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Frontiers in Immunology 2024Equine asthma (EA) is a common lower airway disease in horses, but whether its pathogenesis is allergic is ambiguous. Extrinsic stimuli like hay dust induce acute...
INTRODUCTION
Equine asthma (EA) is a common lower airway disease in horses, but whether its pathogenesis is allergic is ambiguous. Extrinsic stimuli like hay dust induce acute exacerbation of clinical signs and sustained local neutrophilic inflammation in susceptible horses. is an EA stimulus, but it is unclear if it merely acts as an IgE-provoking allergen. We aimed to comprehensively analyze immunoglobulin (Ig) isotypes in EA, elucidating their binding to different antigens, and their quantities systemically in serum and locally in bronchoalveolar lavage fluid (BALF).
METHODS
Serum and BALF from healthy horses (HE, = 18) and horses with mild-moderate asthma (MEA, = 20) or severe asthma (SEA, = 24) were compared. Ig isotype (IgG1, IgG3/5, IgG4/7, IgG6, IgA, and IgE) binding to nine antigens ( lysate, and recombinant Asp f 1, Asp f 7, Asp f 8, dipeptidyl-peptidase 5, class II aldolase/adducin domain protein, glucoamylase, beta-hexosaminidase, and peptide hydrolase) was compared by enzyme-linked immunosorbent assays. Total Ig isotype contents were determined by bead-based assays.
RESULTS
MEA and SEA differed from HE but hardly from each other. Compared to HE, asthmatic horses showed increased anti- binding of IgG (BALF and serum) and IgA (BALF). Serum and BALF IgE binding and total IgE contents were similar between HE and EA. Single antigens, as well as lysate, yielded similar Ig binding patterns. Serum and BALF IgG1 binding to all antigens was increased in SEA and to several antigens in MEA. Serum IgG4/7 binding to two antigens was increased in SEA. BALF IgA binding to all antigens was increased in SEA and MEA. Total BALF IgG1 and IgG4/7 contents were increased in SEA, and serum IgG4/7 content was increased in MEA compared to HE. Yet, total isotype contents differentiated EA and HE less clearly than antigen-binding Ig.
DISCUSSION
immunogenicity was confirmed without identification of single dominant antigens here. provoked elevated BALF IgG1 and IgA binding, and these isotypes appear relevant for neutrophilic EA, which does not support allergy. BALF Ig isotype differentiation beyond IgE is crucial for a comprehensive analysis of immune responses to fungi in EA pathogenesis.
Topics: Animals; Horses; Aspergillus fumigatus; Bronchoalveolar Lavage Fluid; Asthma; Immunoglobulin G; Immunoglobulin A; Horse Diseases; Antigens, Fungal; Male; Neutrophils; Female; Immunoglobulin E; Antibodies, Fungal
PubMed: 38953030
DOI: 10.3389/fimmu.2024.1406794 -
Frontiers in Immunology 2024Antiglycine receptor (anti-GlyR) antibody mediates multiple immune-related diseases. This study aimed to summarize the clinical features to enhance our understanding of... (Review)
Review
BACKGROUND AND OBJECTIVES
Antiglycine receptor (anti-GlyR) antibody mediates multiple immune-related diseases. This study aimed to summarize the clinical features to enhance our understanding of anti-GlyR antibody-related disease.
METHODS
By collecting clinical information from admitted patients positive for glycine receptor (GlyR) antibody, the clinical characteristics of a new patient positive for GlyR antibody were reported in this study. To obtain additional information regarding anti-GlyR antibody-linked illness, clinical data and findings on both newly reported instances in this study and previously published cases were merged and analyzed.
RESULTS
A new case of anti-GlyR antibody-related progressive encephalomyelitis with rigidity and myoclonus (PERM) was identified in this study. A 20-year-old man with only positive cerebrospinal fluid anti-GlyR antibody had a good prognosis with first-line immunotherapy. The literature review indicated that the common clinical manifestations of anti-GlyR antibody-related disease included PERM or stiff-person syndrome (SPS) (n = 179, 50.1%), epileptic seizure (n = 94, 26.3%), and other neurological disorders (n = 84, 24.5%). Other neurological issues included demyelination, inflammation, cerebellar ataxia and movement disorders, encephalitis, acute psychosis, cognitive impairment or dementia, celiac disease, Parkinson's disease, neuropathic pain and allodynia, steroid-responsive deafness, hemiballism/tics, laryngeal dystonia, and generalized weakness included respiratory muscles. The group of PERM/SPS exhibited a better response to immunotherapy than others.
CONCLUSIONS
The findings suggest the presence of multiple clinical phenotypes in anti-GlyR antibody-related disease. Common clinical phenotypes include PERM, SPS, epileptic seizure, and paraneoplastic disease. Patients with RERM/SPS respond well to immunotherapy.
