High-dose atorvastatin therapy progressively decreases skeletal muscle mitochondrial respiratory capacity in humans.

BACKGROUNDWhile the benefits of statin therapy on atherosclerotic cardiovascular disease are clear, patients often experience mild to moderate skeletal myopathic symptoms, the mechanism for which is unknown. This study investigated the potential effect of high-dose atorvastatin therapy on skeletal muscle mitochondrial function and whole-body aerobic capacity in humans.METHODSEight overweight (BMI, 31.9 ± 2.0) but otherwise healthy sedentary adults (4 females, 4 males) were studied before (day 0) and 14, 28, and 56 days after initiating atorvastatin (80 mg/d) therapy.RESULTSMaximal ADP-stimulated respiration, measured in permeabilized fiber bundles from muscle biopsies taken at each time point, declined gradually over the course of atorvastatin treatment, resulting in > 30% loss of skeletal muscle mitochondrial oxidative phosphorylation capacity by day 56. Indices of in vivo muscle oxidative capacity (via near-infrared spectroscopy) decreased by 23% to 45%. In whole muscle homogenates from day 0 biopsies, atorvastatin inhibited complex III activity at midmicromolar concentrations, whereas complex IV activity was inhibited at low nanomolar concentrations.CONCLUSIONThese findings demonstrate that high-dose atorvastatin treatment elicits a striking progressive decline in skeletal muscle mitochondrial respiratory capacity, highlighting the need for longer-term dose-response studies in different patient populations to thoroughly define the effect of statin therapy on skeletal muscle health.FUNDINGNIH R01 AR071263.

Necessary Role of Ceramides in the Human Microvascular Endothelium During Health and Disease.

BACKGROUND: Elevated plasma ceramides and microvascular dysfunction both independently predict adverse cardiac events. Despite the known detrimental effects of ceramide on the microvasculature, evidence suggests that activation of the shear-sensitive, ceramide-forming enzyme NSmase (neutral sphingomyelinase) elicits formation of vasoprotective nitric oxide (NO). Here, we explore a novel hypothesis that acute ceramide formation through NSmase is necessary for maintaining NO signaling within the human microvascular endothelium. We further define the mechanism through which ceramide exerts beneficial effects and discern key mechanistic differences between arterioles from otherwise healthy adults (non-coronary artery disease [CAD]) and patients diagnosed with CAD. METHODS: Human arterioles were dissected from discarded surgical adipose tissue (n=166), and vascular reactivity to flow and C2-ceramide was assessed. Shear-induced NO and mitochondrial hydrogen peroxide (H2O2) production were measured in arterioles using fluorescence microscopy. H2O2 fluorescence was assessed in isolated human umbilical vein endothelial cells. RESULTS: Inhibition of NSmase in arterioles from otherwise healthy adults induced a switch from NO to NOX-2 (NADPH-oxidase 2)-dependent H2O2-mediated flow-induced dilation. Endothelial dysfunction was prevented by treatment with sphingosine-1-phosphate (S1P) and partially prevented by C2-ceramide and an agonist of S1P-receptor 1 (S1PR1); the inhibition of the S1P/S1PR1 signaling axis induced endothelial dysfunction via NOX-2. Ceramide increased NO production in arterioles from non-CAD adults, an effect that was diminished with inhibition of S1P/S1PR1/S1P-receptor 3 signaling. In arterioles from patients with CAD, inhibition of NSmase impaired the overall ability to induce mitochondrial H2O2 production and subsequently dilate to flow, an effect not restored with exogenous S1P. Acute ceramide administration to arterioles from patients with CAD promoted H2O2 as opposed to NO production, an effect dependent on S1P-receptor 3 signaling. CONCLUSION: These data suggest that despite differential downstream signaling between health and disease, NSmase-mediated ceramide formation is necessary for proper functioning of the human microvascular endothelium. Therapeutic strategies that aim to significantly lower ceramide formation may prove detrimental to the microvasculature.

Biomarkers of immediate drug hypersensitivity.

