Quaternary ammoniums activate human dendritic cells and induce a specific T-cell response in vitro.

Background: In many countries, neuro-muscular blocking agents (NMBAs) are the first cause of perioperative anaphylaxis. Epidemiological studies identified pholcodine, a quaternary ammonium-containing opiate as one of the sensitization sources. However, NMBA anaphylaxis exists in countries where pholcodine was unavailable, prompting the hypothesis of other sensitizing molecules, most likely quaternary ammonium compounds (QACs).

Drug hypersensitivity reactions: review of the state of the science for prediction and diagnosis.

Drug hypersensitivity reactions (DHRs) are a type of adverse drug reaction that can occur with different classes of drugs and affect multiple organ systems and patient populations. DHRs can be classified as allergic or non-allergic based on the cellular mechanisms involved. Whereas nonallergic reactions rely mainly on the innate immune system, allergic reactions involve the generation of an adaptive immune response.

Sensitive B-cell receptor repertoire analysis shows repopulation correlates with clinical response to rituximab in rheumatoid arthritis.

Background: Although B-cell depleting therapy in rheumatoid arthritis (RA) is clearly effective, response is variable and does not correlate with B cell depletion itself.

Methods: The B-cell receptor (BCR) repertoire was prospectively analyzed in peripheral blood samples of twenty-eight RA patients undergoing rituximab therapy. Timepoints of achieved BCR-depletion and -repopulation were defined based on the percentage of unmutated BCRs in the repertoire.

Antibodies internalization mechanisms by dendritic cells and their role in therapeutic antibody immunogenicity.

Internalization and processing by antigen-presenting cells such as dendritic cells (DCs) are critical steps for initiating a T-cell response to therapeutic antibodies. Consequences are the production of neutralizing antidrug antibodies altering the clinical response, the presence of immune complexes, and, in some rare cases, hypersensitivity reactions. In recent years, significant progress has been made in the knowledge of cellular uptake mechanisms of antibodies in DCs.

Drug-induced hypersensitivity reactions in a Lebanese outpatient population: A decade-long retrospective analysis (2012-2021).

Background: Drug hypersensitivity reactions (DHRs) are becoming more common as a result of increasing prevalence and case complexity. Allergists and clinical immunologists worldwide are challenged daily to adequately diagnose and manage these reactions. Data in the literature regarding DHR outpatient consultations are scarce worldwide, limited in the Middle East, and currently unavailable in Lebanon.

Nervous system development related gene expression regulation in the zebrafish embryo after exposure to valproic acid and retinoic acid: A genome wide approach.

The evaluation of chemical and pharmaceutical safety for humans is moving from animal studies to New Approach Methodologies (NAM), reducing animal use and focusing on mechanism of action, whilst enhancing human relevance. In developmental toxicology, the mechanistic approach is facilitated by the assessment of predictive biomarkers, which allow mechanistic pathways perturbation monitoring at the basis of human hazard assessment. In our search for biomarkers of maldevelopment, we focused on chemically-induced perturbation of the retinoic acid signaling pathway (RA-SP), a major pathway implicated in a plethora of developmental processes.

Retinoic acid signaling pathway perturbation impacts mesodermal-tissue development in the zebrafish embryo: Biomarker candidate identification using transcriptomics.

The zebrafish embryo (ZE) model provides a developmental model well conserved throughout vertebrate embryogenesis, with relevance for early human embryo development. It was employed to search for gene expression biomarkers of compound-induced disruption of mesodermal development. We were particularly interested in the expression of genes related to the retinoic acid signaling pathway (RA-SP), as a major morphogenetic regulating mechanism.

Human dendritic cell maturation induced by amorphous silica nanoparticles is Syk-dependent and triggered by lipid raft aggregation.

Background: Synthetic amorphous silica nanoparticles (SAS-NPs) are widely employed in pharmaceutics, cosmetics, food and concretes. Workers and the general population are exposed daily via diverse routes of exposure. SAS-NPs are generally recognized as safe (GRAS) by the Food and Drug Administration, but because of their nanoscale size and extensive uses, a better assessment of their immunotoxicity is required.

Dynamic regulation of gene expression and morphogenesis in the zebrafish embryo test after exposure to all-trans retinoic acid.

The zebrafish embryotoxicity test (ZET) is widely used in developmental toxicology. The analysis of gene expression regulation in ZET after chemical exposure provides mechanistic information about the effects of chemicals on morphogenesis in the test. The gene expression response magnitude has been shown to change with exposure duration.

Immediate hypersensitivity to COVID-19 vaccines: Focus on biological diagnosis.