Topics: Humans; Male; Receptors, Glycine; Autoantibodies; Young Adult; Encephalomyelitis; Muscle Rigidity; Myoclonus; Stiff-Person Syndrome; Adult
PubMed: 38953026
DOI: 10.3389/fimmu.2024.1387591 -
Frontiers in Immunology 2024Mast cell (MC) degranulation is a key process in allergic reactions and inflammatory responses. Aspartate aminotransferase 1 (AAT1)-derived endogenous sulfur dioxide...
OBJECTIVES
Mast cell (MC) degranulation is a key process in allergic reactions and inflammatory responses. Aspartate aminotransferase 1 (AAT1)-derived endogenous sulfur dioxide (SO) is an important regulator of MC function. However, the mechanism underlying its role in MC degranulation remains unclear. This study aimed to investigate the mechanism by which endogenous SO controlled MC degranulation.
METHODS
HMC-1 and Rat basophilic leukemia cell MC line (RBL-2H3) were used in the cell experiments. SO content was detected by fluorescent probe. MC degranulation represented by the release rate of MC β-hexosaminidase was determined using a colorimetric assay. Sulfenylation of galectin-9 (Gal-9) in MCs and purified protein was detected using a biotin switch assay. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine the exact sulfenylation sites of Gal-9 by SO. Animal models of passive cutaneous anaphylaxis (PCA) and hypoxia-driven pulmonary vascular remodeling were used to investigate the effect of SO on mast cell activation . Site-directed mutation of Gal-9 was conducted to confirm the exact site of SO and support the significance of SO/Gal-9 signal axis in the regulation of MC degranulation.
RESULTS
Degranulation was increased in AAT1-knockdowned MCs, and SO supplementation reversed the increase in MC degranulation. Furthermore, deficiency of endogenous SO contributed to IgE-mediated degranulation Besides, SO inhibited IgE-mediated and hypoxia-driven MC degranulation . Mechanistically, LC-MS/MS analysis and site-directed mutation results showed that SO sulfenylated Gal-9 at cysteine 74. Sulfenylation of the 74 cysteine of Gal-9 protein was required in the SO-inhibited MC degranulation under both physiological and pathophysiological conditions.
CONCLUSION
These findings elucidated that SO inhibited MC degranulation via sulfenylating Gal-9 under both physiological and pathophysiological conditions, which might provide a novel treatment approach for MC activation-related diseases.
Topics: Animals; Cell Degranulation; Mast Cells; Cysteine; Rats; Sulfur Dioxide; Humans; Galectins; Mice; Male; Passive Cutaneous Anaphylaxis; Cell Line
PubMed: 38953022
DOI: 10.3389/fimmu.2024.1369326 -
Western Pacific Surveillance and... 2024On 12 September 2022, a 10-year-old female in Paracelis municipality, Mountain Province, the Philippines, without travel history outside the municipality, experienced...
On 12 September 2022, a 10-year-old female in Paracelis municipality, Mountain Province, the Philippines, without travel history outside the municipality, experienced acute onset of fever and a change in mental status with disorientation, an altered level of consciousness and new onset of seizures. She was hospitalized at the district hospital from 1 to 3 October 2022, before being transferred to the regional hospital. As diphtheria was originally suspected, the investigation team reviewed records and reports and interviewed key informants to gather additional information and organize case finding and contact tracing. The patient's condition was laboratory-confirmed for Japanese encephalitis virus infection. An environmental survey was carried out at the patient's residence to check for the presence of vectors and contributing factors. Exemplifying inadequate vaccination coverage for Japanese encephalitis virus in Mountain Province, the patient had not been vaccinated against the disease. It is recommended that vaccination campaigns be immediately implemented in the affected area and the surveillance system be strengthened for early detection and prompt response to the emergence of cases and outbreaks. Overall, the investigation highlighted the importance of strong surveillance and response systems for early detection and control of diseases, such as Japanese encephalitis virus. It also underscores the need for comprehensive vaccination programmes to prevent outbreaks and protect vulnerable populations.
Topics: Humans; Philippines; Female; Encephalitis, Japanese; Child; Encephalitis Virus, Japanese
PubMed: 38953004
DOI: 10.5365/wpsar.2024.15.2.1049 -
Leukemia Research Reports 2024Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with various combinations of gene mutations, epigenetic abnormalities, and chromosome...
Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with various combinations of gene mutations, epigenetic abnormalities, and chromosome rearrangement-related gene fusions. Despite the significant degree of heterogeneity in its pathogenesis, many gene fusions and point mutations are recurrent in AML and have been employed in risk stratification over the last several decades. Gene fusions have long been recognized for understanding tumorigenesis and their proven roles in clinical diagnosis and targeted therapies. Advances in DNA sequencing technologies and computational biology have contributed significantly to the detection of known fusion genes as well as for the discovery of novel ones. Several recurring gene fusions in AML have been linked to prognosis, treatment response, and disease progression. In this report, we present a case with a long history of essential thrombocythemia and hallmark mutation transforming to AML characterized by a previously unreported fusion gene. We propose mechanisms by which this fusion may contribute to the pathogenesis of AML and its potential as a molecular target for tyrosine kinase inhibitors.
