Construction by artificial intelligence and immunovalidation of hypoallergenic mite allergen Der f 36 vaccine.

Background: The house dust mite (HDM) is widely recognized as the most prevalent allergen in allergic diseases. Allergen-specific immunotherapy (AIT) has been successfully implemented in clinical treatment for HDM. Hypoallergenic B-cell epitope-based vaccine designed by artificial intelligence (AI) represents a significant progression of recombinant hypoallergenic allergen derivatives. Method: The three-dimensional protein structure of Der f 36 was constructed using Alphafold2. AI-based tools were employed to predict B-cell epitopes, which were subsequently verified through IgE-reaction testing. Hypoallergenic Der f 36 was then synthesized, expressed, and purified. The reduced allergenicity was assessed by enzyme-linked immunosorbent assay (ELISA), immunoblotting, and basophil activation test. T-cell response to hypoallergenic Der f 36 and Der f 36 was evaluated based on cytokine expression in the peripheral blood mononuclear cells (PBMCs) of patients. The immunogenicity was evaluated and compared through rabbit immunization with hypoallergenic Der f 36 and Der f 36, respectively. The inhibitory effect of the blocking IgG antibody on the specific IgE-binding activity and basophil activation of Der f 36 allergen was also examined. Results: The final selected non-allergic B-cell epitopes were 25-48, 57-67, 107-112, 142-151, and 176-184. Hypoallergenic Der f 36 showed significant reduction in IgE-binding activity. The competitive inhibition of IgE-binding to Der f 36 was investigated using the hypoallergenic Der f 36, and only 20% inhibition could be achieved, which is greatly reduced when compared with inhibition by Der f 36 (98%). The hypoallergenic Der f 36 exhibited a low basophil-stimulating ratio similar to that of the negative control, and it could induce an increasing level of IFN-γ but not Th2 cytokines IL-5 and IL-13 in PBMCs. The vaccine-specific rabbit blocking IgG antibodies could inhibit the patients' IgE binding and basophil stimulation activity of Derf 36. Conclusion: This study represents the first application of an AI strategy to facilitate the development of a B-cell epitope-based hypoallergenic Der f 36 vaccine, which may become a promising immunotherapy for HDM-allergic patients due to its reduced allergenicity and its high immunogenicity in inducing blocking of IgG.

Natural killer T cells in allergic asthma: implications for the development of novel immunotherapeutical strategies.

Allergic asthma has emerged as a prevalent allergic disease worldwide, affecting most prominently both young individuals and lower-income populations in developing and developed countries. To devise effective and curative immunotherapy, it is crucial to comprehend the intricate nature of this condition, characterized by an immune response imbalance that favors a proinflammatory profile orchestrated by diverse subsets of immune cells. Although the involvement of Natural Killer T (NKT) cells in asthma pathology is frequently implied, their specific contributions to disease onset and progression remain incompletely understood. Given their remarkable ability to modulate the immune response through the rapid secretion of various cytokines, NKT cells represent a promising target for the development of effective immunotherapy against allergic asthma. This review provides a comprehensive summary of the current understanding of NKT cells in the context of allergic asthma, along with novel therapeutic approaches that leverage the functional response of these cells.

Development and validation of a health practitioner survey on ocular allergy.

Survey studies have played a significant role in understanding the gaps in the knowledge and practices of health practitioners. However, there have been no such survey studies on Ocular Allergy (OA). Thus, the purpose of this study was to develop and validate a survey on OA to better understand the gaps in the diagnostic, treatment, and collaborative care approaches of health practitioners in OA. The survey is titled "Survey on Ocular Allergy for Health Practitioners (SOAHP)". SOAHP was developed in a five-stage process. First, item extraction via the use of a literature review, second, face and content validity, third, a pilot study, fourth, test-retest reliability, and fifth, finalisation of the survey. 65 items under 6 domains were initially generated in the item extraction phase. Content validity was conducted on 15 experts in the field. This was conducted twice to reach consensus whereby items and domains were added, edited, kept, or removed, resulting in 50 items under 7 domains. The pilot study was conducted on 15 participants from the five relevant health practitioner fields (Allergists/Immunologists, General Practitioners (GPs), Ophthalmologists, Optometrists and Pharmacists). This altered the survey further to 40 items under 7 domains. Test-retest reliability was conducted on 25 participants from the five health practitioner fields. Reliability was moderate to almost perfect for most (97%) investigated items. The finalised survey was 40 items under 7 domains. SOAHP is the first survey created to assess diagnostic, treatment and collaborative care approaches of Allergists/Immunologists, GPs, Ophthalmologists, Optometrists and Pharmacists on OA. SOAHP will be a useful tool in clinical research on OA.