Immediate drug hypersensitivity reactions (IDHRs) are a burden for patients and the health systems. This problem increases when taking into account that only a small proportion of patients initially labelled as allergic are finally confirmed after an allergological workup. The diverse nature of drugs involved will imply different interactions with the immunological system. Therefore, IDHRs can be produced by a wide array of mechanisms mediated by the drug interaction with specific antibodies or directly on effector target cells. These heterogeneous mechanisms imply an enhanced complexity for an accurate diagnosis and the identification of the phenotype and endotype at early stages of the reaction is of vital importance. Currently, several endophenotypic categories (type I IgE/non-IgE, cytokine release, Mast-related G-protein coupled receptor X2 (MRGPRX2) or Cyclooxygenase-1 (COX-1) inhibition and their associated biomarkers have been proposed. A precise knowledge of endotypes will permit to discriminate patients within the same phenotype, which is crucial in order to personalise diagnosis, future treatment and prevention to improve the patient's quality of life.

Hypersensitivity reactions to proton pump inhibitors. An EAACI position paper.

Proton pump inhibitors (PPIs) are invaluable therapeutic options in a variety of dyspeptic diseases. In addition to their well-known risk profile, PPI consumption is related to food and environmental allergies, dysbiosis, osteoporosis, as well as immediate and delayed hypersensitivity reactions (HSRs). The latter, although a rare event, around 1%-3%, due to the extraordinarily high rate of prescription and consumption of PPIs are related to a substantial risk. In this Position Paper, we provide clinicians with practical evidence-based recommendations for the diagnosis and management of HSRs to PPIs. Furthermore, the unmet needs proposed in the document aim to stimulate more in-depth investigations in the topic.

The copper-responsive regulator CsoR is indirectly involved in Bradyrhizobium diazoefficiens denitrification.

The soybean endosymbiont Bradyrhizobium diazoefficiens harbours the complete denitrification pathway that is catalysed by a periplasmic nitrate reductase (Nap), a copper (Cu)-containing nitrite reductase (NirK), a c-type nitric oxide reductase (cNor), and a nitrous oxide reductase (Nos), encoded by the napEDABC, nirK, norCBQD, and nosRZDFYLX genes, respectively. Induction of denitrification genes requires low oxygen and nitric oxide, both signals integrated into a complex regulatory network comprised by two interconnected cascades, FixLJ-FixK2-NnrR and RegSR-NifA. Copper is a cofactor of NirK and Nos, but it has also a role in denitrification gene expression and protein synthesis. In fact, Cu limitation triggers a substantial down-regulation of nirK, norCBQD, and nosRZDFYLX gene expression under denitrifying conditions. Bradyrhizobium diazoefficiens genome possesses a gene predicted to encode a Cu-responsive repressor of the CsoR family, which is located adjacent to copA, a gene encoding a putative Cu+-ATPase transporter. To investigate the role of CsoR in the control of denitrification gene expression in response to Cu, a csoR deletion mutant was constructed in this work. Mutation of csoR did not affect the capacity of B. diazoefficiens to grow under denitrifying conditions. However, by using qRT-PCR analyses, we showed that nirK and norCBQD expression was much lower in the csoR mutant compared to wild-type levels under Cu-limiting denitrifying conditions. On the contrary, copA expression was significantly increased in the csoR mutant. The results obtained suggest that CsoR acts as a repressor of copA. Under Cu limitation, CsoR has also an indirect role in the expression of nirK and norCBQD genes.

Necessary Role of Acute Ceramide Formation in The Human Microvascular Endothelium During Health and Disease.