PubMed: 38952949
DOI: 10.1016/j.lrr.2024.100465 -
Biological Psychiatry Apr 2024Responding to social signals by expressing the correct behavior is not only challenged in autism, but also in diseases with high prevalence of autism, like Prader-Willi...
Disengagement of somatostatin neurons from lateral septum circuitry by oxytocin and vasopressin restores social-fear extinction and suppresses aggression outbursts in Prader-Willi syndrome model.
BACKGROUND
Responding to social signals by expressing the correct behavior is not only challenged in autism, but also in diseases with high prevalence of autism, like Prader-Willi Syndrome (PWS). Clinical evidence suggests aberrant pro-social behavior in patients can be regulated by intranasal oxytocin (OXT) or vasopressin (AVP). However, what neuronal mechanisms underlie impaired behavioral responses in a socially-aversive context, and how can they be corrected, remains largely unknown.
METHODS
Using the knocked-out (KO) mouse model of PWS (crossed with CRE-dependent transgenic lines), we devised optogenetic, physiological and pharmacological strategies in a social-fear-conditioning paradigm. Pathway specific roles of OXT and AVP signaling were investigated converging on the lateral septum (LS), a region which receives dense hypothalamic inputs.
RESULTS
OXT and AVP signaling promoted inhibitory synaptic transmission in the LS, which failure in KO mice disinhibited somatostatin (SST) neurons and disrupted social-fear extinction. The source of OXT and AVP deficits mapped specifically in the supraoptic nucleus→LS pathway of KO mice disrupting social-fear extinction, which could be corrected by optogenetic or pharmacological inhibition of SST-neurons in the LS. Interestingly, LS SST-neurons also gated the expression of aggressive behavior, possibly as part of functional units operating beyond local septal circuits.
CONCLUSIONS
SST cells in the LS play a crucial role in integration and expression of disrupted neuropeptide signals in autism, thereby altering the balance in expression of safety versus fear. Our results uncover novel mechanisms underlying dysfunction in a socially-aversive context, and provides a new framework for future treatments in autism-spectrum disorders.
Topics: Animals; Oxytocin; Somatostatin; Fear; Extinction, Psychological; Neurons; Mice; Prader-Willi Syndrome; Mice, Knockout; Disease Models, Animal; Vasopressins; Aggression; Male; Social Behavior; Septal Nuclei; Optogenetics; Mice, Inbred C57BL; Intracellular Signaling Peptides and Proteins; Intrinsically Disordered Proteins
PubMed: 38952926
DOI: 10.1016/j.biopsych.2023.10.016 -
Biology of Sport Jul 2024This study examined the acute effects of exercise testing on immunology markers, established blood-based biomarkers, and questionnaires in endurance athletes, with a...
This study examined the acute effects of exercise testing on immunology markers, established blood-based biomarkers, and questionnaires in endurance athletes, with a focus on biological sex differences. Twenty-four healthy endurance-trained participants (16 men, age: 29.2± 7.6 years, maximal oxygen uptake ( ): 59.4 ± 7.5 ml · min · kg; 8 women, age: 26.8 ± 6.1 years, : 52.9 ± 3.1 ml · min · kg) completed an incremental submaximal exercise test and a ramp test. The study employed exploratory bioinformatics analysis: mixed ANOVA, k-means clustering, and uniform manifold approximation and projection, to assess the effects of exhaustive exercise on biomarkers and questionnaires. Significant increases in biomarkers (lymphocytes, platelets, procalcitonin, hemoglobin, hematocrit, red blood cells, cell-free DNA (cfDNA)) and fatigue were observed post-exercise. Furthermore, differences pre- to post-exercise were observed in cytokines, cfDNA, and other blood biomarkers between male and female participants. Three distinct groups of athletes with differing proportions of females (Cluster 1: 100% female, Cluster 2: 85% male, Cluster 3: 37.5% female and 65.5% male) were identified with k-means clustering. Specific biomarkers (e.g., interleukin-2 (IL-2), IL-10, and IL-13, as well as cfDNA) served as primary markers for each cluster, potentially informing individualized exercise responses. In conclusion, our study identified exercise-sensitive biomarkers and provides valuable insights into the relationships between biological sex and biomarker responses.
PubMed: 38952916
DOI: 10.5114/biolsport.2024.132998 -
The Journal of Allergy and Clinical... Aug 2024Over the last 3 decades, hematopoietic stem cell transplantation (HSCT) has been successfully used to treat severe and refractory autoimmune diseases (AIDs)....
