine-site and heathland isolates. • Populations of H. ericae on the contaminated mine sites have developed adaptive resistance to AsO₄ ^3-. By contrast, Cu²⁺ resistance appears to be constitutive.

Abundant genetic overlap between blood lipids and immune-mediated diseases indicates shared molecular genetic mechanisms

Epidemiological studies suggest a relationship between blood lipids and immune-mediated diseases, but the nature of these associations is not well understood. We used genome-wide association studies (GWAS) to investigate shared single nucleotide polymorphisms (SNPs) between blood lipids and immune-mediated diseases. We analyzed data from GWAS (n~200,000 individuals), applying new False Discovery Rate (FDR) methods, to investigate genetic overlap between blood lipid levels [triglycerides (TG), low density lipoproteins (LDL), high density lipoproteins (HDL)] and a selection of archetypal immune-mediated diseases (Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, psoriasis and sarcoidosis). We found significant polygenic pleiotropy between the blood lipids and all the investigated immune-mediated diseases. We discovered several shared risk loci between the immune-mediated diseases and TG (n = 88), LDL (n = 87) and HDL (n = 52). Three-way analyses differentiated the pattern of pleiotropy among the immune-mediated diseases. The new pleiotropic loci increased the number of functional gene network nodes representing blood lipid loci by 40%. Pathway analyses implicated several novel shared mechanisms for immune pathogenesis and lipid biology, including glycosphingolipid synthesis (e.g. FUT2) and intestinal host-microbe interactions (e.g. ATG16L1). We demonstrate a shared genetic basis for blood lipids and immune-mediated diseases independent of environmental factors. Our findings provide novel mechanistic insights into dyslipidemia and immune-mediated diseases and may have implications for therapeutic trials involving lipid-lowering and anti-inflammatory agents.

The role of the seed bank in recovery of temperate heath and blanket bog following wildfires

Questions - Are the germinable seed banks of upland heath and blanket bog reduced following wildfires? Are some species at particular risk? Do the impacts of wildfires on seed banks differ between heathlands and blanket bog?

Location - Northern Ireland, United Kingdom.

Methods - Vegetation surveys and seed bank sampling were conducted in 2012 at burned and unburned areas within six upland sites where large wildfires had occurred during spring 2011. Differences in seedling abundance, species richness and Jaccard similarity indices between burned and unburned areas were compared using GLMMs. Differences in the community composition were examined using pRDA.

Results - In total, 24 of the 51 species in the vegetation were detected in the germinable seed bank. Species richness and the abundance of seedlings other than Calluna vulgaris were lower in areas where wildfires had occurred. Species composition of both germinable seed banks and vegetation differed between burned and unburned areas within sites; with negative associations between burned areas and some key indicator species including Drosera rotundifolia, Eriophorum vaginatum, Empetrum nigrum, Narthecium ossifragum and Trichophorum germanicum. We did not find any evidence of significant interactions between burning and habitat, suggesting that wildfires had similar impacts on each species regardless of the habitat in which they occurred.

Conclusions - This study differs from other UK studies in that it examines impacts of wildfires at sites that have not been previously intensively managed by burning. In particular, we highlight potential impacts on N. ossifragum and D. rotundifolia, which are key components of the upland flora and, to our knowledge, were not present in previous UK studies.