Soon after the release of the new anti-COVID mRNA vaccines, reports came in from the US and the UK of anaphylactic reactions. Fueled by the necessary caution toward these new vaccine platforms, these reports had a great impact and were largely commented upon in the scientific literature and global media. The current estimated frequency is of 5 cases per million doses.

Consensus on the Key Characteristics of Immunotoxic Agents as a Basis for Hazard Identification.

Background: Key characteristics (KCs), properties of agents or exposures that confer potential hazard, have been developed for carcinogens and other toxicant classes. KCs have been used in the systematic assessment of hazards and to identify assay and data gaps that limit screening and risk assessment. Many of the mechanisms through which pharmaceuticals and occupational or environmental agents modulate immune function are well recognized.

Machine learning predicts response to TNF inhibitors in rheumatoid arthritis: results on the ESPOIR and ABIRISK cohorts.

Objectives: Around 30% of patients with rheumatoid arthritis (RA) do not respond to tumour necrosis factor inhibitors (TNFi). We aimed to predict patient response to TNFi using machine learning on simple clinical and biological data.

Methods: We used data from the RA ESPOIR cohort to train our models.

Longitudinal analysis of anti-drug antibody development in multiple sclerosis patients treated with interferon beta-1a (Rebif™) using B cell receptor repertoire analysis.

A significant proportion of multiple sclerosis (MS) patients treated with interferon beta-1a (Rebif™) develop anti-drug antibodies (ADA) with a negative impact on treatment efficacy. We hypothesized that high-throughput B-cell receptor (BCR) repertoire analysis could be used to predict and monitor ADA development. To study this we analyzed 228 peripheral blood samples from 68 longitudinally followed patients starting on interferon beta-1a.

Immunosafety evaluation in Juvenile Göttingen Minipigs.

Although an extrapolation from the clinical experience in adults can often be considered to support the pediatric use for most pharmaceutical compounds, differences in safety profiles between adult and pediatric patients can be observed. The developing immune system may be affected due to exaggerated pharmacological or non-expected effects of a new drug. Toxicology studies in juvenile animals could therefore be required to better evaluate the safety profile of any new pharmaceutical compound targeting the pediatric population.

A Genetic Association Test Accounting for Skewed X-Inactivation With Application to Biotherapy Immunogenicity in Patients With Autoimmune Diseases.

Despite being assayed on commercialized DNA chips, the X chromosome is commonly excluded from genome-wide association studies (GWAS). One of the reasons is the complexity to analyze the data taking into account the X-chromosome inactivation (XCI) process in women and in particular the XCI process with a potentially skewed pattern. This is the case when investigating the role of X-linked genetic variants in the occurrence of anti-drug antibodies (ADAs) in patients with autoimmune diseases treated by biotherapies.

Models of Dendritic Cells to Assess Skin Sensitization.

Allergic contact dermatitis (ACD) is a complex skin pathology occurring in reaction against environmental substances found in the workplace (cement, hair dyes, textile dyes), in the private environment (e.g., household products, cosmetic ingredients), or following skin exposure to drugs.

The Inflammatory Response in Human Keratinocytes Exposed to Cinnamaldehyde Is Regulated by Nrf2.

Keratinocytes (KC) play a crucial role in epidermal barrier function, notably through their metabolic activity and the detection of danger signals. Chemical sensitizers are known to activate the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2), leading to cellular detoxification and suppressed proinflammatory cytokines such as IL-1β, a key cytokine in skin allergy. We investigated the role of Nrf2 in the control of the proinflammatory response in human KC following treatment with Cinnamaldehyde (CinA), a well-known skin sensitizer.

Synthetic Amorphous Silica Nanoparticles Promote Human Dendritic Cell Maturation and CD4+ T-Lymphocyte Activation.

Innate immune cells such as dendritic cells (DCs) sense and engulf nanomaterials potentially leading to an adverse immune response. Indeed, as described for combustion-derived particles, nanomaterials could be sensed as danger signals, enabling DCs to undergo a maturation process, migrate to regional lymph nodes and activate naive T lymphocytes. Synthetic amorphous silica nanoparticles (SAS-NPs) are widely used as food additives, cosmetics, and construction materials.

Drug and Chemical Allergy: A Role for a Specific Naive T-Cell Repertoire?

Allergic reactions to drugs and chemicals are mediated by an adaptive immune response involving specific T cells. During thymic selection, T cells that have not yet encountered their cognate antigen are considered naive T cells. Due to the artificial nature of drug/chemical-T-cell epitopes, it is not clear whether thymic selection of drug/chemical-specific T cells is a common phenomenon or remains limited to few donors or simply does not exist, suggesting T-cell receptor (TCR) cross-reactivity with other antigens.