Tolerogenic nanoparticles suppress central nervous system inflammation.

Therapeutic approaches for the induction of immune tolerance remain an unmet clinical need for the treatment of autoimmune diseases, including multiple sclerosis (MS). Based on its role in the control of the immune response, the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) is a candidate target for novel immunotherapies. Here, we report the development of AhR-activating nanoliposomes (NLPs) to induce antigen-specific tolerance. NLPs loaded with the AhR agonist ITE and a T cell epitope from myelin oligodendrocyte glycoprotein (MOG)35-55 induced tolerogenic dendritic cells and suppressed the development of experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS, in preventive and therapeutic setups. EAE suppression was associated with the expansion of MOG35-55-specific FoxP3+ regulatory T cells (Treg cells) and type 1 regulatory T cells (Tr1 cells), concomitant with a reduction in central nervous system-infiltrating effector T cells (Teff cells). Notably, NLPs induced bystander suppression in the EAE model established in C57BL/6 × SJL F1 mice. Moreover, NLPs ameliorated chronic progressive EAE in nonobese diabetic mice, a model which resembles some aspects of secondary progressive MS. In summary, these studies describe a platform for the therapeutic induction of antigen-specific tolerance in autoimmune diseases.

Highlights in allergic contact dermatitis 2018/2019.

PURPOSE OF REVIEW: The purpose was to highlight recent findings especially concerning new and old allergens, trends, diagnosis and causes of contact allergy. RECENT FINDINGS: Nickel is still the most frequent cause of contact allergy in women and piercings remain an important risk factor. Countries with a long history of regulation of contact allergens have the lowest level of contact allergy to nickel and chromium in Europe. Among the most frequent causes of fragrance contact allergy is terpenes, which are oxidized such as limonene, linalool and in some countries: geraniol. Methylisothiazolinone is still causing considerable problems due to hidden exposures. Acrylates are emerging allergens and 2-hydroxyethyl methacrylate has been included in the 2019 update of the baseline series, as many new cases are seen due to long-lasting nail polish based on acrylates and glue (isobornyl acrylate) in insulin pumps. More than 10 new allergens have been described, which need to be considered in diagnosing contact allergy. SUMMARY: Allergic contact dermatitis is a frequent problem, it also constitutes a challenge to diagnose due to many potential contact allergens. The main culprit allergens remain the same, new significant causes are found especially within acrylates.

A case-control analysis of skin contact allergy in children and adolescents.

BACKGROUND: Contact sensitization in children is increasing. The offending allergens differ depending on patient age and sex. We aimed to determine the sensitization profiles in children (aged 6-12) and adolescents (aged 13-18), to compare these to a control group of adults (aged 60-66), and to evaluate differences in sensitization patterns between working and non-working adolescents. PATIENTS/MATERIALS/METHODS: We analyzed Information Network of Departments of Dermatology (IVDK) data from 2009 to 2016 using multiple logistic regression analysis. Of the 99 082 patients documented in the IVDK database, 591 children, 2451 adolescents and 12 122 adults were included in further analysis. RESULTS: Nickel was the most frequent contact allergen among all age-groups. Children and adolescents showed significantly lower reaction rates to fragrance mix, methyldibromo-glutaronitrile, methylisothiazolinone, and propolis than adults. Positive reactions to sorbitan sesquioleate and mercapto mix among children and to cobalt among adolescents were significantly more frequent than in adults. Working adolescents had more often positive reactions to methyl(chloro)isothiazolinone (skin lesions predominantly on hands) and paraben mix (skin lesions predominantly on feet) when compared to non-working peers. Patch-tested children were more often diagnosed with atopic dermatitis than adults (P < 0.0001). CONCLUSIONS: Contact allergens display age-specific patterns, which should be considered in a standardized series targeting different patient populations (children and adolescents). Employed adolescents should preferably be tested with the baseline series to optimize allergen identification.

A multiepitopic theoretical fusion construct based on in-silico epitope screening of known vaccine candidates for protection against wide range of enterobacterial pathogens.

