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Biofabrication Jul 2024Plasma cells (PCs) in bone marrow (BM) play an important role in both protective and pathogenic humoral immune responses, e.g., in various malignant and non-malignant...
Plasma cells (PCs) in bone marrow (BM) play an important role in both protective and pathogenic humoral immune responses, e.g., in various malignant and non-malignant diseases such as multiple myeloma (MM), primary and secondary immunodeficiencies and autoimmune diseases. Dedicated microenvironmental niches in the BM provide PCs with biomechanical and soluble factors that support their long-term survival. There is a high need for appropriate and robust model systems to better understand PCs biology, to develop new therapeutic strategies for PCs-related diseases and perform targeted preclinical studies with high predictive value. Most preclinical data have been derived from in vivo studies in mice, as in vitro studies of human PCs are limited due to restricted survival and functionality in conventional 2D cultures that do not reflect the unique niche architecture of the BM. We have developed a microphysiological, dynamic 3D BM culture system (BM-MPS) based on human primary tissue (femoral biopsies), mechanically supported by a hydrogel scaffold casing. While a bioinert agarose casing did not support PCs survival, a photo-crosslinked collagen-hyaluronic acid (Col-HA) hydrogel preserved the native BM niche architecture and allowed PCs survival in vitro for up to 2 weeks. Further, the Col-HA hydrogel was permissive to lymphocyte migration into the microphysiological system´s circulation. Long-term PCs survival was related to the stable presence in the culture of soluble factors, as APRIL, BAFF, and IL-6. Increasing immunoglobulins concentrations in the medium confirm their functionality over culture time. To the best of our knowledge, this study is the first report of successful long-term maintenance of primary-derived non-malignant PCs in vitro. Our innovative model system is suitable for in-depth in vitro studies of human PCs regulation and exploration of targeted therapeutic approaches such as CAR-T cell therapy or biologics.
PubMed: 38955197
DOI: 10.1088/1758-5090/ad5dfe -
The American Journal of Tropical... Jul 2024Dengue is among the most important mosquito-borne viral diseases worldwide. Although its acute manifestations are well known, little is known about the long-term impact...
Dengue is among the most important mosquito-borne viral diseases worldwide. Although its acute manifestations are well known, little is known about the long-term impact of dengue on the population's health status. Madeira Island experienced a single outbreak of autochthonous dengue from September 2012 to March 2013. To extend our knowledge about the clinical impact of the outbreak on this naive population, we applied an online questionnaire to 168 adults diagnosed with dengue at the time to characterize retrospectively their symptoms during the infection and to identify long-term manifestations, possibly triggered by dengue. The most frequent symptoms during the clinical period, reported by more than three-quarters of our participants, were fever, myalgia, extreme tiredness, and headaches, whereas vomiting, pruritus, nausea, retro-orbital pain, and arthralgia occurred in 35% to 50% of participants. In the 8 years after dengue, 61.5% of participants reported at least one recurrent previously nonexistent symptom, the most frequent being headaches, abundant hair loss, extreme tiredness, arthralgia, and myalgia, experienced by 25% to 35% of participants. Nearly 20% of the participants with persistent symptoms reported the onset of chronic illness in the 4 years after dengue, most frequently ophthalmological and autoimmune diseases (5.6% each), versus only 2.2% of chronic disease onset in participants without persistent symptoms. Our results suggest that the occurrence of persistent symptoms after primary dengue might be more frequent than anticipated and may persist for several years, having an impact on the health status and well-being of a considerable proportion of the infected population.
PubMed: 38955194
DOI: 10.4269/ajtmh.23-0502 -
Cell Host & Microbe Jun 2024Plant immune homeostasis is achieved through a balanced immune activation and suppression, enabling effective defense while averting autoimmunity. In Arabidopsis,...
