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Developmental Medicine and Child... Mar 2024A neurological deterioration in a child presents a significant worry to the family and often a diagnostic challenge to the clinician. A dysregulated immune response is... (Review)
Review
A neurological deterioration in a child presents a significant worry to the family and often a diagnostic challenge to the clinician. A dysregulated immune response is implicated in a wide and growing spectrum of neurological conditions. In this review we consider the current paradigms in which immune-mediated encephalopathies are considered; the development of paediatric specific diagnostic criteria that facilitate early consideration and treatment of immune-mediated conditions and the limitations and potential developments in diagnostic testing. We consider the expanding phenotype of myelin oligodendrocyte glycoprotein antibody, the spectrum of virus-associated encephalopathy syndromes, and the strategies that have been employed to build an evidence base for the management of these rare conditions. Looking forward we explore the potential for advanced molecular investigations to improve our understanding of immune-mediated encephalitides and guide future treatment strategies. Recently characterized immune-mediated central nervous system disorders include new antibodies causing previously recognized phenotypes. Aggregation of conditions with similar clinical triggers, and characterization of unique imaging features in virus-associated encephalopathy syndromes. Immune treatment iscurrently guided by meta-analysis of individualized patient data and/or multi-national consensus.
Topics: Child; Humans; Autoantibodies; Brain Diseases; Encephalitis; Myelin-Oligodendrocyte Glycoprotein; Nervous System Diseases; Syndrome
PubMed: 37438863
DOI: 10.1111/dmcn.15694 -
International Journal of Biological... 2023The centromere proteins (CENPs), a critical mitosis-related protein complexes, are involved in the kinetochore assembly and chromosome segregation. In this study, we...
The centromere proteins (CENPs), a critical mitosis-related protein complexes, are involved in the kinetochore assembly and chromosome segregation. In this study, we identified that CENPA was significantly up-regulated in HCC and highly expressed CENPA correlated with poor prognosis for HCC patients. Knockdown of CENPA inhibited HCC cell proliferation and tumor growth and . Mechanistically, CENPA transcriptionally activated and cooperated with YY1 to drive the expression of cyclin D1 (CCND1) and neuropilin 2 (NRP2). Moreover, we identified that CENPA can be lactylated at lysine 124 (K124). The lactylation of CENPA at K124 promotes CENPA activation, leading to enhanced expression of its target genes. In summary, CENPA function as a transcriptional regulator to promote HCC via cooperating with YY1. Targeting the CENPA-YY1-CCND1/NRP2 axis may provide candidate therapeutic targets for HCC.
Topics: Humans; Carcinoma, Hepatocellular; Cell Cycle Proteins; Cell Line, Tumor; Histones; Liver Neoplasms; YY1 Transcription Factor; Centromere Protein A
PubMed: 37928273
DOI: 10.7150/ijbs.85656 -
The Journal of Clinical Investigation Dec 2023BACKGROUNDPemphigus, a rare autoimmune bullous disease mediated by antidesmoglein autoantibodies, can be controlled with systemic medication like rituximab and high-dose... (Clinical Trial)
Clinical Trial
BACKGROUNDPemphigus, a rare autoimmune bullous disease mediated by antidesmoglein autoantibodies, can be controlled with systemic medication like rituximab and high-dose systemic corticosteroids combined with immunosuppressants. However, some patients continue to experience chronically recurrent blisters in a specific area and require long-term maintenance systemic therapy.METHODSSkin with chronic blisters was obtained from patients with pemphigus. Immunologic properties of the skin were analyzed by immunofluorescence staining, bulk and single-cell RNA and TCR sequencing, and a highly multiplex imaging technique known as CO-Detection by indEXing (CODEX). Functional analyses were performed by flow cytometry and bulk RNA-Seq using peripheral blood from healthy donors. Intralesional corticosteroid was injected into patient skin, and changes in chronically recurrent blisters were observed.RESULTSWe demonstrated the presence of skin tertiary lymphoid structures (TLSs) with desmoglein-specific B cells in chronic blisters from patients with pemphigus. In the skin TLSs, CD4+ T cells predominantly produced CXCL13. These clonally expanded CXCL13+CD4+ T cells exhibited features of activated Th1-like cells and downregulated genes associated with T cell receptor-mediated signaling. Tregs are in direct contact with CXCL13+CD4+ memory T cells and increased CXCL13 production of CD4+ T cells through IL-2 consumption and TGF-β stimulation. Finally, intralesional corticosteroid injection improved chronic blisters and reduced skin TLSs in patients with pemphigus.CONCLUSIONThrough this study we conclude that skin TLSs are associated with the persistence of chronically recurrent blisters in patients with pemphigus, and the microenvironmental network involving CXCL13+CD4+ T cells and Tregs within these structures plays an important role in CXCL13 production.TRIAL REGISTRATIONClinicalTrials.gov NCT04509570.FUNDINGThis work was supported by National Research Foundation of South Korea (NRF-2021R1C1C1007179) and Korea Drug Development Fund, which is funded by Ministry of Science and ICT; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare (grant RS-2022-00165917).
