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Inflammatory Bowel Diseases Oct 2023Ulcerative colitis (UC) and Crohn's disease are 2 types of inflammatory bowel disease (IBD), a group of chronic digestive disorders caused by aberrant immune responses...
BACKGROUND
Ulcerative colitis (UC) and Crohn's disease are 2 types of inflammatory bowel disease (IBD), a group of chronic digestive disorders caused by aberrant immune responses to intestinal microbes. Although changes in the composition of immune cell subsets in the context of IBD have been previously described, the interactions and communication among cells are less well understood. Moreover, the precise mechanisms of action underlying many biologic therapies, including the anti-α4β7 integrin antagonist vedolizumab, remain incompletely understood. Our study aimed to explore possible additional mechanisms through which vedolizumab acts.
METHODS
We performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) on peripheral blood and colon immune cells derived from patients with ulcerative colitis treated with the anti-α4β7 integrin antagonist vedolizumab. We applied a previously published computational approach, NicheNet, to predict immune cell-cell interactions, revealing putative ligand-receptor pairs and key transcriptional changes downstream of these cell-cell communications (CCC).
RESULTS
We observed decreased proportions of T helper 17 (TH17) cells in UC patients who responded to vedolizumab and therefore focused the study on identifying cell-cell communications and signals of TH17 cells with other immune cells. For example, we observed that colon TH17 cells from vedolizumab nonresponders were predicted to have a greater degree of interactions with classical monocytes compared with responders, whereas colon TH17 cells from vedolizumab responders exhibited more interactions with myeloid dendritic cells compared with nonresponders.
CONCLUSIONS
Overall, our results indicate that efforts to elucidate cell-cell communications among immune and nonimmune cell types may increase the mechanistic understanding of current and investigational therapies for IBD.
Topics: Humans; Colitis, Ulcerative; Inflammatory Bowel Diseases; Integrins; Cell Communication; Gastrointestinal Agents
PubMed: 37235748
DOI: 10.1093/ibd/izad084 -
Frontiers in Immunology 2024Significant advancements have been achieved in understanding the roles of different immune cells, as well as cytokines and chemokines, in the pathogenesis of... (Review)
Review
Significant advancements have been achieved in understanding the roles of different immune cells, as well as cytokines and chemokines, in the pathogenesis of eosinophilic airway conditions. This review examines the pathogenesis of Chronic Rhinosinusitis with Nasal Polyps (CRSwNP), marked by complex immune dysregulation, with major contributions from type 2 inflammation and dysfunctional airway epithelium. The presence of eosinophils and the role of T-cell subsets, particularly an imbalance between Treg and Th17 cells, are crucial to the disease's pathogenesis. The review also investigates the pathogenesis of eosinophilic asthma, a unique asthma subtype. It is characterized by inflammation and high eosinophil levels, with eosinophils playing a pivotal role in triggering type 2 inflammation. The immune response involves Th2 cells, eosinophils, and IgE, among others, all activated by genetic and environmental factors. The intricate interplay among these elements, chemokines, and innate lymphoid cells results in airway inflammation and hyper-responsiveness, contributing to the pathogenesis of eosinophilic asthma. Another scope of this review is the pathogenesis of Eosinophilic Granulomatosis with Polyangiitis (EGPA); a complex inflammatory disease that commonly affects the respiratory tract and small to medium-sized blood vessels. It is characterized by elevated eosinophil levels in blood and tissues. The pathogenesis involves the activation of adaptive immune responses by antigens leading to T and B cell activation and eosinophil stimulation, which causes tissue and vessel damage. On the other hand, Allergic Bronchopulmonary Aspergillosis (ABPA) is a hypersensitive response that occurs when the airways become colonized by aspergillus fungus, with the pathogenesis involving activation of Th2 immune responses, production of IgE antibodies, and eosinophilic action leading to bronchial inflammation and subsequent lung damage. This analysis scrutinizes how an imbalanced immune system contributes to these eosinophilic diseases. The understanding derived from this assessment can steer researchers toward designing new potential therapeutic targets for efficient control of these disorders.
Topics: Animals; Humans; Asthma; Chronic Disease; Cytokines; Eosinophils; Inflammation; Nasal Polyps; Rhinitis; Sinusitis; Th2 Cells
PubMed: 38680486
DOI: 10.3389/fimmu.2024.1285598 -
RMD Open Jul 2023Almost all patients with systemic sclerosis (SSc) harbour autoantibodies. Anti-topoisomerase antibodies (ATA) and anti-centromere antibodies (ACA) are most prevalent and...