Enterobacterial pathogens that have acquired antibiotic resistance genes are a leading cause of community and hospital acquired infections. In such a situation vaccination is considered as a better option to prevent such infections. In the current study reverse vaccinology approach has been used to select peptides from already known immunogenic proteins to design a chimeric construct. We selected Yersiniabactin receptor of Escherichia coli UMN026 and Flagellin of Stenotrophomonas maltophila. B-cell linear epitopes were predicted using Bepipred prediction tool. Peptide binding with reference sets of 27 alleles of MHC class I and class II was also analyzed. The predicted peptides-MHC complexes were further validated using simulation dynamics. The in-silico construction of chimera was done by restriction mapping and codon optimization. Chimera was evaluated using the immunoinformatic approach as done for the selected proteins. From the 673 amino acids of FyuA protein, a region from 1 to 492 was selected for containing more linear epitopes and the processing scores obtained were significant for MHC class I and class II binding. Similarly, from Flagellin, a region between 60 and 328 amino acids was selected and the peptides present in the selected region showed lower percentile ranks for binding with MHC molecules. The simulation studies validated the predictions of peptide-MHC complexes. The selected gene fragments accommodating maximum part of these peptides were used to design a chimaeric construct of 2454 bp. From the immunoinformatic analysis, the chimera was found to be more immunogenic in terms of increased number of B-cell and T-cell epitopes along with increased coverage of global populations with allelic variability.

Allergic contact dermatitis to slime: The epidemic of isothiazolinone allergy encompasses school glue.

The slime craze is all the rage among tweens. Slime is a homemade stretchy play material created by mixing together household items such as school glue, borax, shaving cream, and contact lens solution. We present a case of allergic contact dermatitis secondary to methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) in school glue used to make slime; mass spectroscopy confirmed MCI/MI in the patient's glue. Clinicians should be aware of slime as an emerging source of MCI/MI contact allergy.

Isothiazolinone derivatives and allergic contact dermatitis: a review and update.

Allergic contact dermatitis (ACD) from isothiazolinones has frequently been described in the literature. Following an epidemic of sensitization to methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) in the 1980s, and more recently to MI, the Scientific Committee on Consumer Safety of the European Commission banned their use in leave-on products, while restricting that in rinse-off cosmetics. Despite a decreasing prevalence of ACD from MCI/MI and MI, cases caused by occupational exposure and non-cosmetic isothiazolinone sources are on the rise. Moreover, sensitization to newer and lesser known isothiazolinones has been reported. This paper reviews the epidemiology of contact allergy to different isothiazolinones, clinical presentation of isothiazolinone-induced ACD, most relevant sensitization sources and potential cross-reactions between isothiazolinone derivatives. It also provides an update on recent legislative measures.

An endogenous aryl hydrocarbon receptor ligand, ITE, induces regulatory T cells and ameliorates experimental colitis.

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that affects millions of people with high morbidity and health care costs. The precise etiology of IBD is unknown, but clear evidence suggests that intestinal inflammation is caused by an excessive immune response to mucosal antigens. Recent studies have shown that activation of the aryl hydrocarbon receptor (AhR) induces regulatory T cells (Tregs) and suppresses autoimmune diseases. In the current study, we investigated if a nontoxic ligand of AhR, 2-(1' H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), can attenuate dextran sodium sulfate-induced colitis. Our studies demonstrated that in mice that received ITE treatment in vivo, colitis pathogenesis, including a decrease in body weight, was significantly reversed along with the systemic and intestinal inflammatory cytokines. ITE increased the expression of Tregs in spleen, mesenteric lymph nodes (MLNs), and colon lamina propria lymphocytes (cLPL) of mice with colitis when compared with controls. This induction of Tregs was reversed by AhR antagonist treatment in vitro. ITE treatment also increased dendritic cells (CD11c+) and decreased macrophages (F4/80+) from the spleen, MLNs, and cLPL in mice with colitis. ITE also reversed the systemic and intestinal frequency of CD4+ T cells during colitis and suppressed inflammatory cytokines including IFN-γ, TNF-α, IL-17, IL-6, and IL-1 as well as induced IL-10 levels. These findings suggest that ITE attenuates colitis through induction of Tregs and reduction in inflammatory CD4+ T cells and cytokines. Therefore, our work demonstrates that the nontoxic endogenous AhR ligand ITE may serve as a therapeutic modality to treat IBD. NEW & NOTEWORTHY We report the novel finding that activation of the aryl hydrocarbon receptor with the nontoxic ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) induces regulatory T cells (Tregs) and suppresses inflammatory bowel disease (IBD). Our data suggest that ITE diminishes colitis pathology through induction of Tregs; reduces inflammatory cytokines, inflammation score, and macrophage frequency; and induces DCs resulting in amelioration of colitis. Therefore, nontoxic endogenous ITE promotes the induction of Tregs and may be useful for the treatment of IBD.