Topics: Humans; Adrenal Cortex Hormones; Autoantibodies; Autoimmune Diseases; Blister; CD4-Positive T-Lymphocytes; Chemokine CXCL13; Desmoglein 3; Pemphigus
PubMed: 37815865
DOI: 10.1172/JCI166357 -
Biomolecules Dec 2023Centromeres play essential roles in the faithful segregation of chromosomes. CENP-A, the centromere-specific histone H3 variant, and heterochromatin characterized by di-... (Review)
Review
Centromeres play essential roles in the faithful segregation of chromosomes. CENP-A, the centromere-specific histone H3 variant, and heterochromatin characterized by di- or tri-methylation of histone H3 9th lysine (H3K9) are the hallmarks of centromere chromatin. Contrary to the epigenetic marks, DNA sequences underlying the centromere region of chromosomes are not well conserved through evolution. However, centromeres consist of repetitive sequences in many eukaryotes, including animals, plants, and a subset of fungi, including fission yeast. Advances in long-read sequencing techniques have uncovered the complete sequence of human centromeres containing more than thousands of alpha satellite repeats and other types of repetitive sequences. Not only tandem but also inverted repeats are present at a centromere. DNA recombination between centromere repeats can result in gross chromosomal rearrangement (GCR), such as translocation and isochromosome formation. CENP-A chromatin and heterochromatin suppress the centromeric GCR. The key player of homologous recombination, Rad51, safeguards centromere integrity through conservative noncrossover recombination between centromere repeats. In contrast to Rad51-dependent recombination, Rad52-mediated single-strand annealing (SSA) and microhomology-mediated end-joining (MMEJ) lead to centromeric GCR. This review summarizes recent findings on the role of centromere and recombination proteins in maintaining centromere integrity and discusses how GCR occurs at centromeres.
Topics: Animals; Humans; Histones; Centromere Protein A; Heterochromatin; Centromere; Chromosome Aberrations; Chromatin
PubMed: 38254628
DOI: 10.3390/biom14010028 -
Seminars in Ophthalmology Aug 2023Despite the high incidence of optic neuritis (ON), and the growing number of therapeutic options for the long-term treatment of diseases associated with ON including... (Review)
Review
Despite the high incidence of optic neuritis (ON), and the growing number of therapeutic options for the long-term treatment of diseases associated with ON including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD) and MOG antibody associated disease (MOGAD), there are still only limited therapeutic options for treating an acute event of optic neuritis. These include steroids, plasma exchange (PLEX) and intravenous immunoglobulin (IVIG). High-dose steroids remain the mainstay of acute treatment. However, evidence is emerging that when optic neuritis is accompanied with certain atypical features that suggest a more unfavorable outcome this mandates special consideration such as early addition of other therapeutic agents or tapering the steroid very slowly. This review will distinguish between typical and atypical neuritis and discuss acute treatment options.
Topics: Humans; Myelin-Oligodendrocyte Glycoprotein; Optic Neuritis; Neuromyelitis Optica; Multiple Sclerosis; Autoantibodies
PubMed: 37162276
DOI: 10.1080/08820538.2023.2211662 -
Journal of Neurology, Neurosurgery, and... Dec 2023Limited data exist on brain MRI enhancement in myelin-oligodendrocyte-glycoprotein (MOG) antibody-associated disease (MOGAD) and differences from... (Observational Study)
Observational Study
INTRODUCTION
Limited data exist on brain MRI enhancement in myelin-oligodendrocyte-glycoprotein (MOG) antibody-associated disease (MOGAD) and differences from aquaporin-4-IgG-positive-neuromyelitis-optica-spectrum-disorder (AQP4+NMOSD), and multiple sclerosis (MS).