Plant immune homeostasis is achieved through a balanced immune activation and suppression, enabling effective defense while averting autoimmunity. In Arabidopsis, disrupting a mitogen-activated protein (MAP) kinase cascade triggers nucleotide-binding leucine-rich-repeat (NLR) SUPPRESSOR OF mkk1/2 2 (SUMM2)-mediated autoimmunity. Through an RNAi screen, we identify PUB5, a putative plant U-box E3 ligase, as a critical regulator of SUMM2-mediated autoimmunity. In contrast to typical E3 ligases, PUB5 stabilizes CRCK3, a calmodulin-binding receptor-like cytoplasmic kinase involved in SUMM2 activation. A closely related E3 ligase, PUB44, functions oppositely with PUB5 to degrade CRCK3 through monoubiquitylation and internalization. Furthermore, CRCK3, highly expressed in roots and conserved across plant species, confers resistance to Fusarium oxysporum, a devastating soil-borne fungal pathogen, in both Arabidopsis and cotton. These findings demonstrate the antagonistic role of an E3 ligase pair in fine-tuning kinase proteostasis for the regulation of NLR-mediated autoimmunity and highlight the function of autoimmune activators in governing plant root immunity against fungal pathogens.
PubMed: 38955187
DOI: 10.1016/j.chom.2024.06.004 -
Computers in Biology and Medicine Jul 2024This study delves into the therapeutic efficacy of A. pyrethrum in addressing vitiligo, a chronic inflammatory disorder known for inducing psychological distress and...
Inhibition of the Janus kinase protein (JAK1) by the A. Pyrethrum Root Extract for the treatment of Vitiligo pathology. Design, Molecular Docking, ADME-Tox, MD Simulation, and in-silico investigation.
This study delves into the therapeutic efficacy of A. pyrethrum in addressing vitiligo, a chronic inflammatory disorder known for inducing psychological distress and elevating susceptibility to autoimmune diseases. Notably, JAK inhibitors have emerged as promising candidates for treating immune dermatoses, including vitiligo. Our investigation primarily focuses on the anti-vitiligo potential of A. pyrethrum root extract, specifically targeting N-alkyl-amides, utilizing computational methodologies. Density Functional Theory (DFT) is deployed to meticulously scrutinize molecular properties, while comprehensive evaluations of ADME-Tox properties for each molecule contribute to a nuanced understanding of their therapeutic viability, showcasing remarkable drug-like characteristics. Molecular docking analysis probes ligand interactions with pivotal site JAK1, with all compounds demonstrating significant interactions; notably, molecule 6 exhibits the most interactions with crucial inhibition residues. Molecular dynamics simulations over 500ns further validate the importance and sustainability of these interactions observed in molecular docking, favoring energetically both molecules 6 and 1; however, in terms of stability, the complex with molecule 6 outperforms others. DFT analyses elucidate the distribution of electron-rich oxygen atoms and electron-poor regions within heteroatoms-linked hydrogens. Remarkably, N-alkyl-amides extracted from A. pyrethrum roots exhibit similar compositions, yielding comparable DFT and Electrostatic Potential (ESP) results with subtle distinctions. These findings underscore the considerable potential of A. pyrethrum root extracts as a natural remedy for vitiligo.
PubMed: 38955123
DOI: 10.1016/j.compbiomed.2024.108816 -
International Immunopharmacology Jul 2024Guillain-Barré syndrome (GBS) is an auto-inflammatory peripheral nerve disease. Dendritic cell-mediated T cell polarization is of pivotal importance in demyelinating...
BACKGROUND
Guillain-Barré syndrome (GBS) is an auto-inflammatory peripheral nerve disease. Dendritic cell-mediated T cell polarization is of pivotal importance in demyelinating lesions of peripheral nerves and nerve roots. However, the regulatory function of VX-509 (Decernotinib)-modified tolerogenic dendritic cells (VX-509-tolDCs) during immune remodeling following GBS remains unclear. Here, we used experimental autoimmune neuritis (EAN) as a model to investigate these aspects of GBS.
METHODS
DCs were treated with varying concentrations of VX-509 (0.25, 1, and 4 μM) or served as a control using 10 M 1,25-(OH)D. Flow cytometry was employed to assess the apoptosis, phenotype, and capacity to induce T cell responses of the treated DCs. In the in vivo experiments, EAN mice received administration of VX-509-tolDCs or 1,25-(OH)D-tolDCs via the tail vein at a dose of 1x10 cells/mouse on days 5, 9, 13, and 17.
RESULTS
VX-509 inhibited the maturation of DCs and promoted the development of tolDCs. The function of antigen-specific CD4 + T cells ex vivo was influenced by VX-509-tolDCs. Furthermore, the adoptive transfer of VX-509-tolDCs effectively alleviated inflammatory demyelinating lesions in EAN by promoting Th17/Treg (T helper 17 and regulatory T cells) rebalance.
