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Journal of Clinical Immunology Apr 2024Autoimmunity is a significant feature of APDS1 patients. We aimed to explore the pathogenic immune phenotype and possible mechanisms of autoimmunity in APDS1 patients.
PURPOSE
Autoimmunity is a significant feature of APDS1 patients. We aimed to explore the pathogenic immune phenotype and possible mechanisms of autoimmunity in APDS1 patients.
METHODS
The clinical records and laboratory data of 42 APDS1 patients were reviewed. Immunophenotypes were evaluated by multiparametric flow cytometry. Autoantibodies were detected via antigen microarray analysis.
RESULTS
A total of 42 children with PIK3CD gene mutations were enrolled. Immunological tests revealed increased proportions of effector memory cells (86%) and central memory cells (59%) among CD4+ T cells; increased proportions of effector memory cells (83%) and terminally differentiated effector memory T cells (38%) among CD8+ T cells. Fewer CD3+ T cells and B cells and higher IgG levels were reported in patients with autoimmunity. The proportion of Tregs was decreased, and the proportions of Th9, Tfh, and Tfr cells were increased in APDS1 patients. Among APDS1 patients, higher proportion of Th2 and Tfr cells were found in those with autoimmunity. The proportions of CD11c+ B and CD21lo B cells in patients with autoimmunity were significantly increased. Antigen microarray analysis revealed a wide range of IgG/IgM autoantibodies in patients with APDS1. In patients with autoimmunity, the proportion of Tfr might be positively correlated with autoantibodies.
CONCLUSIONS
The pathogenic immune phenotype of APDS1 patients included (1) deceased CD3+ T-cell and B-cell counts and increased IgG levels in patients with autoimmunity, (2) an imbalanced T helper cell subset, (3) increased proportions of autoreactive B cells, and (4) distinct autoantibody reactivities in patients with autoimmunity.
Topics: Child; Humans; Autoimmunity; Autoantibodies; B-Lymphocytes; Phenotype; Syndrome; Immunoglobulin G
PubMed: 38634985
DOI: 10.1007/s10875-024-01705-w -
Neurology(R) Neuroimmunology &... Jul 2024Acute disseminated encephalomyelitis (ADEM) is one characteristic manifestation of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). A previously...
Acute disseminated encephalomyelitis (ADEM) is one characteristic manifestation of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). A previously healthy man presented with retro-orbital headache and urinary retention 14 days after Tdap vaccination. Brain and spine MRI suggested a CNS demyelinating process. Despite treatment with IV steroids, he deteriorated, manifesting hemiparesis and later impaired consciousness, requiring intubation. A repeat brain MRI demonstrated new bilateral supratentorial lesions associated with venous sinus thrombosis, hemorrhage, and midline shift. Anti-MOG antibody was present at a high titer. CSF IL-6 protein was >2,000 times above the upper limits of normal. He improved after plasma exchange, then began monthly treatment alone with anti-IL-6 receptor antibody, tocilizumab, and has remained stable. This case highlights how adult-onset MOGAD, like childhood ADEM, can rapidly become life-threatening. The markedly elevated CSF IL-6 observed here supports consideration for evaluating CSF cytokines more broadly in patients with acute MOGAD.
Topics: Male; Adult; Humans; Child; Encephalomyelitis, Acute Disseminated; Interleukin-6; Myelin-Oligodendrocyte Glycoprotein; Brain; Cytokines
PubMed: 38630950
DOI: 10.1212/NXI.0000000000200243 -
Journal of Neuroimmunology May 2024Since the 1980s it is known that immune responses to the Epstein-Barr virus (EBV) are elevated in multiple sclerosis (MS) patients. Recent seroepidemiologial data have... (Review)
Review
Since the 1980s it is known that immune responses to the Epstein-Barr virus (EBV) are elevated in multiple sclerosis (MS) patients. Recent seroepidemiologial data have shown that this alteration after primary EBV infection identifies individuals with a more than 30-fold increased risk to develop MS. The mechanisms by which EBV infection might erode tolerance for the central nervous system (CNS) in these individuals, years prior to clinical MS onset, remain unclear. In this review I will discuss altered frequencies of EBV life cycle stages and their tissue distribution, EBV with CNS autoantigen cross-reactive immune responses and loss of immune control for autoreactive B and T cells as possible mechanisms. This discussion is intended to stimulate future studies into these mechanisms with the aim to identify candidates for interventions that might correct EBV specific immune control and/or resulting cross-reactivities with CNS autoantigens in MS patients and thereby ameliorate disease activity.