OBJECTIVES
Almost all patients with systemic sclerosis (SSc) harbour autoantibodies. Anti-topoisomerase antibodies (ATA) and anti-centromere antibodies (ACA) are most prevalent and associate with distinct clinical phenotypes. B cell responses underlying these phenotypes are ill-defined. To understand how B cell autoreactivity and disease pathology connect, we determined phenotypic and functional characteristics of autoreactive B cells in ATA-positive and ACA-positive patients.
METHODS
Levels and isotypes of autoantibodies secreted by ex vivo cultured peripheral blood mononuclear cells from patients with ATA-positive (n=22) and ACA-positive (n=20) SSc were determined. Antibody secreting cells (ASCs) were isolated by cell sorting and cultured separately. Correlations were studied between the degree of spontaneous autoantibody production and the presence and degree of interstitial lung disease (ILD).
RESULTS
Circulating B cells secreting either ATA-immunoglobulin G (IgG) or ACA-IgG on stimulation was readily detectable in patients. The ATA response, but not the ACA response, showed additional secretion of autoreactive IgA. ATA-IgG and ATA-IgA were also secreted spontaneously. Additional cell sorting confirmed the presence of ATA-secreting plasmablasts. The degree of spontaneous ATA-secretion was higher in patients with ILD than in those without (p<0.001) and correlated with the degree of pulmonary fibrosis (p<0.001).
CONCLUSION
In contrast to ACA-positive patients, ATA-positive patients show signs of recent activation of the B cell response that hallmarks this disease. The degree of activation correlates with the presence and severity of ILD, the most deleterious disease manifestation. This could explain differential responsiveness to B cell depleting therapy. The abundant and spontaneous secretion of ATA-IgG and ATA-IgA may point toward a continuously activating trigger.
Topics: Humans; Pulmonary Fibrosis; Leukocytes, Mononuclear; Scleroderma, Systemic; Autoantibodies; Lung Diseases, Interstitial; Immunoglobulin G; Immunoglobulin A
PubMed: 37507206
DOI: 10.1136/rmdopen-2023-003148 -
Nanotheranostics 2023Medical imaging is an important factor for diagnosis. It can be used to diagnose patients, differentiate disease stages, and monitor treatment regimens. Although... (Review)
Review
Medical imaging is an important factor for diagnosis. It can be used to diagnose patients, differentiate disease stages, and monitor treatment regimens. Although different imaging technologies are available, MRI is sensitive over other imaging modalities as it is capable of deep tissue penetration allowing to image the anatomical, structural, and molecular level of diseased organs. Thus, it can be used as screening tool for disease staging. One of the important components of imaging is contrast agents which are used to increase the sensitivity of MRI technology. While different types of contrast agents are available, iron-oxide based nanoparticles (IONPS) are widely used as these are easy to formulate, functionalize, biocompatible and cost effective. In addition to its use as contrast agents, these have been used as drug carriers for the treatment of different types of diseases ranging from cancer, cardiovascular diseases, neurological disorders, autoimmune diseases, and infectious diseases. For the last two decades, there has been advancement in nanotheranostics, where IONPs are formulated to carry drug and be used as contrast agents in one system so that these can be used for image-guided therapy and monitor real-life treatment response in diseased tissue. This technology can be used to stratify patients into responders and non-responders and reduce adverse drug toxicity and lead to a tailored treatment. However, success of nanotheranostics depends on several factor, including identification of disease associated biomarkers that can be targeted on IONPs during formulation. While many challenges exist for the clinical translation of nanotheranostics, it still has the potential to be implemented in personalized treatment strategy. In this review article, we discussed the use of MRI technology and IONPs in relation to their application in disease diagnosis and nanotheranostics application in personalized medicine.