Background: Elevated plasma ceramides independently predict adverse cardiac events and we have previously shown that exposure to exogenous ceramide induces microvascular endothelial dysfunction in arterioles from otherwise healthy adults (0-1 risk factors for heart disease). However, evidence also suggests that activation of the shear-sensitive, ceramide forming enzyme neutral sphingomyelinase (NSmase) enhances vasoprotective nitric oxide (NO) production. Here we explore a novel hypothesis that acute ceramide formation through NSmase is necessary for maintaining NO signaling within the human microvascular endothelium. We further define the mechanism through which ceramide exerts beneficial effects and discern key mechanistic differences between arterioles from otherwise healthy adults and patients with coronary artery disease (CAD). Methods: Human arterioles were dissected from otherwise discarded surgical adipose tissue (n=123), and vascular reactivity to flow and C2-ceramide was assessed. Shear-induced NO production was measured in arterioles using fluorescence microscopy. Hydrogen peroxide (H2O2) fluorescence was assessed in isolated human umbilical vein endothelial cells. Results: Inhibition of NSmase in arterioles from otherwise healthy adults induced a switch from NO to H2O2-mediated flow-induced dilation within 30 minutes. In endothelial cells, NSmase inhibition acutely increased H2O2 production. Endothelial dysfunction in both models was prevented by treatment with C2-ceramide, S1P, and an agonist of S1P-receptor 1 (S1PR1), while the inhibition of S1P/S1PR1 signaling axis induced endothelial dysfunction. Ceramide increased NO production in arterioles from healthy adults, an effect that was diminished with inhibition of S1P/S1PR1/S1PR3 signaling. In arterioles from patients with CAD, inhibition of NSmase impaired dilation to flow. This effect was not restored with exogenous S1P. Although, inhibition of S1P/S1PR3 signaling impaired normal dilation to flow. Acute ceramide administration to arterioles from patients with CAD also promoted H2O2 as opposed to NO production, an effect dependent on S1PR3 signaling. Conclusion: These data suggest that despite key differences in downstream signaling between health and disease, acute NSmase-mediated ceramide formation and its subsequent conversion to S1P is necessary for proper functioning of the human microvascular endothelium. As such, therapeutic strategies that aim to significantly lower ceramide formation may prove detrimental to the microvasculature.

A synthetic glycodendropeptide induces methylation changes on regulatory T cells linked to tolerant responses in anaphylactic-mice.

Introduction: Lipid transfer proteins (LTPs) are allergens found in a wide range of plant-foods. Specifically, Pru p 3, the major allergen of peach, is commonly responsible for severe allergic reactions. The need for new alternatives to conventional food allergy treatments, like restrictive diets, suggests allergen immunotherapy as a promising option. It has been demonstrated that sublingual immunotherapy (SLIT) with synthetic glycodendropeptides, such as D1ManPrup3, containing mannose and Pru p 3 peptides induced tolerance in mice and that the persistence of this effect depends on treatment dose (2nM or 5nM). Moreover, it produces changes associated with differential gene expression and methylation profile of dendritic cells, as well as phenotypical changes in regulatory T cells (Treg). However, there are no works addressing the study of epigenetic changes in terms of methylation in the cell subsets that sustain tolerant responses, Treg. Therefore, in this work, DNA methylation changes in splenic-Treg from Pru p 3 anaphylactic mice were evaluated. Methods: It was performed by whole genome bisulphite sequencing comparing SLIT-D1ManPrup3 treated mice: tolerant (2nM D1ManPrup3), desensitized (5nM D1ManPrup3), and sensitized but not treated (antigen-only), with anaphylactic mice. Results: Most of the methylation changes were found in the gene promoters from both SLIT-treated groups, desensitized (1,580) and tolerant (1,576), followed by the antigen-only (1,151) group. Although tolerant and desensitized mice showed a similar number of methylation changes, only 445 genes were shared in both. Remarkably, interesting methylation changes were observed on the promoter regions of critical transcription factors for Treg function like Stat4, Stat5a, Stat5b, Foxp3, and Gata3. In fact, Foxp3 was observed exclusively as hypomethylated in tolerant group, whereas Gata3 was only hypomethylated in the desensitized mice. Discussion: In conclusion, diverse D1ManPrup3 doses induce different responses (tolerance or desensitization) in mice, which are reflected by differential methylation changes in Tregs.

The One Health approach for allergic diseases and asthma.

