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Circulation Research Jun 2024Autoimmunity significantly contributes to the pathogenesis of myocarditis, underscored by its increased frequency in autoimmune diseases such as systemic lupus... (Review)
Review
Autoimmunity significantly contributes to the pathogenesis of myocarditis, underscored by its increased frequency in autoimmune diseases such as systemic lupus erythematosus and polymyositis. Even in cases of myocarditis caused by viral infections, dysregulated immune responses contribute to pathogenesis. However, whether triggered by existing autoimmune conditions or viral infections, the precise antigens and immunologic pathways driving myocarditis remain incompletely understood. The emergence of myocarditis associated with immune checkpoint inhibitor therapy, commonly used for treating cancer, has afforded an opportunity to understand autoimmune mechanisms in myocarditis, with autoreactive T cells specific for cardiac myosin playing a pivotal role. Despite their self-antigen recognition, cardiac myosin-specific T cells can be present in healthy individuals due to bypassing the thymic selection stage. In recent studies, novel modalities in suppressing the activity of pathogenic T cells including cardiac myosin-specific T cells have proven effective in treating autoimmune myocarditis. This review offers an overview of the current understanding of heart antigens, autoantibodies, and immune cells as the autoimmune mechanisms underlying various forms of myocarditis, along with the latest updates on clinical management and prospects for future research.
Topics: Myocarditis; Humans; Autoimmune Diseases; Animals; Autoantibodies; Autoimmunity; T-Lymphocytes; Autoantigens; Cardiac Myosins
PubMed: 38843292
DOI: 10.1161/CIRCRESAHA.124.323816 -
Epigenetics & Chromatin Jun 2024Over the past several decades, the use of biochemical and fluorescent tags has elucidated mechanistic and cytological processes that would otherwise be impossible. The...
BACKGROUND
Over the past several decades, the use of biochemical and fluorescent tags has elucidated mechanistic and cytological processes that would otherwise be impossible. The challenging nature of certain nuclear proteins includes low abundancy, poor antibody recognition, and transient dynamics. One approach to get around those issues is the addition of a peptide or larger protein tag to the target protein to improve enrichment, purification, and visualization. However, many of these studies were done under the assumption that tagged proteins can fully recapitulate native protein function.
RESULTS
We report that when C-terminally TAP-tagged CENP-A histone variant is introduced, it undergoes altered kinetochore protein binding, differs in post-translational modifications (PTMs), utilizes histone chaperones that differ from that of native CENP-A, and can partially displace native CENP-A in human cells. Additionally, these tagged CENP-A-containing nucleosomes have reduced centromeric incorporation at early G1 phase and poorly associates with linker histone H1.5 compared to native CENP-A nucleosomes.
CONCLUSIONS
These data suggest expressing tagged versions of histone variant CENP-A may result in unexpected utilization of non-native pathways, thereby altering the biological function of the histone variant.
Topics: Humans; Centromere Protein A; Histones; Protein Processing, Post-Translational; Nucleosomes; HeLa Cells; Kinetochores; Chromosomal Proteins, Non-Histone; Protein Binding
PubMed: 38825690
DOI: 10.1186/s13072-024-00543-9 -
Journal of Neuroinflammation May 2024Cumulative evidence has established that Interferon (IFN)-γ has both pathogenic and protective roles in Multiple Sclerosis and the animal model, Experimental Autoimmune...