Topics: Humans; Multiple Sclerosis; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Animals; Autoantigens
PubMed: 38615370
DOI: 10.1016/j.jneuroim.2024.578343 -
International Journal of Molecular... Mar 2024Chronic primary systemic vasculitis (PSV) comprises a group of heterogeneous diseases that are broadly classified by affected blood vessel size, clinical traits and the...
Chronic primary systemic vasculitis (PSV) comprises a group of heterogeneous diseases that are broadly classified by affected blood vessel size, clinical traits and the presence (or absence) of anti-neutrophil cytoplasmic antibodies (ANCA) against proteinase 3 (PR3) and myeloperoxidase (MPO). In small vessel vasculitis (SVV), ANCA are not present in all patients, and they are rarely detected in patients with vasculitis involving medium (MVV) and large (LVV) blood vessels. Some studies have demonstrated that lysosome-associated membrane protein-2 (LAMP-2/CD107b) is a target of ANCA in SVV, but its presence and prognostic value in childhood MVV and LVV is not known. This study utilized retrospective sera and clinical data obtained from 90 children and adolescents with chronic PSV affecting small (SVV, n = 53), medium (MVV, n = 16), and large (LVV, n = 21) blood vessels. LAMP-2-ANCA were measured in time-of-diagnosis sera using a custom electrochemiluminescence assay. The threshold for seropositivity was established in a comparator cohort of patients with systemic autoinflammatory disease. The proportion of LAMP-2-ANCA-seropositive individuals and sera concentrations of LAMP-2-ANCA were assessed for associations with overall and organ-specific disease activity at diagnosis and one-year follow up. This study demonstrated a greater time-of-diagnosis prevalence and sera concentration of LAMP-2-ANCA in MVV (52.9% seropositive) and LVV (76.2%) compared to SVV (45.3%). Further, LAMP-2-ANCA-seropositive individuals had significantly lower overall, but not organ-specific, disease activity at diagnosis. This did not, however, result in a greater reduction in disease activity or the likelihood of achieving inactive disease one-year after diagnosis. The results of this study demonstrate particularly high prevalence and concentration of LAMP-2-ANCA in chronic PSV that affects large blood vessels and is seronegative for traditional ANCA. Our findings invite reconsideration of roles for autoantigens other than MPO and PR3 in pediatric vasculitis, particularly in medium- and large-sized blood vessels.
Topics: Adolescent; Child; Humans; Antibodies, Antineutrophil Cytoplasmic; Autoantigens; Myeloblastin; Retrospective Studies; Systemic Vasculitis
PubMed: 38612581
DOI: 10.3390/ijms25073771 -
Frontiers in Immunology 2024We have previously argued that the antigen receptors of T and B lymphocytes evolved to be sufficiently specific to avoid massive deletion of clonotypes by negative...
We have previously argued that the antigen receptors of T and B lymphocytes evolved to be sufficiently specific to avoid massive deletion of clonotypes by negative selection. Their optimal 'specificity' level, i.e., probability of binding any particular epitope, was shown to be inversely related to the number of self-antigens that the cells have to be tolerant to. Experiments have demonstrated that T lymphocytes also more specific during negative selection in the thymus, because cells expressing the most crossreactive receptors have the highest likelihood of binding a self-antigen, and hence to be tolerized (i.e., deleted, anergized, or diverted into a regulatory T cell phenotype). Thus, there are two -not mutually exclusive- explanations for the exquisite specificity of T cells, one involving evolution and the other thymic selection. To better understand the impact of both, we extend a previously developed mathematical model by allowing for T cells with very different binding probabilities in the pre-selection repertoire. We confirm that negative selection tends to tolerize the most crossreactive clonotypes. As a result, the average level of specificity in the functional repertoire depends on the number of self-antigens, even if there is no evolutionary optimization of binding probabilities. However, the evolutionary optimal range of binding probabilities in the repertoire also depends on the number of self-antigens. Species with more self antigens need more specific pre-selection repertoires to avoid excessive loss of T cells during thymic selection, and hence mount protective immune responses. We conclude that both evolution and negative selection are responsible for the high level of specificity of lymphocytes.