The One Health approach is a collaborative and interdisciplinary strategy with focal point on human, animal, and environmental health interconnections. One Health can support the advanced management of allergic diseases and asthma, as complex, multifactorial diseases driven by interactions between the resilience response to the exposome. According to the One Health concept allergic diseases and asthma arising from exposures to a wide range of allergens, infectious agents and irritants (such as pollutants) occurring indoors and outdoors can be heavily influenced by environmental health (air, water, and soil quality) intermingled with animal health. These are currently heavily impacted by climate change, land use, urbanization, migration, overpopulation, and many more. Thus, a coordinated response to address the underlying factors that contribute to the development of allergic diseases and asthma needs to focus on the environment, human, and animal health altogether. Collaborative efforts across multiple sectors, including public health, veterinary medicine, environmental science, and community engagement are thus needed. A wide range of activities, including monitoring and surveillance of environmental and health data, targeted interventions to reduce exposures to allergens and irritants, and research on the underlying mechanisms that drive the development of allergic diseases and asthma are needed to move the field forward. In this consensus document elaborated by the European Academy of Allergy and Clinical Immunology (EAACI) and American Academy of Allergy, Asthma, and Immunology (AAAAI) under the practical allergy (PRACTALL) series, we provide insights into the One Heath approach aiming to provide a framework for addressing the complex and multifactorial nature of allergic diseases and asthma.

Current status of pancreatic cancer with oligometastasis.

BACKGROUND: Pancreatic cancer is the seventh leading cause of death worldwide, with ductal adenocarcinoma as the most frequent neoplasm. Half of the patients who are diagnosed have metastases at the time of diagnosis. OBJECTIVE: A review of the treatment of resectable pancreatic adenocarcinoma with oligometastatic disease was carried out in order to present an overview of the existing evidence. METHOD: A bibliographic search was carried in PubMed/Medline, Clinical Key and Index Medicus vhith MESH terms, from the year 1993 to 2022. RESULTS: Patients with liver or lung metastases due to pancreatic ductal adenocarcinoma who undergo surgery and chemotherapy have a longer survival in carefully selected patients. CONCLUSIONS: The evidence regarding surgery in patients with pancreatic ductal adenocarcinoma and oligometastasis is limited and further randomized controlled trials are needed for both scenarios. As well as established criteria that help the selection of patients who can receive this type of treatment.

ANTECEDENTES: El cáncer pancreático es la séptima causa de muerte en el mundo, siendo el adenocarcinoma ductal del páncreas la neoplasia más frecuente. La mitad de los pacientes que son diagnosticados presentan metástasis al momento del diagnóstico. OBJETIVO: Se realizó una revisión sobre el tratamiento del adenocarcinoma pancreático resecable con enfermedad oligometastásica con el fin de presentar un panorama sobre la evidencia existente. MÉTODO: Se realizó una búsqueda bibliográfica en PubMed/Medline, Clinical Key e Index Medicus con términos MESH desde 1993 hasta 2022. RESULTADOS: Los pacientes con metástasis hepáticas o pulmonares por adenocarcinoma ductal de páncreas que son sometidos a cirugía y quimioterapia tienen una mayor sobrevida en casos cuidadosamente seleccionados. CONCLUSIONES: La evidencia respecto a la cirugía en pacientes con adenocarcinoma ductal de páncreas y oligometástasis es limitada y se necesitan ensayos controlados aleatorizados adicionales para ambos escenarios, así como criterios bien establecidos que ayuden a la selección de los pacientes que pueden recibir este tipo de tratamiento.

Influence of Pore Size in Protein G'-Grafted Mesoporous Silica Nanoparticles as a Serum Pretreatment System for In Vitro Allergy Diagnosis.