Blood Transcriptomics Identifies Multiple Gene Expression Pathways Associated with the Clinical Efficacy of Hymenoptera Venom Immunotherapy.

Allergen-specific venom immunotherapy (VIT) is a well-established therapy for Hymenoptera venom allergy (HVA). However, the precise mechanism underlying its clinical effect remains uncertain. Our study aimed to identify the molecular mechanisms associated with VIT efficiency. We prospectively included 19 patients with HVA undergoing VIT (sampled before the beginning of VIT, after reaching the maintenance dose, one year after finishing VIT, and after a sting challenge) and 9 healthy controls. RNA sequencing of whole blood was performed on an Illumina sequencing platform. Longitudinal transcriptomic profiling revealed the importance of the inhibition of the NFκB pathway and the downregulation of DUX4 transcripts for the early protection and induction of tolerance after finishing VIT. Furthermore, successful treatment was associated with inhibiting Th2, Th17, and macrophage alternative signalling pathways in synergy with the inhibition of the PPAR pathway and further silencing of the Th2 response. The immune system became activated when reaching the maintenance dose and was suppressed after finishing VIT. Finally, successful VIT restores the immune system's balance to a state similar to that of healthy individuals. Our results underline the important role of the inhibition of four pathways in the clinical effect of VIT: Th2, Th17, NFκB, and macrophage signalling. Two biomarkers specific for successful VIT, regardless of the time of sampling, were C4BPA and RPS10-NUDT3 and should be further tested as potential biomarkers.

[Angele experiment: innovative care paths for allergy sufferers]. / Expérimentation Angele : des parcours de soins innovants pour les patients allergiques.

The Angele project (for Allergies complexes: prise en charge globale, diététique et environnementale) is an article 51 experiment in shared care pathways in allergology. These care paths, dedicated to patients with allergies to house dust mites and/or food, involve collaboration between doctors and paramedics. The aim of this initiative is to optimize patient care by structuring their care pathways. This article presents these pathways and the preliminary results of the experiment.

Hypersensitive Reactions During Hemodialysis Treatment: What Do We Need to Know?

Kidney replacement therapies (KRTs) including hemodialysis (HD) are one of the treatment options for most of the patients with end-stage kidney disease. Although HD is vital for these patients, it is not hundred percent physiological, and various adverse events including hypersensitivity reactions may occur. Fortunately, these reactions are rare in total and less when compared to previous decades, but it is still very important for at least two reasons: First, the number of patients receiving kidney replacement treatment is increasing globally; and the cumulative number of these reactions may be substantial. Second, although most of these reactions are mild, some of them may be very severe and even lead to mortality. Thus, it is very important to have basic knowledge and skills to diagnose and treat these reactions. Hypersensitivity reactions can occur at any component of dialysis machinery (access, extracorporeal circuit, medications, etc.). The most important preventive measure is to avoid the allergen. However, even with very specific test, sometimes the allergen cannot be found. In mild conditions, HD can be contained with non-specific treatment (topical creams, antihistaminics, corticosteroids). In more severe conditions, treatment must be stopped immediately, blood should not be returned to patient, drugs must be stopped, and rules of general emergency treatment must be followed.

Plain Language Summary: Immunotherapy for Inhalant Allergy.