METHODS
In this retrospective observational study, we identified 122 Mayo Clinic MOGAD patients (1 January 1996-1 July 2020) with cerebral attacks. We explored enhancement patterns using a discovery set (n=41). We assessed enhancement frequency and Expanded Disability Status Scale scores at nadir and follow-up in the remainder (n=81). Two raters assessed T1-weighted-postgadolinium MRIs (1.5T/3T) for enhancement patterns in MOGAD, AQP4+NMOSD (n=14) and MS (n=26). Inter-rater agreement was assessed. Leptomeningeal enhancement clinical correlates were analysed.
RESULTS
Enhancement occurred in 59/81 (73%) MOGAD cerebral attacks but did not influence outcome. Enhancement was often patchy/heterogeneous in MOGAD (33/59 (56%)), AQP4+NMOSD (9/14 (64%); p=0.57) and MS (16/26 (62%); p=0.63). Leptomeningeal enhancement favoured MOGAD (27/59 (46%)) over AQP4+NMOSD (1/14 (7%); p=0.01) and MS (1/26 (4%); p<0.001) with headache, fever and seizures frequent clinical correlates. Ring enhancement favoured MS (8/26 (31%); p=0.006) over MOGAD (4/59 (7%)). Linear ependymal enhancement was unique to AQP4+NMOSD (2/14 (14%)) and persistent enhancement (>3 months) was rare (0%-8%) across all groups. Inter-rater agreement for enhancement patterns was moderate.
CONCLUSIONS
Enhancement is common with MOGAD cerebral attacks and often has a non-specific patchy appearance and rarely persists beyond 3 months. Leptomeningeal enhancement favours MOGAD over AQP4+NMOSD and MS.
Topics: Humans; Ambulatory Care Facilities; Aquaporin 4; Headache; Multiple Sclerosis; Neuroimaging; Neuromyelitis Optica; Myelin-Oligodendrocyte Glycoprotein
PubMed: 37221051
DOI: 10.1136/jnnp-2023-331137 -
The Journal of Experimental Medicine Nov 2023B cells undergo several rounds of selection to eliminate potentially pathogenic autoreactive clones, but in contrast to T cells, evidence of positive selection of...
B cells undergo several rounds of selection to eliminate potentially pathogenic autoreactive clones, but in contrast to T cells, evidence of positive selection of autoreactive B cells remains moot. Using unique tetramers, we traced natural autoreactive B cells (C1-B) specific for a defined triple-helical epitope on collagen type-II (COL2), constituting a sizeable fraction of the physiological B cell repertoire in mice, rats, and humans. Adoptive transfer of C1-B suppressed arthritis independently of IL10, separating them from IL10-secreting regulatory B cells. Single-cell sequencing revealed an antigen processing and presentation signature, including induced expression of CD72 and CCR7 as surface markers. C1-B presented COL2 to T cells and induced the expansion of regulatory T cells in a contact-dependent manner. CD72 blockade impeded this effect suggesting a new downstream suppressor mechanism that regulates antigen-specific T cell tolerization. Thus, our results indicate that autoreactive antigen-specific naïve B cells tolerize infiltrating T cells against self-antigens to impede the development of tissue-specific autoimmune inflammation.
Topics: Humans; Mice; Rats; Animals; T-Lymphocytes, Regulatory; Interleukin-10; Arthritis; Autoantigens; Autoimmune Diseases
PubMed: 37695523
DOI: 10.1084/jem.20230101 -
Annals of the Rheumatic Diseases Sep 2023Identify autoantibodies in anti-Ro/SS-A negative primary Sjögren's syndrome (SS).
OBJECTIVE
Identify autoantibodies in anti-Ro/SS-A negative primary Sjögren's syndrome (SS).
METHODS
This is a proof-of-concept, case-control study of SS, healthy (HC) and other disease (OD) controls. A discovery dataset of plasma samples (n=30 SS, n=15 HC) was tested on human proteome arrays containing 19 500 proteins. A validation dataset of plasma and stimulated parotid saliva from additional SS cases (n=46 anti-Ro, n=50 anti-Ro), HC (n=42) and OD (n=54) was tested on custom arrays containing 74 proteins. For each protein, the mean+3 SD of the HC value defined the positivity threshold. Differences from HC were determined by Fisher's exact test and random forest machine learning using 2/3 of the validation dataset for training and 1/3 for testing. Applicability of the results was explored in an independent rheumatology practice cohort (n=38 Ro, n=36 Ro, n=10 HC). Relationships among antigens were explored using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) interactome analysis.