Particles with the capacity to bind to immunoglobulin G (IgG) can be used for the purification of IgG or to process clinical samples for diagnostic purposes. For in vitro allergy diagnosis, the high IgG levels in serum can interfere with the detection of allergen-specific IgE, the main diagnostic biomarker. Although commercially available, current materials present a low IgG capture capacity at large IgG concentrations or require complex protocols, preventing their use in the clinic. In this work, mesoporous silica nanoparticles are prepared with different pore sizes, to which IgG-binding protein G' is grafted. It is found that for one particular optimal pore size, the IgG capture capacity of the material is greatly enhanced. The capacity of this material to efficiently capture human IgG in a selective way (compared to IgE) is demonstrated in both solutions of known IgG concentrations as well as in complex samples, like serum, from healthy controls and allergic patients using a simple and fast incubation protocol. Interestingly, IgG removal using the best-performing material enhances in vitro IgE detection in sera from patients allergic to amoxicillin. These results highlight the great translation potential of this strategy to the clinic in the context of in vitro allergy diagnosis.

Co-exposure to pathogens in wild ungulates from Doñana National Park, South Spain.

Multiple infections or co-exposure to pathogens should be considered systematically in wildlife to better understand the ecology and evolution of host-pathogen relationships, so as to better determine the potential use of multiple pathogens as indicators to guide health management. We describe the pattern of co-exposure to several pathogens (i.e. simultaneous positive diagnosis to pathogens in an individual considering Mycobacterium tuberculosis complex lesions, and the presence of antibodies against Toxoplasma gondii, bluetongue virus, and hepatitis E virus) and assessed their main drivers in the wild ungulate community from Doñana National Park (red deer, fallow deer, and wild boar) for a 13-years longitudinal study. The lower-than-expected frequency of co-exposure registered in all species was consistent with non-mutually exclusive hypotheses (e.g. antagonism or disease-related mortality), which requires further investigation. The habitat generalist species (red deer and wild boar) were exposed to a greater diversity of pathogens (frequency of co-exposure around 50%) and/or risk factors than fallow deer (25.0% ± CI95% 4.9). Positive relationships between pathogens were evidenced, which may be explained by common risk factors favouring exposure. The specific combination of pathogens in individuals was mainly driven by different groups of factors (individual, environmental, stochastic, and populational), as well as its interaction, defining a complex eco-epidemiological landscape. To deepen into the main determinants and consequences of co-infections in a complex assemblage of wild hosts, and at the interface with humans and livestock, there also is needed to expand the range of pathogens and compare diverse assemblages of hosts under different environmental and management circumstances.

Diagnosis of immediate reactions to amoxicillin: Comparison of basophil activation markers CD63 and CD203c in a prospective study.

BACKGROUND: Amoxicillin (AX) combined or not with clavulanic acid (CLV) is frequently involved in IgE-mediated reactions. Drug provocation test (DPT) is considered as the gold standard for diagnosis, although contraindicated in high-risk patients. Basophil activation test (BAT) can help diagnose immediate reactions to beta-lactams, although controversy exists regarding the best activation marker. We have performed a real-life study in a prospective cohort to analyze the real value of BAT as diagnostic tool and the best activation marker, CD63 and CD203c, for the evaluation of immediate reactions to these drugs. METHODS: We prospectively evaluated patients with a clinical suspicion of immediate reactions after AX or AX-CLV administration during a 6-year period. The allergological work-up was done following the EAACI recommendations. BAT was performed in all patients using CD63 and CD203c as activation markers. RESULTS: In AX-allergic patients, both activation markers, CD63 and CD203c, showed similar SE values (48.6% and 46.7%, respectively); however, specificity was of 81.1% and 94.6%, respectively, with CD203c showing good positive predictive value and like-hood ratio. In CLV-allergic patients, CD203c showed higher SE (50%) than CD63 (42.9%), maintaining the same value of SP (80%). Combining the results of both markers can slightly increase the sensitivity (51.4% for AX and 54.8% for CLV), although decreasing the specificity (79.7% and 73%, respectively). Interestingly, all patients with an anaphylactic shock showed a positive BAT to CLV using CD203c. CONCLUSIONS: BAT using CD203c showed a good confirmatory power, especially for AX allergy. Placing BAT as a first step in the diagnostic procedure can help reduce the need of performing a complete allergological work-up in 46.6% of patients, diminishing the risk of reinducing allergic reactions.

Chemotherapeutic drug screening in 3D-Bioengineered human myobundles provides insight into taxane-induced myotoxicities.