The plain language summary explains allergen immunotherapy to patients, families, and caregivers. The summary is for patients aged 5 years and older who are experiencing symptoms from inhalant allergies and are considering immunotherapy as a treatment option. It is based on the 2024 "Clinical Practice Guideline: Immunotherapy for Inhalant Allergy." This plain language summary is a companion publication to the full guideline, which provides greater detail for health care providers. Guidelines and their recommendations may not apply to every patient, but they can be used to find best practices and quality improvement opportunities.

Abrogation and homeostatic restoration of IgE responses by a universal IgE allergy CTL vaccine-The three signal self/non-self/self (S/NS/S) theory.

Natural IgE cytotoxic peptides (nECPs), which are derived from the constant domain of the heavy chain of human IgE producing B cells via endoplasmic reticulum (ER) stress, are decorated onto MHC class 1a molecules (MHCIa) as unique biomarkers for CTL (cytotoxic T lymphocyte)-mediated immune surveillance. Human IgE exhibits only one isotype and lacks polymorphisms; IgE is pivotal in mediating diverse, allergen-specific allergies. Therefore, by disrupting self-IgE tolerance via costimulation, the CTLs induced by nECPs can serve as universal allergy vaccines (UAVs) in humans to dampen IgE production mediated by diverse allergen-specific IgE-secreting B cells and plasma cells expressing surface nECP-MHCIa as targets. The study herein has enabled the identification of nECPs, A32 and SP-1/SP-2 nonameric natural peptides produced through the correspondence principle. Vaccination using nECP induced nECP-specific CTL that profoundly suppressed human IgE production in vitro as well as chimeric human IgE production in human IgE/HLA-A2.01/HLA-B7.02 triple transgenic rodents. Furthermore, nECP-tetramer-specific CTLs were found to be converted into CD4 Tregs that restored IgE competence via the homeostatic principle, mediatepred by SREBP-1c suppressed DCs. Thus, nECPs showed causal efficacy and safety as UAVs for treating categorically type I hypersensitivity IgE-mediated allergies. The applied vaccination concept presented provides the foundation to unify, integrate through a singular class of tetramer-specific TCR clonotypes for regulaing human IgE production. The three signal theory pertains to mechanisms of three cells underlying central tolerance (S), breaking self tolerance (NS) and regaining peripheral tolerance (S) via homeostasis concerning nECP as an efficacious and safe UAV to treat type I IgE-mediated hypersensitivity. The three signal theory impirically extended, may be heuritic for immuno-regulation of adaptive immune repertoire in general.

Extracellular vesicles: Messengers of allergic immune responses and novel therapeutic strategy.

Extracellular vesicles (EVs) are nanosized particles released by nearly every cell type across all kingdoms of life. As a result, EVs are ubiquitously present in various human body fluids. Composed of a lipid bilayer, EVs encapsulate proteins, nucleic acids, and metabolites, thus playing a crucial role in immunity, for example, by enabling intercellular communication. More recently, there has been increasing evidence that EVs can also act as key regulators of allergic immune responses. Their ability to facilitate cell-to-cell contact and to transport a variety of different biomolecules enables active modulation of both innate and adaptive immune processes associated with allergic reactions. A comprehensive understanding of the intricate mechanisms underlying the interactions among allergens, immune cells, and EVs is imperative to develop innovative strategies for controlling allergic responses. This review highlights the recent roles of host cell- and bacteria-derived EVs in allergic diseases, presenting experimental and clinical evidence that underscores their significance. Additionally, the therapeutic potential of EVs in allergy management is outlined, along with the challenges associated with targeted delivery and cargo stability for clinical use. Optimization of EV composition and targeting strategies holds promise for advancing translational applications and establishing EVs as biomarkers or safe therapeutics for assessing allergic reactions. For these reasons, EVs represent a promising avenue for advancing both our understanding and management of allergic immune processes.

The Role of Regulatory T Cells in Allergic Diseases: Collegium Internationale Allergologicum (CIA) Update 2024.