Topics: Humans; Precision Medicine; Contrast Media; Magnetic Resonance Imaging; Nanoparticles; Oxides; Iron
PubMed: 37650011
DOI: 10.7150/ntno.86467 -
Brain Research Bulletin Aug 2023Illness is often predicated long before the manifestation of its symptoms. Exposure to stressful experiences particularly during critical periods of development, such as... (Review)
Review
Illness is often predicated long before the manifestation of its symptoms. Exposure to stressful experiences particularly during critical periods of development, such as puberty and adolescence, can induce various physical and mental illnesses. Puberty is a critical period of maturation for neuroendocrine systems, such as the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes. Exposure to adverse experiences during puberty can impede normal brain reorganizing and remodelling and result in enduring consequences on brain functioning and behaviour. Stress responsivity differs between the sexes during the pubertal period. This sex difference is partly due to differences in circulating sex hormones between males and females, impacting stress and immune responses differently. The effects of stress during puberty on physical and mental health remains under-examined. The purpose of this review is to summarize the most recent findings pertaining to age and sex differences in HPA axis, HPG axis, and immune system development, and describe how disruption in the functioning of these systems can propagate disease. Lastly, we delve into the notable neuroimmune contributions, sex differences, and the mediating role of the gut microbiome on stress and health outcomes. Understanding the enduring consequences of adverse experiences during puberty on physical and mental health will allow a greater proficiency in treating and preventing stress-related diseases early in development.
Topics: Adolescent; Humans; Male; Female; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Puberty; Sex Characteristics; Brain
PubMed: 37422090
DOI: 10.1016/j.brainresbull.2023.110701 -
Recent theranostic applications of hydrogen peroxide-responsive nanomaterials for multiple diseases.RSC Advances Sep 2023It is well established that hydrogen peroxide (HO) is associated with the initiation and progression of many diseases. With the rapid development of nanotechnology, the... (Review)
Review
It is well established that hydrogen peroxide (HO) is associated with the initiation and progression of many diseases. With the rapid development of nanotechnology, the diagnosis and treatment of those diseases could be realized through a variety of HO-responsive nanomaterials. In order to broaden the application prospects of HO-responsive nanomaterials and promote their development, understanding and summarizing the design and application fields of such materials has attracted much attention. This review provides a comprehensive summary of the types of HO-responsive nanomaterials including organic, inorganic and organic-inorganic hybrids in recent years, and focused on their specific design and applications. Based on the type of disease, such as tumors, bacteria, dental diseases, inflammation, cardiovascular diseases, bone injury and so on, key examples for above disease imaging diagnosis and therapy strategies are introduced. In addition, current challenges and the outlook of HO-responsive nanomaterials are also discussed. This review aims to stimulate the potential of HO-responsive nanomaterials and provide new application ideas for various functional nanomaterials related to HO.
PubMed: 37705984
DOI: 10.1039/d3ra05020c -
Biomaterials Dec 2023Tissue mechanobiology is an emerging field with the overarching goal of understanding the interplay between biophysical and biochemical responses affecting development,... (Review)
Review
Tissue mechanobiology is an emerging field with the overarching goal of understanding the interplay between biophysical and biochemical responses affecting development, physiology, and disease. Changes in mechanical properties including stiffness and viscosity have been shown to describe how cells and tissues respond to mechanical cues and modify critical biological functions. To quantitatively characterize the mechanical properties of tissues at physiologically relevant conditions, atomic force microscopy (AFM) has emerged as a highly versatile biomechanical technology. In this review, we describe the fundamental principles of AFM, typical AFM modalities used for tissue mechanics, and commonly used elastic and viscoelastic contact mechanics models to characterize complex human tissues. Furthermore, we discuss the application of AFM-based mechanobiology to characterize the mechanical responses within complex human tissues to track their developmental, physiological/functional, and diseased states, including oral, hearing, and cancer-related tissues. Finally, we discuss the current outlook and challenges to further advance the field of tissue mechanobiology. Altogether, AFM-based tissue mechanobiology provides a mechanistic understanding of biological processes governing the unique functions of tissues.
Topics: Humans; Microscopy, Atomic Force; Biophysics; Viscosity
PubMed: 37988897
DOI: 10.1016/j.biomaterials.2023.122389 -
Journal of Translational Medicine Sep 2023Cancer is a complex disease with many contributing factors, and researchers have gained extensive knowledge that has helped them understand the diverse and varied nature... (Review)
Review
Cancer is a complex disease with many contributing factors, and researchers have gained extensive knowledge that has helped them understand the diverse and varied nature of cancer. The altered patterns of DNA methylation found in numerous types of cancer imply that they may play a part in the disease's progression. The human cancer condition involves dysregulation of the DNA methyltransferase 3 beta (DNMT3B) gene, a prominent de novo DNA methyltransferase, and its abnormal behavior serves as an indicator for tumor prognosis and staging. The expression of non-coding RNAs (ncRNAs), which include microRNAs (miRNA), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), is critical in controlling targeted gene expression and protein translation and their dysregulation correlates with the onset of tumors. NcRNAs dysregulation of is a critical factor that influences the modulation of several cellular characteristics in cancerous cells. These characteristics include but are not limited to, drug responsiveness, angiogenesis, metastasis, apoptosis, proliferation, and properties of tumor stem cell. The reciprocal regulation of ncRNAs and DNMT3B can act in synergy to influence the destiny of tumor cells. Thus, a critical avenue for advancing cancer prevention and treatment is an inquiry into the interplay between DNMT3B and ncRNAs. In this review, we present a comprehensive overview of the ncRNAs/DNMT3B axis in cancer pathogenesis. This brings about valuable insights into the intricate mechanisms of tumorigenesis and provides a foundation for developing effective therapeutic interventions.