Two prominent frontline breast cancer (BC) chemotherapies commonly used in combination, doxorubicin (DOX) and docetaxel (TAX), are associated with long-lasting cardiometabolic and musculoskeletal side effects. Whereas DOX has been linked to mitochondrial dysfunction, mechanisms underlying TAX-induced myotoxicities remain uncertain. Here, the metabolic and functional consequences of TAX ± DOX were investigated using a 3D-bioengineered model of adult human muscle and a drug dosing regimen designed to resemble in vivo pharmacokinetics. DOX potently reduced mitochondrial respiratory capacity, 3D-myobundle size, and contractile force, whereas TAX-induced acetylation and remodeling of the microtubule network led to perturbations in glucose uptake, mitochondrial respiratory sensitivity, and kinetics of fatigue, without compromising tetanic force generation. These findings suggest TAX-induced remodeling of the microtubule network disrupts glucose transport and respiratory control in skeletal muscle and thereby have important clinical implications related to the cardiometabolic health and quality of life of BC patients and survivors.

Antibacterial activity of Bacillus licheniformis B6 against viability and biofilm formation of foodborne pathogens of health importance.

We studied a strain of Bacillus isolated from an artisanal tannery in Salta, Argentina. It was identified as Bacillus licheniformis B6 by 16 S phylogenetic analysis and MALDI TOF (GenBank accession code No. KP776730). The synthesis of lipopeptides by B6 and their antibacterial activity against clinical pathogenic strains was analyzed both in the cell-free supernatant (CFS) and in the crude fraction of lipopeptides (LF). Overall, the CFS did not significantly reduce the viability of the studied strains (Staphylococcus aureus 269 and ATCC 43,300, Escherichia coli 4591 and 25,922, Klebsiella sp. 1087 and 1101). However, LF at 9 mg/mL reduced the viability of those pathogenic strains by 2 and 3 log orders compared to those of the control. When the effects of LF and ampicillin were compared, they showed different sensitivity against pathogenic strains. For example, E. coli 4591 was the strain most resistant to ampicillin, requiring 250 mg/mL of antibiotic to achieve the same inhibitory effect as 9 mg/mL of B6 LF. SEM observations of the effect of LF on biofilm formation by E. coli 4591 and Klebsiella sp. 1087 clearly showed that biofilm structures were destabilized, these strains turning into weak biofilm formers. Signals in the CFS and LF corresponding to kurstakin and iturin were identified by MALDI TOF. Interestingly, surfactin was detected, rather than lichenysin, the expected lipopeptide in B. licheniformis species. Signals of bacitracin and fengycins were also found, the latter with a higher number of homologues and relative intensity in the LF than the other lipopeptides. These results show that the lipopeptides synthesized by B. licheniformis B6 have both potential antibacterial and anti-biofilm activity against pathogenic bacteria of health importance.

Basophil Activation Test Utility as a Diagnostic Tool in LTP Allergy.

Plant-food allergy is an increasing problem, with nonspecific lipid transfer proteins (nsLTPs) triggering mild/severe reactions. Pru p 3 is the major sensitizer in LTP food allergy (FA). However, in vivo and in vitro diagnosis is hampered by the need for differentiating between asymptomatic sensitization and allergy with clinical relevance. The basophil activation test (BAT) is an ex vivo method able to identify specific IgE related to the allergic response. Thus, we aimed to establish the value of BAT in a precise diagnosis of LTP-allergic patients. Ninety-two individuals with peach allergy sensitized to LTP, Pru p 3, were finally included, and 40.2% of them had symptoms to peanut (n = 37). In addition, 16 healthy subjects were recruited. BAT was performed with Pru p 3 and Ara h 9 (peanut LTP) at seven ten-fold concentrations, and was evaluated by flow cytometry, measuring the percentage of CD63 (%CD63+) and CD203c (%CD203chigh) cells, basophil allergen threshold sensitivity (CD-Sens), and area under the dose−response curve (AUC). Significant changes in BAT parameters (%CD63+ and %CD203chigh) were found between the controls and patients. However, comparisons for %CD63+, %CD203chigh, AUC, and CD-Sens showed similar levels among patients with different symptoms. An optimal cut-off was established from ROC curves, showing a significant positive percentage of BAT in patients compared to controls and great values of sensitivity (>87.5%) and specificity (>85%). In addition, BAT showed differences in LTP-allergic patients tolerant to peanut using its corresponding LTP, Ara h 9. BAT can be used as a potential diagnostic tool for identifying LTP allergy and for differentiating peanut tolerance, although neither reactivity nor sensitivity can distinguish the severity of the clinical symptoms.

