Immunoglobulins G from Patients with Systemic Sclerosis Modify the Molecular Signatures of Endothelial CellsChepy, Vivier, Bray
et alRMD Open (2025) 11 (1)
Abstract: Antinuclear antibodies (ANA) are powerful biomarkers in systemic sclerosis (SSc). Functional antibodies (FA) might be implicated in vasculopathy, in which endothelial cells (EC) are key players. We aimed to explore the effect of purified IgG from patients with SSc on omics signatures of EC and examine the influence of ANA serotypes and FA.EC were cultured in the presence of purified IgG from patients with SSc, patients with systemic lupus erythematosus (SLE) or healthy controls (HC). EC omics profiles were analysed by liquid chromatography with tandem mass spectrometry (LC-MS/MS) and RNA sequencing. EC proteome induced by IgG from patients with SSc was confirmed with an external validation cohort.In the derivation cohort, principal component analysis (PCA) using proteomics data showed three distinct groups of subjects: a first one including mostly anti-topoisomerase-I positive patients (ATA+), a second one including mostly anti-centromere positive patients and a third group comprising anti-RNA polymerase-III positive patients, SLE and HC. In transcriptomics, PCA distinguished one group composed of ATA+patients only from a second group mixing ATA+patients with other individuals. The validation cohort confirmed the existence of two groups of distinct EC proteome profiles and clinical severity in ATA+patients. In both SSc cohorts, no association between FA presence and proteomic profiles was observed. Quantitative proteomics measured the most discriminant proteins in EC exposed to purified IgG.Purified IgG from patients with SSc can modify EC proteome and transcriptome. The observed changes closely associate with ANA serotype.© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.
Hamster and mouse CD25+CD4+ T cell responses to the C-terminal of leptospiral Ig-like protein ADuangsri, Potisap, Techawiwattanaboon
et alVet Immunol Immunopathol (2025) 283, 110920
Abstract: Leptospirosis is a major public health problem in humans and animals worldwide. The variable carboxy-terminal domain 7-13 of LigA (LigAc) is currently the most promising immunogen for the leptospirosis subunit vaccine. Its protective evidence was investigated in susceptible hamsters whose immunity was mostly based on the knowledge of resistant mice. The difference in immunity of these two animals might be an obstacle to successful vaccine development. The protective immunity induced by LigAc was reported to be specific antibodies while T-cell-mediated immunity has never been investigated. We reported for the first time that hamsters and mice gave dissimilar T-cell responses. Mice and hamsters were divided into 3 groups: an adjuvant plus recombinant LigAc (rLigAc) immunized, an adjuvant-injected, and a negative control group. Immunizations were done three times at 2-week intervals. The rLigAc-specific IgG antibody titers in rLigAc immunized mice and hamsters were significantly higher than in the control groups but no significant difference between the animals. The percentages of hamster CD4+ T cells were significantly higher than those of mice. Mouse CD25+CD4+ T cells responded to rLigAc significantly higher than hamsters. Interestingly, the rLigAc significantly reduced the percentage of IFN-γ+CD4+ cells in mice (≅30 %) and more decrease (≅70 %) was found in hamsters. Remarkably, it also reduced considerably hamster IL-4+CD4+ T cells (≅80 %) but an extremely low decrease in mice (≅20 %). Our result indicated that mice and hamsters gave different responses to leptospiral antigens which might be the possible key that plays a role in the outcome of disease.Copyright © 2025 Elsevier B.V. All rights reserved.
Microbial Ecosystem Therapeutics 4 (MET4) elicits treatment-specific IgG responses associated with changes in gut microbiota in immune checkpoint inhibitor recipients with advanced solid tumorsWong, Boukhaled, Armstrong
et alJ Immunother Cancer (2025) 13 (3)
Abstract: Gut microbiome modulation has shown promise in its potential to treat cancer in combination with immunotherapy. Mechanistically, the pathways and routes by which gut microbiota may influence systemic and antitumor immunity remain uncertain. Here, we used blood and stool samples from Microbial Ecosystem Therapeutic 4 (MET4)-IO, an early-phase trial testing the safety and engraftment of the MET4 bacterial consortium in immune checkpoint inhibitor recipients, to assess how MET4 may affect systemic immunity.Circulating antibody responses induced by MET4 were assessed using an antimicrobial antibody flow cytometry assay on pretreatment and post-treatment plasma. Antibody responses were associated with taxonomic changes in stool identified by metagenomic sequencing. Mass cytometry was performed on peripheral blood mononuclear cells to identify shifts in circulating immune subsets associated with antibody responses.Increases in circulating anti-MET4 immunoglobulin G (IgG) responses were measured by flow cytometry post-consortium treatment in MET4 recipients, but not untreated control participants, with five individuals displaying notably higher antibody responses. Stronger IgG responses were associated with greater increases in multiple taxa, including MET4 microbe Collinsella aerofaciens, which was previously linked with immune checkpoint response. However, these taxa were not enriched in the IgG-bound fraction post-MET4 treatment. Greater increases in circulating B cells and FoxP3+ CD4+ T cells post-MET4 treatment were observed in the blood of high IgG responders, while CD14+ and CD16+ monocyte populations were decreased in these individuals.These results demonstrate the induction of treatment-specific circulating humoral immunity by a bacterial consortium and suggest potential mechanisms by which gut microbes may contribute to antitumor immunity.© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.
Epitomic Profiling and Functional Characteristics of Pemphigus Vulgaris Autoantibody Binding to Keratinocyte M3 Muscarinic Acetylcholine ReceptorReyes-Ruiz, Chernyavsky, Grando
et alJ Biol Chem (2025)
Abstract: Patients with pemphigus vulgaris (PV) develop IgG autoantibodies (AuAbs) binding to keratinocyte desmogleins (Dsg), acetylcholine (ACh) receptors, mitochondrial proteins, and some other self-antigens. In this study, we identified linear and discontinuous peptide tetrameric epitope segments (ES) of M3 muscarinic ACh receptor (M3AR) targeted by different anti-M3AR AuAbs. As positive controls, we identified Dsg1 and Dsg3 ES targeted by PV sera. Healthy individuals also possessed natural antibodies targeting M3AR, Dsg1 and Dsg3 epitopes that were different from those targeted by AuAbs produced by PV patients. The two targeted M3AR pentameric ES encompass the 10 amino acids-long epitope LSEPTITFGT included the tetramer TFGT containing Thr235 which is a part of the ACh-binding pocket. Previously, it has been demonstrated that the anti-M3AR AuAb produces an agonist-like effect on downstream signaling, but its long-term effect is receptor desensitization. In this study, we compared the functional consequences of binding anti-M3AR AuAbs that target the ACh-binding pocket with that of AuAbs that target M3AR outside of its ACh-binding pocket. While the former AuAbs induced a very high elevation of phospholipase C, inositol triphosphate and diacylglycerol, which represents an agonist-like effect, the latter AuAbs produced a much weaker signaling response. These results indicate that PV patients develop two types of anti-M3AR AuAbs. One type attaches to orthosteric, ie, ACh-binding, site and elicits a strong signaling response comparable to that induced by a full pharmacologic agonist, whereas another type binds to an allosteric site and elicits submaximal signaling response comparable to that induced by a partial (allosteric) agonist.Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
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