BACKGROUND: Allergy represents a major health problem of increasing prevalence worldwide with a high socioeconomic impact. Our knowledge on the molecular mechanisms underlying allergic diseases and their treatments has significantly improved over the last years. The generation of allergen-specific regulatory T cells (Tregs) is crucial in the induction of healthy immune responses to allergens, preventing the development and worsening of allergic diseases. SUMMARY: In the last decades, intensive research has focused on the study of the molecular mechanisms involved in Treg development and Treg-mediated suppression. These mechanisms are essential for the induction of sustained tolerance by allergen-specific immunotherapy (AIT) after treatment discontinuation. Compelling experimental evidence demonstrated altered suppressive capacity of Tregs in patients suffering from allergic rhinitis, allergic asthma, food allergy, or atopic dermatitis, as well as the restoration of their numbers and functionality after successful AIT. KEY MESSAGE: The better understanding of the molecular mechanisms involved in Treg generation during allergen tolerance induction might well contribute to the development of novel strategies for the prevention and treatment of allergic diseases.

Ockham's Razor: The Application of Parsimonious Medicine in Allergy/Immunology.

The spectacular advances of modern medicine have distracted clinicians from applying the age-old principles of thorough history and examination followed by only ordering tests relevant to the patient's presentation. The most obvious diagnosis is the most likely and should be addressed first. Ockham's razor, or parsimonious medicine, should be applied because plurality of diagnoses is less likely than a single explanation. Component-resolved diagnostics and biological therapies for allergy/immune-mediated diseases have been highly effective when used by specialist allergy services. However, they are accessed too easily and frequently, either before diagnostically appropriate allergy skin testing and challenge have been employed or before the reasons for poor disease control have been investigated. The current fashion to test for vitamin D insufficiency in patients with poorly controlled allergic diseases has rarely achieved benefit but significantly increased costs. There are considerable health/economic benefits from following the proven value of a thorough clinical history, examination, focused allergy/immunology testing, and the judicious use of Ockham's razor.

[Molecular diagnostic strategies and management of dust mite allergy].

Dust mites are one of the most important allergens, widely distributed around the world, especially in household environments. Dermatophagoides pteronyssinus, Dermatophagoides farinae and Blomia tropicalis are the most common species of dust mites. There are more than 35 known sensitization components of dust mites, among which Der p 1, Der p 2 and Der p 23 are the major components. Clinically, allergen skin test and serum specific immunoglobulin E (sIgE) detection are widely used in the preliminary diagnosis of dust mite allergy. However, these methods cannot accurately identify specific dust mite sensitization components. Considering that there are significant differences in the allergenic components of dust mites in different regions and populations, component-resolved diagnosis of dust mite is particularly important in accurately determining the allergenic components. This is not only of guiding significance for allergen avoidance, but also important for determining the immunotherapy regimen for dust mites. In order to strengthen the understanding of the molecular diagnosis of dust mites and promote the integration of allergy science in China with the international standards, this article interprets the "Allergy Molecular Allergology User's Guide 2.0" published recently by the European Academy of Allergy and Clinical Immunology.

Health disparities in allergic diseases.

PURPOSE OF REVIEW: Healthcare disparities impact prevalence, diagnosis, and management of allergic disease. The purpose of this review is to highlight the most recent evidence of healthcare disparities in allergic conditions to provide healthcare providers with better understanding of the factors contributing to disparities and to provide potential management approaches to address them. This review comes at a time in medicine where it is well documented that disparities exist, but we seek to answer the Why , How and What to do next? RECENT FINDINGS: The literature highlights the socioeconomic factors at play including race/ ethnicity, neighborhood, insurance status and income. Management strategies have been implemented with the hopes of mitigating the disparate health outcomes including utilization of school-based health, distribution of educational tools and more inclusive research recruitment. SUMMARY: The studies included describe the associations between upstream structural and social factors with downstream outcomes and provide ideas that can be recreated at other institutions of how to address them. Focus on research and strategies to mitigate healthcare disparities and improve diverse research participant pools are necessary to improve patient outcomes in the future.