Topics: Humans; Clinical Relevance; DNA; DNA Modification Methylases; Neoplasms; RNA, Untranslated; DNA Methyltransferase 3B
PubMed: 37705098
DOI: 10.1186/s12967-023-04510-y -
The Journal of Allergy and Clinical... Nov 2023The emerging role of sphingosine-1-phosphate (S1P) in regulating smooth muscle functions has led to the exploration of the possibility that this sphingolipid could...
BACKGROUND
The emerging role of sphingosine-1-phosphate (S1P) in regulating smooth muscle functions has led to the exploration of the possibility that this sphingolipid could represent a potential therapeutic target in asthma and other lung diseases. Several studies in animal surrogates have suggested a role for S1P-mediated signaling in the regulation of airway smooth muscle (ASM) contraction, airway hyperresponsiveness, and airway remodeling, but evidence from human studies is lacking.
OBJECTIVE
We sought to compare the responsiveness of the airways to S1P in healthy and asthmatic individuals in vivo, in isolated human airways ex vivo, and in murine airways dissected from healthy and house dust mite (HDM)-sensitized animals.
METHODS
Airway responsiveness was measured by spirometry during inhalation challenges and by wire myography in airways isolated from human and mouse lungs. Thymidine incorporation and calcium mobilization assays were used to study human ASM cell responses.
RESULTS
S1P did not induce contraction of airways isolated from healthy and HDM-exposed mice, nor in human airways. Similarly, there was no airway constriction observed in healthy and asthmatic subjects in response to increasing concentrations of inhaled S1P. However, a 30-minute exposure to S1P induced a significant concentration-dependent enhancement of airway reactivity to methacholine and to histamine in murine and human airways, respectively. HDM-sensitized mice demonstrated a significant increase in methacholine responsiveness, which was not further enhanced by S1P treatment. S1P also concentration-dependently enhanced proliferation of human ASM cells, an effect mediated through S1P receptor type 2, as shown by selective antagonism and S1P receptor type 2 small-interfering RNA knockdown.
CONCLUSIONS
Our data suggest that S1P released locally into the airways may be involved in the regulation of ASM hyperresponsiveness and hyperplasia, defining a novel target for future therapies.
Topics: Humans; Mice; Animals; Sphingosine-1-Phosphate Receptors; Methacholine Chloride; Asthma; Muscle, Smooth; Cell Proliferation
PubMed: 37474025
DOI: 10.1016/j.jaci.2023.05.028 -
Neurobiology of Disease Aug 2023Neurological conditions such as Alzheimer's disease (AD) and related dementias (ADRD) present with many challenges due to the heterogeneity of the related disease(s),... (Review)
Review
Neurological conditions such as Alzheimer's disease (AD) and related dementias (ADRD) present with many challenges due to the heterogeneity of the related disease(s), making it difficult to develop effective treatments. Additionally, the progression of ADRD-related pathologies presents differently between men and women. With two-thirds of the population affected with ADRD being women, ADRD has presented itself with a bias toward the female population. However, studies of ADRD generally do not incorporate sex-based differences in investigating the development and progression of the disease, which is detrimental to understanding and treating dementia. Additionally, recent implications for the adaptive immune system in the development of ADRD bring in new factors to be considered as part of the disease, including sex-based differences in immune response(s) during ADRD development. Here, we review the sex-based differences of pathological hallmarks of ADRD presentation and progression, sex-based differences in the adaptive immune system and how it changes with ADRD, and the importance of precision medicine in the development of a more targeted and personalized treatment for this devastating and prevalent neurodegenerative condition.
Topics: Male; Female; Humans; Alzheimer Disease; Dementia; Immune System
PubMed: 37330146
DOI: 10.1016/j.nbd.2023.106202