Photoaggravated allergic contact dermatitis and transient photosensitivity caused by methylisothiazolinone.

BACKGROUND: Photoaggravated allergic contact dermatitis caused by methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI) and MI has been reported. OBJECTIVES: To describe the clinical characteristics and results of (photo)patch tests and photo-tests of 10 patients in Belgium and France suffering from photoaggravated contact dermatitis caused by MI. PATIENTS AND METHODS: Five men and five women, with a median age of 49.5 years, were investigated between January 2012 and February 2017 because of suspected photoaggravated contact dermatitis. Patch tests, photopatch tests and/or photo-tests were performed. RESULTS: Seven patients had positive patch test reactions to both MCI/MI and MI, whereas 3 patients had positive patch test reactions only to MI. In most cases, MI was the (strong) primary sensitizer. Photopatch tests with MCI/MI and/or MI gave stronger reactions than patch tests with these derivatives, indicating photoaggravation. Sensitization probably took place from cosmetics and work-related biocides, whereas elicitation of dermatitis was remarkably often related to airborne exposure to MI present in paints or industrial biocides. Four patients suffered from transient photosensitivity. CONCLUSION: Photoaggravated allergic contact dermatitis and transient photosensitivity caused by MI is a peculiar clinical presentation of allergic contact dermatitis caused by this preservative, and should be considered in daily clinical practice.

Recombinant Peptidomimetic-Nano Luciferase Tracers for Sensitive Single-Step Immunodetection of Small Molecules.

Phage borne peptides isolated from phage libraries have proven to be valuable reagents for the development of small-molecule immunoassays. However, the large size, low diffusion rate, and biological nature of the phage particles create some limitations to their use and require secondary reagents for its detection. In this work, we explore the use of the Nano luciferase (NanoLuc) as a fusion partner to generate recombinant tracers for immunoassay development. The imidaclothiz peptidomimetic C2-15 that specifically binds to the anti-imidaclothiz monoclonal antibody (mAb) 1E7 was fused to NanoLuc, both at the N terminus (C2-15-NanoLuc) and C terminus (NanoLuc-C2-15). NanoLuc-C2-15 showed better performance than C2-15-NanoLuc and was adopted to develop a bioluminescent enzyme immunoassay (BLEIA) and a bioluminescence lateral flow immunoassay (BLLFIA) for imidaclothiz. The luminescence signal of NanoLuc-C2-15 rapidly reaches high intensity with slow attenuation, which enabled one to capture the BLLFIA readout by using a smartphone without an external light source. The IC50 of the BLEIA and BLLFIA were 3.3 ± 0.2 and 6.4 ± 0.4 ng mL-1, respectively. Both immunoassays exhibited good accuracy for the detection of imidaclothiz in environmental and agricultural samples.

Allergic Contact Dermatitis Due to Methylisothiazolinone in a Young Girl's Laundry Detergent.

Methylisothiazolinone (MI) is an emerging and increasing cause of allergic contact dermatitis (ACD) in children. We present the case of a 7-year-old girl with an unusual dermatitis suspicious for contact allergy. Patch testing confirmed allergy to MI, found only in the patient's laundry detergent. This case highlights the importance of checking household product ingredients and the role of MI as an increasing cause of ACD in children.

Occupational contact sensitization in female geriatric nurses: Data of the Information Network of Departments of Dermatology (IVDK) 2005-2014.

BACKGROUND: Geriatric nurses (GN) have a high risk of occupational contact dermatitis (OCD), with chronic irritant contact dermatitis predominating. However, allergic contact dermatitis is an important issue as well. Little is known whether the relevant occupational allergen spectrum reported in the 1990s, including fragrances, preservatives, rubber chemicals and ingredients of surface disinfectants to be the most common sensitizers in GN, is still valid. OBJECTIVES: To monitor the current allergen spectrum in GN with OCD and verify the validity of the patch test recommendations (baseline-, preservative-, ointment base-, rubber-, disinfectant, series and fragrances) in GN with suspected OCD given by the German Contact Dermatitis Research Group (DKG). METHODS: Retrospective analysis of IVDK data (2005-2014) of 743 female GN with OCD, in comparison to 695 GN without OCD. RESULTS: GN with OCD reacted significantly more frequently to both fragrance mixes, hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC), thiuram mix, zinc diethyldithiocarbamate and mercaptobenzothiazole than GN without OCD. Reactions to MDBGN, methylchloroisothiazolinone/methylisothiazolinone and oil of turpentine occurred substantially, but not significantly more frequently among GN with OCD. The latter may be due to former use of a special alcoholic liniment in geriatric care. Among material from the patients' workplaces, tetrazepam was a frequent allergen, due to dust exposure from pill crushing. Furthermore, occupationally used protective gloves, body care products as well as surface disinfectants were often tested positively. CONCLUSIONS: The general allergen spectrum in GN with OCD is unchanged, so the DKG patch test recommendations are still valid. Prevention of occupational sensitization should focus on fragrance-free hygiene and body care products, usage of accelerator-free protective gloves and avoidance of drug dust exposure.