BACKGROUND
Over the last 3 decades, hematopoietic stem cell transplantation (HSCT) has been successfully used to treat severe and refractory autoimmune diseases (AIDs). A multidisciplinary appraisal of potential benefits and risks by disease and transplant specialists is essential to determine individual suitability for HSCT.
OBJECTIVE
Our aim was to observe that patient-reported outcomes (PROs) and health-related quality of life instruments can capture the unique patient perspective on disease burden and impact of treatment.
METHODS
Herein, we describe the basis and complexity of end points measuring patient-reported perceptions of efficacy and tolerability used in clinical practice and trials for patients with AIDs undergoing autologous HSCT.
RESULTS
PRO measures and patient-reported experience measures are key tools to evaluate the impact and extent of disease burden for patients affected by AIDs. For formal scientific assessment, it is essential that validated general instruments are used, whereas adaptations have resulted in disease-specific instruments that may help guide tailored interventions. An additional approach relates to qualitative evaluations, from carefully structured qualitative research to informal narratives, as patient stories. The patients' subjectively reported responses to HSCT may be influenced by their preprocedure expectations and investment in the HSCT journey.
CONCLUSIONS
The complexity of AIDs advocates for individualized and multidisciplinary approach to positively affect the patient journey. PROs and health-related quality of life need to be collected using validated instruments in clinical practice and trials to enable robustness of data and to ensure the impact of the intervention is comprehensively assessed, addressing the main questions and needs of the involved stakeholders.
PubMed: 38952895
DOI: 10.1016/j.jacig.2024.100283 -
Network Neuroscience (Cambridge, Mass.) 2024In recent years, there has been an increasing interest in studying brain-heart interactions. Methodological advancements have been proposed to investigate how the brain...
In recent years, there has been an increasing interest in studying brain-heart interactions. Methodological advancements have been proposed to investigate how the brain and the heart communicate, leading to new insights into some neural functions. However, most frameworks look at the interaction of only one brain region with heartbeat dynamics, overlooking that the brain has functional networks that change dynamically in response to internal and external demands. We propose a new framework for assessing the functional interplay between cortical networks and cardiac dynamics from noninvasive electrophysiological recordings. We focused on fluctuating network metrics obtained from connectivity matrices of EEG data. Specifically, we quantified the coupling between cardiac sympathetic-vagal activity and brain network metrics of clustering, efficiency, assortativity, and modularity. We validate our proposal using open-source datasets: one that involves emotion elicitation in healthy individuals, and another with resting-state data from patients with Parkinson's disease. Our results suggest that the connection between cortical network segregation and cardiac dynamics may offer valuable insights into the affective state of healthy participants, and alterations in the network physiology of Parkinson's disease. By considering multiple network properties, this framework may offer a more comprehensive understanding of brain-heart interactions. Our findings hold promise in the development of biomarkers for diagnostic and cognitive/motor function evaluation.
PubMed: 38952808
DOI: 10.1162/netn_a_00369 -
BioRxiv : the Preprint Server For... May 2024Osteoarthritis (OA) poses a significant healthcare burden with limited treatment options. While genome-wide association studies (GWAS) have identified over 100...
UNLABELLED
Osteoarthritis (OA) poses a significant healthcare burden with limited treatment options. While genome-wide association studies (GWAS) have identified over 100 OA-associated loci, translating these findings into therapeutic targets remains challenging. Integrating expression quantitative trait loci (eQTL), 3D chromatin structure, and other genomic approaches with OA GWAS data offers a promising approach to elucidate disease mechanisms; however, comprehensive eQTL maps in OA-relevant tissues and conditions remain scarce. We mapped gene expression, chromatin accessibility, and 3D chromatin structure in primary human articular chondrocytes in both resting and OA-mimicking conditions. We identified thousands of differentially expressed genes, including those associated with differences in sex and age. RNA-seq in chondrocytes from 101 donors across two conditions uncovered 3782 unique eGenes, including 420 that exhibited strong and significant condition-specific effects. Colocalization with OA GWAS signals revealed 13 putative OA risk genes, 10 of which have not been previously identified. Chromatin accessibility and 3D chromatin structure provided insights into the mechanisms and conditional specificity of these variants. Our findings shed light on OA pathogenesis and highlight potential targets for therapeutic development.
HIGHLIGHTS
∘ Comprehensive analysis of sex- and age-related global gene expression in human chondrocytes revealed differences that correlate with osteoarthritis ∘ First response eQTLs in chondrocytes treated with an OA-related stimulus ∘ Deeply sequenced Hi-C in resting and activated chondrocytes helps connect OA risk variants to their putative causal genes ∘ Colocalization analysis reveals 13 (including 10 novel) putative OA risk genes.
PubMed: 38952796
DOI: 10.1101/2024.05.05.592567