COVID-19 vaccination in patients receiving allergen immunotherapy (AIT) or biologicals-EAACI recommendations.

Immune modulation is a key therapeutic approach for allergic diseases, asthma and autoimmunity. It can be achieved in an antigen-specific manner via allergen immunotherapy (AIT) or in an endotype-driven approach using biologicals that target the major pathways of the type 2 (T2) immune response: immunoglobulin (Ig)E, interleukin (IL)-5 and IL-4/IL-13 or non-type 2 response: anti-cytokine antibodies and B-cell depletion via anti-CD20. Coronavirus disease 2019 (COVID-19) vaccination provides an excellent opportunity to tackle the global pandemics and is currently being applied in an accelerated rhythm worldwide. The vaccine exerts its effects through immune modulation, induces and amplifies the response against the severe acute respiratory syndrome coronavirus (SARS-CoV-2). Thus, as there may be a discernible interference between these treatment modalities, recommendations on how they should be applied in sequence are expected. The European Academy of Allergy and Clinical Immunology (EAACI) assembled an expert panel under its Research and Outreach Committee (ROC). This expert panel evaluated the evidence and have formulated recommendations on the administration of COVID-19 vaccine in patients with allergic diseases and asthma receiving AIT or biologicals. The panel also formulated recommendations for COVID-19 vaccine in association with biologicals targeting the type 1 or type 3 immune response. In formulating recommendations, the panel evaluated the mechanisms of COVID-19 infection, of COVID-19 vaccine, of AIT and of biologicals and considered the data published for other anti-infectious vaccines administered concurrently with AIT or biologicals.

Methylation changes induced by a glycodendropeptide immunotherapy and associated to tolerance in mice.

Introduction: Allergen-specific immunotherapy (AIT) is applied as treatment to rise tolerance in patients with food allergies. Although AIT is thoroughly used, the underlying epigenetic events related to tolerant induction are still unknown. Thus, we aim to investigate epigenetic changes that could be related to tolerance in dendritic cells (DCs) from anaphylactic mice to lipid transfer proteins, Pru p 3, in the context of a sublingual immunotherapy (SLIT) with a glycodendropeptide (D1ManPrup3) that has demonstrated tolerant or desensitization responses depending on the treatment dose. Methods: Changes in DNA methylation in CpG context were determined comparing Sensitized (Antigen-only) animals and two groups receiving SLIT with the D1ManPrup3 nanostructure (D1ManPrup3-SLIT): Tolerant (2nM D1ManPrup3) and Desensitized (5nM D1ManPrup3), against anaphylactic animals. DNA from lymph nodes-DCs were isolated and then, Whole Genome Bisulphite Sequencing was performed to analyze methylation. Results: Most differentially methylated regions were found on the area of influence of gene promoters (DMPRs). Compared to the Anaphylactic group, the highest value was found in Desensitized mice (n = 7,713 DMPRs), followed by Tolerant (n = 4,091 DMPRs) and Sensitized (n = 3,931 DMPRs) mice. Moreover, many of these epigenetic changes were found in genes involved in immune and tolerance responses (Il1b, Il12b, Il1a, Ifng, and Tnf) as shown by functional enrichment (DCs regulation, B cell-mediated immunity, and effector mechanisms). Discussion: In conclusion, different doses of D1ManPrup3-SLIT induce different DNA methylation changes, which are reflected in the induction of distinct responses, tolerance, or desensitization.