In situ chemical behaviour of methylisothiazolinone (MI) and methylchloroisothiazolinone (MCI) in reconstructed human epidermis: a new approach to the cross-reactivity issue.

BACKGROUND: Methylisothiazolinone (MI) [with methylchloroisothiazolinone (MCI) in a ratio of 1:3, a well-recognized allergenic preservative] was released as an individual preservative in the 2000s for industrial products and in 2005 for cosmetics. The high level of exposure to MI since then has provoked an epidemic of contact allergy to MI, and an increase in MI/MCI allergy. There are questions concerning the MI/MCI cross-reaction pattern. OBJECTIVES: To bring a new perspective on the MI/MCI cross-reactivity issue by studying their in situ chemical behaviour in 3D reconstructed human epidermis (RHE). METHODS: MI and MCI were synthesized with (13) C substitution at positions C-4/C-5 and C-5, respectively. Their in situ chemical behaviours in an RHE model were followed by use of the high-resolution magic angle spinning nuclear magnetic resonance technique. RESULTS: MI was found to react exclusively with cysteine thiol residues, whereas MCI reacted with histidines and lysines. The reaction mechanisms were found to be different for MI and MCI, and the adducts formed had different molecular structures. CONCLUSION: In RHE, different MI/MCI reactions towards different nucleophilic amino acids were observed, making it difficult to explain cross-reactivity between MI and MCI.

American Contact Dermatitis Society Contact Allergy Management Program: An Epidemiologic Tool to Quantify Ingredient Usage.

BACKGROUND: The usage prevalence of ingredients in topical products is important to dermatologists and industry. OBJECTIVE: To determine the prevalence of methylisothiazolinone (MI) in various types of consumer products METHODS: The Contact Allergy Management Program (CAMP) database was mapped and sorted in spreadsheet format to determine the prevalence of MI in various types of consumer products. RESULTS: Methylisothiazolinone was found in 13.2% of 4660 total products in CAMP. High usage of MI was seen in dishwashing products (64%), shampoos (53%), bathroom/kitchen/all-purpose cleaners (47%), hair conditioners (45%), hair dyes (43%), laundry additives/fresheners/softeners (30%), soaps/cleansers (29%), and surface cleaners/disinfectants (27%). Of the products containing MI, MI alone (without methylchloroisothiazolinone) was most common in makeup products (100%), cleaning/dish/laundry products (>99%), moisturizers (82%), shaving products (78%), sunscreens (71%), and antiaging products (67%). CONCLUSIONS: The American Contact Dermatitis Society's CAMP is a valuable tool to collect epidemiologic data on the incidence of specific ingredient usage in various types of topical products.

Blocking yersiniabactin import attenuates extraintestinal pathogenic Escherichia coli in cystitis and pyelonephritis and represents a novel target to prevent urinary tract infection.

The emergence and spread of extended-spectrum beta-lactamases and carbapenemases among common bacterial pathogens are threatening our ability to treat routine hospital- and community-acquired infections. With the pipeline for new antibiotics virtually empty, there is an urgent need to develop novel therapeutics. Bacteria require iron to establish infection, and specialized pathogen-associated iron acquisition systems like yersiniabactin, common among pathogenic species in the family Enterobacteriaceae, including multidrug-resistant Klebsiella pneumoniae and pathogenic Escherichia coli, represent potentially novel therapeutic targets. Although the yersiniabactin system was recently identified as a vaccine target for uropathogenic E. coli (UPEC)-mediated urinary tract infection (UTI), its contribution to UPEC pathogenesis is unknown. Using an E. coli mutant (strain 536ΔfyuA) unable to acquire yersiniabactin during infection, we established the yersiniabactin receptor as a UPEC virulence factor during cystitis and pyelonephritis, a fitness factor during bacteremia, and a surface-accessible target of the experimental FyuA vaccine. In addition, we determined through transcriptome sequencing (RNA-seq) analyses of RNA from E. coli causing cystitis in women that iron acquisition systems, including the yersiniabactin system, are highly expressed by bacteria during natural uncomplicated UTI. Given that yersiniabactin contributes to the virulence of several pathogenic species in the family Enterobacteriaceae, including UPEC, and is frequently associated with multidrug-resistant strains, it represents a promising novel target to combat antibiotic-resistant infections.