Cumulative evidence has established that Interferon (IFN)-γ has both pathogenic and protective roles in Multiple Sclerosis and the animal model, Experimental Autoimmune Encephalomyelitis (EAE). However, the underlying mechanisms to the beneficial effects of IFN-γ are not well understood. In this study, we found that IFN-γ exerts therapeutic effects on chronic, relapsing-remitting, and chronic progressive EAE models. The frequency of regulatory T (Treg) cells in spinal cords from chronic EAE mice treated with IFN-γ was significantly increased with no effect on Th1 and Th17 cells. Consistently, depletion of FOXP3-expressing cells blocked the protective effects of IFN-γ, indicating that the therapeutic effect of IFN-γ depends on the presence of Treg cells. However, IFN-γ did not trigger direct in vitro differentiation of Treg cells. In vivo administration of blocking antibodies against either interleukin (IL)-10, transforming growth factor (TGF)-β or program death (PD)-1, revealed that the protective effects of IFN-γ in EAE were also dependent on TGF-β and PD-1, but not on IL-10, suggesting that IFN-γ might have an indirect role on Treg cells acting through antigen-presenting cells. Indeed, IFN-γ treatment increased the frequency of a subset of splenic CD11b myeloid cells expressing TGF-β-Latency Associated Peptide (LAP) and program death ligand 1 (PD-L1) in a signal transducer and activator of transcription (STAT)-1-dependent manner. Furthermore, splenic CD11b cells from EAE mice preconditioned in vitro with IFN-γ and myelin oligodendrocyte glycoprotein (MOG) peptide exhibited a tolerogenic phenotype with the capability to induce conversion of naïve CD4 T cells mediated by secretion of TGF-β. Remarkably, adoptive transfer of splenic CD11b cells from IFN-γ-treated EAE mice into untreated recipient mice ameliorated clinical symptoms of EAE and limited central nervous system infiltration of mononuclear cells and effector helper T cells. These results reveal a novel cellular and molecular mechanism whereby IFN-γ promotes beneficial effects in EAE by endowing splenic CD11b myeloid cells with tolerogenic and therapeutic activities.
Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Mice; Interferon-gamma; Myeloid Cells; Spleen; Mice, Inbred C57BL; CD11b Antigen; Female; Myelin-Oligodendrocyte Glycoprotein; T-Lymphocytes, Regulatory; Peptide Fragments; Transforming Growth Factor beta; Programmed Cell Death 1 Receptor; Forkhead Transcription Factors; Disease Models, Animal
PubMed: 38822334
DOI: 10.1186/s12974-024-03126-3 -
Biomedicine & Pharmacotherapy =... Jul 2024Ganglioside GM3 is one of the most common membrane-bound glycosphingolipids. The over-expression of GM3 on tumor cells makes it defined as a tumor-associated... (Review)
Review
Ganglioside GM3 is one of the most common membrane-bound glycosphingolipids. The over-expression of GM3 on tumor cells makes it defined as a tumor-associated carbohydrate antigen (TACA). The specific expression property in cancers, especially in melanoma, make it become an important target to develop anticancer vaccines or immunotherapies. However, in the manner akin to most TACAs, GM3 is an autoantigen facing with problems of low immunogenicity and easily inducing immunotolerance, which means itself only cannot elicit a powerful enough immune response to prevent or treat cancer. With a comparative understanding of the mechanisms that how immune system responses to the carbohydrate vaccines, this review summarizes the studies on the recent efforts to development GM3-based anticancer vaccines.
Topics: G(M3) Ganglioside; Humans; Cancer Vaccines; Animals; Neoplasms
PubMed: 38820973
DOI: 10.1016/j.biopha.2024.116824 -
Frontiers in Immunology 2024Myelin oligodendrocyte glycoprotein (MOG) IgG is frequently elevated in pediatric patients with acquired demyelinating syndrome (ADS). However, no specific biomarkers...
BACKGROUND AND PURPOSE
Myelin oligodendrocyte glycoprotein (MOG) IgG is frequently elevated in pediatric patients with acquired demyelinating syndrome (ADS). However, no specific biomarkers exist for phenotype classification, symptom severity, prognosis, and treatment guidance of MOG-IgG-associated disease (MOGAD). This study evaluated neurofilament light chain (NfL) and endothelial growth factor receptor (EGFR) mRNA expression levels in serum and cerebrospinal fluid (CSF) as potential biomarkers for MOGAD in Chinese children.