Topics: Thymus Gland; T-Lymphocytes, Regulatory; Autoantigens; B-Lymphocytes; Epitopes
PubMed: 38605941
DOI: 10.3389/fimmu.2024.1266349 -
CNS Neuroscience & Therapeutics Apr 2024Although radiotherapy is a core treatment modality for various human cancers, including glioblastoma multiforme (GBM), its clinical effects are often limited by...
AIMS
Although radiotherapy is a core treatment modality for various human cancers, including glioblastoma multiforme (GBM), its clinical effects are often limited by radioresistance. The specific molecular mechanisms underlying radioresistance are largely unknown, and the reduction of radioresistance is an unresolved challenge in GBM research.
METHODS
We analyzed and verified the expression of nuclear autoantigenic sperm protein (NASP) in gliomas and its relationship with patient prognosis. We also explored the function of NASP in GBM cell lines. We performed further mechanistic experiments to investigate the mechanisms by which NASP facilitates GBM progression and radioresistance. An intracranial mouse model was used to verify the effectiveness of combination therapy.
RESULTS
NASP was highly expressed in gliomas, and its expression was negatively correlated with the prognosis of glioma. Functionally, NASP facilitated GBM cell proliferation, migration, invasion, and radioresistance. Mechanistically, NASP interacted directly with annexin A2 (ANXA2) and promoted its nuclear localization, which may have been mediated by phospho-annexin A2 (Tyr23). The NASP/ANXA2 axis was involved in DNA damage repair after radiotherapy, which explains the radioresistance of GBM cells that highly express NASP. NASP overexpression significantly activated the signal transducer and activator of transcription 3 (STAT3) signaling pathway. The combination of WP1066 (a STAT3 pathway inhibitor) and radiotherapy significantly inhibited GBM growth in vitro and in vivo.
CONCLUSION
Our findings indicate that NASP may serve as a potential biomarker of GBM radioresistance and has important implications for improving clinical radiotherapy.
Topics: Animals; Humans; Mice; Annexin A2; Brain Neoplasms; Cell Proliferation; Glioblastoma; STAT3 Transcription Factor; Cell Line, Tumor
PubMed: 38605477
DOI: 10.1111/cns.14709 -
The EMBO Journal Jun 2024The centromeric histone H3 variant CENP-A is overexpressed in many cancers. The mislocalization of CENP-A to noncentromeric regions contributes to chromosomal...
The centromeric histone H3 variant CENP-A is overexpressed in many cancers. The mislocalization of CENP-A to noncentromeric regions contributes to chromosomal instability (CIN), a hallmark of cancer. However, pathways that promote or prevent CENP-A mislocalization remain poorly defined. Here, we performed a genome-wide RNAi screen for regulators of CENP-A localization which identified DNAJC9, a J-domain protein implicated in histone H3-H4 protein folding, as a factor restricting CENP-A mislocalization. Cells lacking DNAJC9 exhibit mislocalization of CENP-A throughout the genome, and CIN phenotypes. Global interactome analysis showed that DNAJC9 depletion promotes the interaction of CENP-A with the DNA-replication-associated histone chaperone MCM2. CENP-A mislocalization upon DNAJC9 depletion was dependent on MCM2, defining MCM2 as a driver of CENP-A deposition at ectopic sites when H3-H4 supply chains are disrupted. Cells depleted for histone H3.3, also exhibit CENP-A mislocalization. In summary, we have defined novel factors that prevent mislocalization of CENP-A, and demonstrated that the integrity of H3-H4 supply chains regulated by histone chaperones such as DNAJC9 restrict CENP-A mislocalization and CIN.
Topics: Humans; Centromere Protein A; Chromosomal Instability; Histones; Minichromosome Maintenance Complex Component 2; HeLa Cells; HSP40 Heat-Shock Proteins; Chromosomal Proteins, Non-Histone; Centromere
PubMed: 38600242
DOI: 10.1038/s44318-024-00093-6 -
Nature Communications Apr 2024The presence of autoantibodies is a defining feature of many autoimmune diseases. The number of unique autoantibody clones is conceivably limited by immune tolerance...