CONCLUSION
The adoptive transfer of VX-509-tolDCs alleviated inflammatory demyelinating lesions in a mouse model of GBS, known as the EAN mouse, by partially restoring the balance between Treg and Th17 cells.
PubMed: 38955025
DOI: 10.1016/j.intimp.2024.112597 -
Seminars in Arthritis and Rheumatism Jun 2024Systemic sclerosis (SSc) is a heterogenous, multi-system autoimmune disease that causes progressive fibrosis of the skin and internal organs, resulting in high morbidity... (Review)
Review
BACKGROUND
Systemic sclerosis (SSc) is a heterogenous, multi-system autoimmune disease that causes progressive fibrosis of the skin and internal organs, resulting in high morbidity and mortality. Intravenous Immunoglobulin (IVIG) is a therapeutic option for SSc; however, reports of its efficacy have been variable, and its use across multiple organ manifestations of SSc has not been comprehensively reviewed.
AIM
The aim of this study was to systematically assess the existing literature on the role of IVIG use across a range of SSc manifestations.
METHODS
Medline, Embase, Cochrane, Web of Science and Scopus were searched from 01/01/2003-15/04/2024 using terms related to SSc and IVIG. Included studies were English-language full texts, where ≥5 adults with SSc received IVIG, and where a reportable outcome was documented.
RESULTS
Of 418 potentially relevant records, 12 were included in this review, comprising 266 patients across one randomised control trial, two pilot studies, one open label study, seven retrospective studies and one case control study. Eighteen outcomes were documented across five different organ systems: cutaneous, respiratory, musculoskeletal, gastrointestinal, and other (clinical improvement and corticosteroid sparing benefit). Results showed a favourable effect of IVIG in reducing the extent of skin thickening, muscle and joint pain, gastrointestinal symptoms, steroid dosing and improving patient/physician reported quality of life. Whilst IVIG may appear to be less beneficial for respiratory disease, the stabilisation in pulmonary function tests and radiological features may be considered a positive outcome in itself. Limitations included a lack of high-quality studies, and the use of concomitant therapies in many studies, rendering the efficacy of IVIG alone difficult to ascertain.
CONCLUSION
IVIG showed benefit in treating some manifestations of SSc, however there was a lack of convincing evidence for the efficacy in others. The lack of high-quality data highlights the need for further well-designed clinical trials to confirm these findings and inform guidelines for IVIG use.
PubMed: 38954999
DOI: 10.1016/j.semarthrit.2024.152471 -
Neuromuscular Disorders : NMD Jun 2024Myasthenia gravis (MG) is an autoimmune disease that targets neuromuscular junctions. While immunotherapy remains the cornerstone of treatment, the effects of Janus...
Myasthenia gravis (MG) is an autoimmune disease that targets neuromuscular junctions. While immunotherapy remains the cornerstone of treatment, the effects of Janus kinase (JAK) inhibitors on MG remain underexplored. In this report, we describe the case of a 58-year-old woman with ocular myasthenia gravis who received treatment with the JAK inhibitor, baricitinib for alopecia areata. The patient presented with left eyelid ptosis and an inadequate response to steroids and pyridostigmine, along with symptoms of alopecia areata. Following diagnosis, we initiated a treatment regimen consisting of baricitinib for six months. After initiation of baricitinib, we observed a complete resolution of the patient's MG symptoms, accompanied by hair regrowth, even when steroids were tapered and pyridostigmine was discontinued. Furthermore, the titer of the anti-acetylcholine receptor antibody was decreased. This report represents the first reported case of anti-acetylcholine receptor antibody-positive MG that was successfully treated through the inhibition of JAK activity.
PubMed: 38954991
DOI: 10.1016/j.nmd.2024.06.006 -
Human Immunology Jul 2024Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder characterized by a hyperactive immune system with multiple abnormalities in B-cell proliferation,... (Review)
Review
Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder characterized by a hyperactive immune system with multiple abnormalities in B-cell proliferation, antibody production, T-cell regulation, and immune complex (IC) formation. In humans, Immunoglobulin (Ig) G is found in four subclasses. IgG1-IgG4, which are distinguished by both structural and biological differences. Fab-arm Exchange (FAE), specific biases in the IgG4 response repertoire, and a decreased capacity to induce effector functions mediated by interactions in the fragment crystallizable (Fc) region are just a few of the distinctive characteristics of IgG4. The recent finding of the presence of double-stranded DNA (dsDNA) and antinuclear antibody (ANA)-IgG4 has raised attention to this IgG subclass and its possible role in SLE. IgG4 was previously believed to just have anti-inflammatory effects by inhibiting immune responses, but recent studies have shown that these antibodies can also play a role in the onset and development of some clinical disorders. To consider the clinical effects of IgG4 presence, it is necessary to discuss its characteristics, which could underlie the potential role it can play in SLE. Therefore, this study aimed to comprehensively review the role of IgG4 in SLE to elucidate the collective incidence of high IgG4 levels reported in some SLE patients.