METHODS
This was a cross-sectional and single-center study. We enrolled 22 consecutive pediatric patients hospitalized with MOGAD and 20 control pediatric patients hospitalized for noninflammatory neurological diseases in Hebei Children's Hospital. Serum and CSF were collected from MOGAD patients within 3 days before immunotherapy. The mRNA levels of NfL and EGFR in serum and CSF were measured by real-time polymerase chain reaction (qPCR), and the EGFR/NfL ratio mRNA was calculated. These measurement values were then compared between disease groups and among MOGAD phenotypes. In addition, the correlations between the mRNAs of three markers (NfL, EGFR, EGFR/NfL ratio), extended disability status scale (EDSS) scores, and clinical phenotypes were analyzed.
RESULTS
Serum and CSF NfL mRNA levels were significantly higher of acute-stage MOGAD patients than those of control patients ( 0.05 and 0.01, respectively), while the mRNA levels of serum EGFR and EGFR/NfL ratio were significantly lower of MOGAD patients than those of controls ( 0.05, 0.0001). Serum NfL mRNA was significantly correlated with mRNA of serum EGFR ( =0.480, < 0.05). Serum and CSF NfL mRNA levels in MOGAD patients with the ADEM-like phenotype were also significantly higher than those in control patients ( < 0.01, < 0.01) and optic neuritis (ON) phenotype ( < 0.05, < 0.05). Both mRNAs of NfL in CSF and EGFR/NfL ratio in serum were correlated with EDSS scores ( < 0.05, = 0.424; < 0.05, = -0.521).
CONCLUSION
The mRNA levels of elevated NfL in serum and CSF as well as lower EGFR and EGFR/NfL ratio in serum could help distinguish acute-phase MOGAD. Higher mRNA levels of NfL in serum and CSF of MOGAD patients help distinguish ADEM-like phenotype. In addition, serum EGFR/NfL mRNA ratio is indicative of disease severity in pediatric patients with MOGAD. Further investigations are warranted to elucidate the pathological mechanisms underlying these associations.
Topics: Humans; Male; Female; Biomarkers; Child; Neurofilament Proteins; Myelin-Oligodendrocyte Glycoprotein; RNA, Messenger; ErbB Receptors; Cross-Sectional Studies; Child, Preschool; Severity of Illness Index; Phenotype; Immunoglobulin G; Adolescent; Autoantibodies
PubMed: 38807603
DOI: 10.3389/fimmu.2024.1388734 -
Biomedicine & Pharmacotherapy =... Jul 2024Acute kidney injury (AKI) is associated with both kidney function loss and increased mortality. In the pathological progression of ischemia-reperfusion-induced AKI, the...
Acute kidney injury (AKI) is associated with both kidney function loss and increased mortality. In the pathological progression of ischemia-reperfusion-induced AKI, the surge of reactive oxygen species (ROS) plays a crucial role. To combat this, mitochondrial-targeted antioxidant therapy shows great promise as mitochondria are the primary source of ROS in AKI. However, most strategies aiming to target mitochondria directly result in nanodrugs that are too large to pass through the glomerular system and reach the renal tubules, which are the main site of damage in AKI. This study focused on synthesizing a Megalin receptor-targeted polymeric prodrug, low molecular weight chitosan-thioketal-elamipretide (LMWC/TK/Ela), to mitigate excessive ROS in renal tubular epithelial cells for AKI. This soluble polymeric prodrug has the ability to successfully reach the tubular site by crossing the glomerular barrier. Once there, it can responsively release elamipretide, which possesses excellent antioxidative properties. Therefore, this research offers a novel approach to actively target renal tubular epithelial cells and intracellular mitochondria for the relief of AKI.