The presence of autoantibodies is a defining feature of many autoimmune diseases. The number of unique autoantibody clones is conceivably limited by immune tolerance mechanisms, but unknown due to limitations of the currently applied technologies. Here, we introduce an autoantigen-specific liquid chromatography-mass spectrometry-based IgG1 Fab profiling approach using the anti-citrullinated protein antibody (ACPA) repertoire in rheumatoid arthritis (RA) as an example. We show that each patient harbors a unique and diverse ACPA IgG1 repertoire dominated by only a few antibody clones. In contrast to the total plasma IgG1 antibody repertoire, the ACPA IgG1 sub-repertoire is characterised by an expansion of antibodies that harbor one, two or even more Fab glycans, and different glycovariants of the same clone can be detected. Together, our data indicate that the autoantibody response in a prominent human autoimmune disease is complex, unique to each patient and dominated by a relatively low number of clones.
Topics: Humans; Autoantibodies; Arthritis, Rheumatoid; Anti-Citrullinated Protein Antibodies; Immunoglobulin G; Autoantigens
PubMed: 38600082
DOI: 10.1038/s41467-024-47337-x -
Frontiers in Immunology 2024The autoimmune response in type 1 diabetes (T1D), in which the beta cells expressing aberrant or modified proteins are killed, resembles an effective antitumor response....
INTRODUCTION
The autoimmune response in type 1 diabetes (T1D), in which the beta cells expressing aberrant or modified proteins are killed, resembles an effective antitumor response. Defective ribosomal protein products in tumors are targets of the anti-tumor immune response that is unleashed by immune checkpoint inhibitor (ICI) treatment in cancer patients. We recently described a defective ribosomal product of the insulin gene (INS-DRiP) that is expressed in stressed beta cells and targeted by diabetogenic T cells. T1D patient-derived INS-DRiP specific T cells can kill beta cells and are present in the insulitic lesion. T cells reactive to INS-DRiP epitopes are part of the normal T cell repertoire and are believed to be kept in check by immune regulation without causing autoimmunity.
METHOD
T cell autoreactivity was tested using a combinatorial HLA multimer technology measuring a range of epitopes of islet autoantigens and neoantigen INS-DRiP. INS-DRiP expression in human pancreas and insulinoma sections was tested by immunohistochemistry.
RESULTS
Here we report the induction of islet autoimmunity to INS-DRiP and diabetes after ICI treatment and successful tumor remission. Following ICI treatment, T cells of the cancer patient were primed against INS-DRiP among other diabetogenic antigens, while there was no sign of autoimmunity to this neoantigen before ICI treatment. Next, we demonstrated the expression of INS-DRiP as neoantigen in both pancreatic islets and insulinoma by staining with a monoclonal antibody to INS-DRiP.
DISCUSSION
These results bridge cancer and T1D as two sides of the same coin and point to neoantigen expression in normal islets and insulinoma that may serve as target of both islet autoimmunity and tumor-related autoimmunity.
Topics: Humans; Diabetes Mellitus, Type 1; Autoimmunity; Insulinoma; Autoantigens; Insulin; Epitopes; Immunotherapy; Pancreatic Neoplasms
PubMed: 38596681
DOI: 10.3389/fimmu.2024.1384406 -
Cell Communication and Signaling : CCS Apr 2024Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the...
Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the mechanisms underlying the initiation of the TLR7/8-mediated autoimmune signaling remain to be fully elucidated. Here, we demonstrate that miR-574-5p is aberrantly upregulated in tissues of lupus prone mice and in the plasma of lupus patients, with its expression levels correlating with the disease activity. miR-574-5p binds to and activates human hTLR8 or its murine ortholog mTlr7 to elicit a series of MyD88-dependent immune and inflammatory responses. These responses include the overproduction of cytokines and interferons, the activation of STAT1 signaling and B lymphocytes, and the production of autoantigens. In a transgenic mouse model, the induction of miR-574-5p overexpression is associated with increased secretion of antinuclear and anti-dsDNA antibodies, increased IgG and C3 deposit in the kidney, elevated expression of inflammatory genes in the spleen. In lupus-prone mice, lentivirus-mediated silencing of miR-574-5p significantly ameliorates major symptoms associated with lupus and lupus nephritis. Collectively, these results suggest that the miR-574-5p-hTLR8/mTlr7 signaling is an important axis of immune and inflammatory responses, contributing significantly to the development of lupus and lupus nephritis.
Topics: Humans; Mice; Animals; Lupus Nephritis; Toll-Like Receptor 7; Toll-Like Receptor 8; Kidney; Mice, Transgenic; MicroRNAs
PubMed: 38589923
DOI: 10.1186/s12964-024-01601-1