PubMed: 38954949
DOI: 10.1016/j.humimm.2024.110826 -
Neurology(R) Neuroimmunology &... Sep 2024Neutrophils, underestimated in multiple sclerosis (MS), are gaining increased attention for their significant functions in patients with MS and the experimental...
BACKGROUND AND OBJECTIVES
Neutrophils, underestimated in multiple sclerosis (MS), are gaining increased attention for their significant functions in patients with MS and the experimental autoimmune encephalomyelitis (EAE) animal model. However, the precise role of neutrophils in cervical lymph nodes (CLNs), the primary CNS-draining lymph nodes where the autoimmune response is initiated during the progression of EAE, remains poorly understood.
METHODS
Applying single-cell RNA sequencing (scRNA-seq), we constructed a comprehensive immune cell atlas of CLNs during development of EAE. Through this atlas, we concentrated on and uncovered the transcriptional landscape, phenotypic and functional heterogeneity of neutrophils, and their crosstalk with immune cells within CLNs in the neuroinflammatory processes in EAE.
RESULTS
Notably, we observed a substantial increase in the neutrophil population in EAE mice, with a particular emphasis on the significant rise within the CLNs. Neutrophils in CLNs were categorized into 3 subtypes, and we explored the specific roles and developmental trajectories of each distinct neutrophil subtype. Neutrophils were found to engage in extensive interactions with other immune cells, playing crucial roles in T-cell activation. Moreover, our findings highlighted the strong migratory ability of neutrophils to CLNs, partly regulated by triggering the receptor expressed on myeloid cells 1 (TREM-1). Inhibiting TREM1 with LR12 prevents neutrophil migration both in vivo and in vitro. In addition, in patients with MS, we confirmed an increase in peripheral neutrophils with an upregulation of TREM-1.
DISCUSSION
Our research provides a comprehensive and precise single-cell atlas of CLNs in EAE, highlighting the role of neutrophils in regulating the periphery immune response. In addition, TREM-1 emerged as an essential regulator of neutrophil migration to CLNs, holding promise as a potential therapeutic target in MS.
Topics: Encephalomyelitis, Autoimmune, Experimental; Neutrophils; Animals; Triggering Receptor Expressed on Myeloid Cells-1; Mice; Single-Cell Analysis; Mice, Inbred C57BL; Female; Sequence Analysis, RNA; Lymph Nodes
PubMed: 38954781
DOI: 10.1212/NXI.0000000000200278 -
PloS One 2024Autoimmune diseases affect 5-10% of the global population and cause chronic pain and impaired functionality. Chronic pain management involves pharmacological and...
BACKGROUND
Autoimmune diseases affect 5-10% of the global population and cause chronic pain and impaired functionality. Chronic pain management involves pharmacological and non-pharmacological interventions, with non-pharmacological options gaining attention as safe, effective, and cost-effective alternatives. However, further research is needed to determine the effectiveness of these therapies in African patients with autoimmune diseases, as existing evidence varies.
METHODS
This review protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO, CRD42023449896). Electronic databases (PubMed, Africa Index Medicus, Cochrane Library, CINAHL, PsycINFO, and Web of Science) will be used for searching published articles. The study will use R for data synthesis, employing a random-effects meta-analysis approach to calculate pooled effect sizes, assess heterogeneity using the I2 statistic, and evaluate publication bias. In conclusion, this protocol aims to fill the knowledge gap on non-pharmacological therapies for chronic pain in patients with autoimmune diseases in Africa. It will potentially enhance evidence-based decision-making to improve pain management and, hence, the quality of life of people with autoimmune diseases in Africa.
Topics: Humans; Systematic Reviews as Topic; Chronic Pain; Autoimmune Diseases; Meta-Analysis as Topic; Africa; Pain Management; Quality of Life
PubMed: 38954682
DOI: 10.1371/journal.pone.0306564