Swedish Experiences From Patch Testing Methylisothiazolinone Separately.

The preservative methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) is a well-known sensitiser and present in the Swedish baseline series since the 1980s. The proportions of MCI/MI are 3:1. MI alone has been used as a preservative since less than 10 years. This study was conducted on behalf of the Swedish Contact Dermatitis Research Group to evaluate inclusion of MI in the Swedish baseline series since the preparation of MCI/MI might fail to detect contact-allergic reactions to MI alone. Patients with suspected allergic contact dermatitis at 5 Swedish dermatology departments were consecutively patch tested with MI 2,000 ppm aq and MCI/MI 200 ppm aq. The number of cases with exclusive contact allergy to MI varied between 0.8-4.2%. In total, 1.9% reacted exclusively to MI and not to MCI/MI. Due to the considerable frequency of contact allergy to MI not traced by MCI/MI, MI 2,000 ppm aq is included in the Swedish baseline series from January 2014. This corresponds to a dose of 60 µg/cm2.

The patterns and clinical relevance of contact allergen sensitization in a pediatric population with atopic dermatitis.

BACKGROUND/AIM: Data about contact allergen sensitization (CAS) in children with atopic dermatitis (AD) are limited. The purpose of this study was to identify the frequency and patterns of CAS in children with AD by using a ready-to-use patch test system. MATERIALS AND METHODS: After receiving the history of CAS in the patients, the severity of AD and IgE-mediated allergen sensitization were determined. RESULTS: Of 134 children with AD, 33.8% (n = 45) had at least 1 positive reaction. The most frequent positive reaction was to nickel sulfate (NS) (37.8%, 17/45), followed by methylchloroisothiazolinone (20.0%, 9/45) and thimerosal (15.6%, 7/45). The total Scoring Atopic Dermatitis (SCORAD) score was significantly higher in the NS-sensitized group (P = 0.036). The patients with NS sensitization had moderate-severe AD more frequently than those without any reaction (P = 0.020). When the SCORAD score was evaluated in detail, extent of eczema, score of sleep loss, and pruritus were significantly higher in the patients with NS sensitization than those without any reaction (P = 0.002, P = 0.001, and P = 0.002, respectively). CONCLUSION: Our study confirms the necessity of CAS in the management of AD. In particular, NS sensitization should be considered for children with severe AD or larger extent of eczema and trunk involvement.

Inhibitors of SRC kinases impair antitumor activity of anti-CD20 monoclonal antibodies.

Clinical trials with SRC family kinases (SFKs) inhibitors used alone or in a combination with anti-CD20 monoclonal antibodies (mAbs) are currently underway in the treatment of B-cell tumors. However, molecular interactions between these therapeutics have not been studied so far. A transcriptional profiling of tumor cells incubated with SFKs inhibitors revealed strong downregulation of MS4A1 gene encoding CD20 antigen. In a panel of primary and established B-cell tumors we observed that SFKs inhibitors strongly affect CD20 expression at the transcriptional level, leading to inhibition of anti-CD20 mAbs binding and increased resistance of tumor cells to complement-dependent cytotoxicity. Activation of the AKT signaling pathway significantly protected cells from dasatinib-triggered CD20 downregulation. Additionally, SFKs inhibitors suppressed antibody-dependent cell-mediated cytotoxicity by direct inhibition of natural killer cells. Abrogation of antitumor activity of rituximab was also observed in vivo in a mouse model. Noteworthy, the effects of SFKs inhibitors on NK cell function are largely reversible. The results of our studies indicate that development of optimal combinations of novel treatment modalities with anti-CD20 mAbs should be preceded by detailed preclinical evaluation of their effects on target cells.