Topics: Acute Kidney Injury; Prodrugs; Reactive Oxygen Species; Low Density Lipoprotein Receptor-Related Protein-2; Oligopeptides; Animals; Antioxidants; Polymers; Chitosan; Mitochondria; Humans; Kidney Tubules; Mice
PubMed: 38805970
DOI: 10.1016/j.biopha.2024.116804 -
Journal of Personalized Medicine May 2024Psoriasis is a chronic recurrent inflammatory autoimmune pathology with a significant genetic component and several interferences of immunological cells and their... (Review)
Review
Psoriasis is a chronic recurrent inflammatory autoimmune pathology with a significant genetic component and several interferences of immunological cells and their cytokines. The complex orchestration of psoriasis pathogenesis is related to the synergic effect of immune cells, polygenic alterations, autoantigens, and several other external factors. The major act of the IL-23/IL-17 axis, strongly influencing the inflammatory pattern established during the disease activity, is visible as a continuous perpetuation of the pro-inflammatory response and keratinocyte activation and proliferation, leading to the development of psoriatic lesions. Genome-wide association studies (GWASs) offer a better view of psoriasis pathogenic pathways, with approximately one-third of psoriasis's genetic impact on psoriasis development associated with the MHC region, with genetic loci located on chromosome 6. The most eloquent genetic factor of psoriasis, PSORS1, was identified in the MHC I site. Among the several factors involved in its complex etiology, dysbiosis, due to genetic or external stimulus, induces a burst of pro-inflammatory consequences; both the cutaneous and gut microbiome get involved in the psoriasis pathogenic process. Cutting-edge research studies and comprehensive insights into psoriasis pathogenesis, fostering novel genetic, epigenetic, and immunological factors, have generated a spectacular improvement over the past decades, securing the path toward a specific and targeted immunotherapeutic approach and delayed progression to inflammatory arthritis. This review aimed to offer insight into various domains that underline the pathogenesis of psoriasis and how they influence disease development and evolution. The pathogenesis mechanism of psoriasis is multifaceted and involves an interplay of cellular and humoral immunity, which affects susceptible microbiota and the genetic background. An in-depth understanding of the role of pathogenic factors forms the basis for developing novel and individualized therapeutic targets that can improve disease management.
PubMed: 38793117
DOI: 10.3390/jpm14050535 -
Genes May 2024Alport syndrome (AS) is a common and heterogeneous genetic kidney disease, that often leads to end-stage kidney disease (ESKD).
BACKGROUND
Alport syndrome (AS) is a common and heterogeneous genetic kidney disease, that often leads to end-stage kidney disease (ESKD).
METHODS
This is a single-center, retrospective study that included 36 adults with type IV collagen (COL4) mutations. Our main scope was to describe how genetic features influence renal survival.
RESULTS
A total of 24 different mutations were identified, of which eight had not been previously described. Mutations affecting each of the type IV collagen α chains were equally prevalent (33.3%). Most of the patients had pathogenic variants (61.1%). Most patients had a family history of kidney disease (71%). The most prevalent clinical picture was nephritic syndrome (64%). One-third of the subjects had extrarenal manifestations, 41.6% of patients had ESKD at referral, and another 8.3% developed ESKD during follow-up. The median renal survival was 42 years (95% CI, 29.98-54.01). The COL4A4 group displayed better renal survival than the COL4A3 group ( = 0.027). Patients with missense variants had higher renal survival ( = 0.023). Hearing loss was associated with lower renal survival ( < 0.001).
CONCLUSIONS
Patients with COL4A4 variants and those with missense mutations had significantly better renal survival, whereas those with COL4A3 variants and those with hearing loss had worse prognoses.
Topics: Humans; Nephritis, Hereditary; Female; Male; Collagen Type IV; Adult; Middle Aged; Genetic Association Studies; Kidney Failure, Chronic; Mutation; Retrospective Studies; Autoantigens
PubMed: 38790222
DOI: 10.3390/genes15050593 -
PloS One 2024Type 1 diabetes (T1D) is characterized by HLA class I-mediated presentation of autoantigens on the surface of pancreatic β-cells. Recognition of these autoantigens by...