RESULTS
Ro SS parotid saliva contained autoantibodies binding to Ro60, Ro52, La/SS-B and muscarinic receptor 5. SS plasma contained 12 novel autoantibody specificities, 11 of which were detected in both the discovery and validation datasets. Binding to ≥1 of the novel antigens identified 54% of Ro SS and 37% of Ro SS cases, with 100% specificity in both groups. Machine learning identified 30 novel specificities showing receiver operating characteristic area under the curve of 0.79 (95% CI 0.64 to 0.93) for identifying Ro SS. Sera from Ro cases of an independent cohort bound 17 of the non-canonical antigens. Antigenic targets in both Ro and Ro SS were part of leukaemia cell, ubiquitin conjugation and antiviral defence pathways.
CONCLUSION
We identified antigenic targets of the autoantibody response in SS that may be useful for identifying up to half of Ro seronegative SS cases.
Topics: Humans; Autoantibodies; Sjogren's Syndrome; Case-Control Studies; Autoantigens; ROC Curve; Immunoglobulin G; Antibodies, Antinuclear
PubMed: 37147113
DOI: 10.1136/ard-2022-223105 -
Nucleic Acids Research Mar 2024Albeit N1-Methyladenosine (m1A) RNA modification represents an important regulator of RNA metabolism, the role of m1A modification in carcinogenesis remains enigmatic....
Albeit N1-Methyladenosine (m1A) RNA modification represents an important regulator of RNA metabolism, the role of m1A modification in carcinogenesis remains enigmatic. Herein, we found that histone lactylation enhances ALKBH3 expression and simultaneously attenuates the formation of tumor-suppressive promyelocytic leukemia protein (PML) condensates by removing the m1A methylation of SP100A, promoting the malignant transformation of cancers. First, ALKBH3 is specifically upregulated in high-risk ocular melanoma due to excessive histone lactylation levels, referring to m1A hypomethylation status. Moreover, the multiomics analysis subsequently identified that SP100A, a core component for PML bodies, serves as a downstream candidate target for ALKBH3. Therapeutically, the silencing of ALKBH3 exhibits efficient therapeutic efficacy in melanoma both in vitro and in vivo, which could be reversed by the depletion of SP100A. Mechanistically, we found that YTHDF1 is responsible for recognition of the m1A methylated SP100A transcript, which increases its RNA stability and translational efficacy. Conclusively, we initially demonstrated that m1A modification is necessary for tumor suppressor gene expression, expanding the current understandings of dynamic m1A function during tumor progression. In addition, our results indicate that lactylation-driven ALKBH3 is essential for the formation of PML nuclear condensates, which bridges our knowledge of m1A modification, metabolic reprogramming, and phase-separation events.
Topics: Humans; AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; Demethylation; DNA Methylation; Histones; Melanoma; Promyelocytic Leukemia Protein; RNA; Transcription Factors; Antigens, Nuclear; Autoantigens; Eye Neoplasms
PubMed: 38118002
DOI: 10.1093/nar/gkad1193 -
Science Advances Nov 2023Mammalian centromeres direct faithful genetic inheritance and are typically characterized by regions of highly repetitive and rapidly evolving DNA. We focused on a mouse...
Mammalian centromeres direct faithful genetic inheritance and are typically characterized by regions of highly repetitive and rapidly evolving DNA. We focused on a mouse species, that we found has evolved to house centromere-specifying centromere protein-A (CENP-A) nucleosomes at the nexus of a satellite repeat that we identified and termed π-satellite (π-sat), a small number of recruitment sites for CENP-B, and short stretches of perfect telomere repeats. One chromosome, however, houses a radically divergent centromere harboring ~6 mega-base pairs of a homogenized π-sat-related repeat, π-sat, that contains >20,000 functional CENP-B boxes. There, CENP-B abundance promotes accumulation of microtubule-binding components of the kinetochore and a microtubule-destabilizing kinesin of the inner centromere. We propose that the balance of pro- and anti-microtubule binding by the new centromere is what permits it to segregate during cell division with high fidelity alongside the older ones whose sequence creates a markedly different molecular composition.
Topics: Mice; Animals; Chromosomal Proteins, Non-Histone; Autoantigens; Centromere; Centromere Protein A; Nucleosomes; Mammals
PubMed: 37967185
DOI: 10.1126/sciadv.adi5764