Type 1 diabetes (T1D) is characterized by HLA class I-mediated presentation of autoantigens on the surface of pancreatic β-cells. Recognition of these autoantigens by CD8+ T cells results in the destruction of pancreatic β-cells and, consequently, insulin deficiency. Most epitopes presented at the surface of β-cells derive from the insulin precursor molecule proinsulin. The intracellular processing pathway(s) involved in the generation of these peptides are poorly defined. In this study, we show that a proinsulin B-chain antigen (PPIB5-14) originates from proinsulin molecules that are processed by ER-associated protein degradation (ERAD) and thus originate from ER-resident proteins. Furthermore, screening genes encoding for E2 ubiquitin conjugating enzymes, we identified UBE2G2 to be involved in proinsulin degradation and subsequent presentation of the PPIB10-18 autoantigen. These insights into the pathway involved in the generation of insulin-derived peptides emphasize the importance of proinsulin processing in the ER to T1D pathogenesis and identify novel targets for future T1D therapies.
Topics: Proinsulin; Autoantigens; Humans; Ubiquitin-Conjugating Enzymes; Endoplasmic Reticulum-Associated Degradation; Proteolysis; Diabetes Mellitus, Type 1; Antigen Presentation; Insulin-Secreting Cells
PubMed: 38787820
DOI: 10.1371/journal.pone.0287877 -
Cells May 2024Chronic obstructive pulmonary disease (COPD) is characterized, at least in part, by autoimmunity through amplified T helper 1 and 17 (Th1 and Th17) immune responses. The...
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is characterized, at least in part, by autoimmunity through amplified T helper 1 and 17 (Th1 and Th17) immune responses. The loss of immune tolerance controlled by programmed death-ligand 1 (PD-L1) may contribute to this.
OBJECTIVES
We studied the tolerogenic role of PD-L1 dendritic cells (DCs) and their subtypes in relation to specific T cell immunity and the clinical phenotypes of COPD.
METHODS
We used flow cytometry to analyze PD-L1 expression by the DCs and their subtypes in the peripheral blood mononuclear cells (PBMCs) from normal participants and those with COPD. T cell proliferation and the signature cytokines of T cell subtypes stimulated with elastin as autoantigens were measured using flow cytometry and enzyme-linked immunosorbent assays (ELISA), respectively.
MEASUREMENT AND MAIN RESULTS
A total of 83 participants were enrolled (normal, = 29; COPD, = 54). A reduced PD-L1 conventional dendritic cell 1 (cDC1) ratio in the PBMCs of the patients with COPD was shown (13.7 ± 13.7%, = 0.03). The decrease in the PD-L1 cDC1 ratio was associated with a rapid decline in COPD ( = 0.02) and correlated with the CD4 T cells ( = -0.33, = 0.02). This is supported by the NCBI GEO database accession number GSE56766, the researchers of which found that the gene expressions of and , but not were negatively correlated from PBMC in COPD patients (r = -0.43, = 0.002). Functionally, the PD-L1 blockade enhanced CD4 T cell proliferation stimulated by CD3/elastin (31.2 ± 22.3%, = 0.04) and interleukin (IL)-17A production stimulated by both CD3 (156.3 ± 54.7, = 0.03) and CD3/elastin (148 ± 64.9, = 0.03) from the normal PBMCs. The PD-L1 blockade failed to increase IL-17A production in the cDC1-depleted PBMCs. By contrast, there was no significant change in interferon (IFN)-γ, IL-4, or IL-10 after the PD-L1 blockade. Again, these findings were supported by the NCBI GEO database accession number GSE56766, the researchers of which found that only the expression of , a master transcription factor driving the Th17 cells, was significantly negatively correlated to PD-L1 (r = -0.33, = 0.02).
CONCLUSIONS
Circulating PD-L1 cDC1 was reduced in the patients with COPD, and the tolerogenic role was suppressed with susceptibility to self-antigens and linked to rapid decline caused by Th17-skewed chronic inflammation.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Dendritic Cells; B7-H1 Antigen; Female; Male; Middle Aged; Immune Tolerance; Aged; Leukocytes, Mononuclear; Cytokines
PubMed: 38786101
DOI: 10.3390/cells13100878