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PubMed2026

A plasmid-associated immunoglobulin-binding protein in Acinetobacter baumannii.

BACKGROUND: Acinetobacter baumannii is a critical global health threat due to multidrug resistance and high mortality. Although antimicrobial resistance mechanisms are well characterised, the virulence determinants that drive severe infections remain poorly understood. METHODS: We screened 89 carbapenem-resistant clinical isolates of A. baumannii for virulence in animal infection models and combined comparative genomics with functional assays to identify virulence factors. An immunoglobulin-binding protein from A. baumannii (ImbA) encoded on the type D plasmid was selected and characterised. Protein-immunoglobulin interactions were analysed by pull-down and biolayer interferometry. Additional ImbA inhibition of IgG-Fcγ receptor binding by flow cytometry were tested. Protective efficacy was evaluated in mice using vaccination or anti-ImbA antibodies. FINDINGS: A type D plasmid was consistently linked to high virulence in clinical isolates. The deletion of plasmid-encoded ImbA attenuated virulence. ImbA bound murine IgA and IgG with high affinity. The binding to the Fc region of IgG disrupted IgG-Fcγ receptor interactions. Vaccination with recombinant ImbA improved survival and reduced bacterial dissemination in female mice with anti-ImbA antibodies partially protecting against lethal infection. Bacterial burdens in the blood were reduced in treated groups. INTERPRETATION: Our study demonstrates ImbA as an unrecognised plasmid-encoded virulence factor in A. baumannii. By intercepting host immunoglobulins, ImbA drives immune evasion and hypervirulence. Blocking ImbA by vaccination and antibody therapy restored host defence and improved outcomes in female mice, highlighting ImbA as a non-antibiotic therapeutic target with potential against multidrug-resistant A. baumannii. FUNDING: Bio&Medical Technology Development Program of the National Research Foundation (NRF), funded by the Korean government (MSIT) (No. RS-2023-00219213); Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program.

Animals↗

PubMed2026

Molecular dynamics simulations of positively selected codons in FcγRI reveal novel biochemical binding properties.

FcγRI is a high-affinity receptor for IgG, associated with autoimmune disease pathology and determines clinical responses to antibody-based immunotherapies. FcγRI has a complex evolutionary history that is not fully understood, and to address this we explored signatures of positive selection in the receptor's functional gene, FCGR1A, using codon-based selection tests on aligned 1-1 orthologous sequences from placental mammals (n = 32). Signatures of positive selection have occurred at several locations within the gene, with two sites (H148 (M2a ω 0.997 & M8 ω = 0.993)) and (W149 (M2a ω = 0.999 & M8 ω = 1.000)) exhibiting highest posterior probabilities, suggesting strong evidence of positive selection; these positions are known to form one of the FcγRI-IgG binding interfaces. We employed ancestral reconstruction to statistically infer prior codon sequences at these sites and identified ancestral H148P and W149R codons at different nodes in the phylogeny. Employing molecular dynamics simulations, we determined how evolutionary changes at these sites may have influenced the binding of FcγRI-IgG of modern-day Homo sapiens. Measuring RMSD, free energy, radius of gyration, hydrogen bond formation, and analyzing free energy landscapes, we demonstrate that structural instability between mutant structures vs the WT counterpart; however, overall binding potential increases at position 148, yet decreases at 149 in potential. H148P protonation at physiological pH remains similar, yet during acidotic calculations, protonation is likely reduced, with predicted reduction in affinity for IgG. While ancestral W149R substitutions demonstrate an implication for electron conjugation. Examining key sites at this binding FcγRI-IgG interface, our data demonstrate that these two codons have evolved in humans to be relatively insensitive to shifts in pH promoting a more stable interaction with the Fc portion of IgG during diseases that promote acidosis.

Receptors, IgG↗

PubMed2026

Generation of FCGR3A-EGFP knock-in reporter human embryonic stem cell line, WAe001-A-3S, using CRISPR/Cas9n-based gene targeting.

Fc gamma receptor IIIA (FCGR3A) encodes CD16a, a key mediator of antibody-dependent cellular cytotoxicity (ADCC) that regulates innate and adaptive immunity, especially in natural killer (NK) cells and monocytes. We generated an FCGR3A-EGFP knock-in human embryonic stem cell (hESC) line via CRISPR/Casn9n. The cell line showed a normal karyotype, maintained expression ofthe pluripotency markers OCT4, SOX2, and NANOG, and retained trilineage differentiation potential. This reporter line enables real-time tracking of FCGR3A expression during immune cell differentiation, serving as a useful tool for studying FCGR3A+ immune cell development and related immune mechanisms.

Humans↗

PubMed2026

Pathogenic properties of myasthenia gravis AChR autoantibodies associate with clinical response to efgartigimod.

BACKGROUND: Efgartigimod, a neonatal Fc receptor (FcRn) blocker, effectively reduces total IgG, including pathogenic acetylcholine receptor (AChR) autoantibodies in myasthenia gravis (MG); however, clinical responses vary. To investigate this variability, we studied how efgartigimod impacts AChR-specific autoantibody profiles and associated pathogenic mechanisms, including complement activation, AChR internalisation and ACh-binding site blockade. METHODS: Serum samples (N=150) were sourced from 50 AChR autoantibody-positive generalised MG patients participating in the phase 3 ADAPT study, randomised to receive efgartigimod (N=40) or placebo (N=10) in cycles of 4-weekly infusions. Samples were collected at baseline, day 29 and day 57 during the first cycle. Live cell-based assays quantified AChR-specific IgG subclasses and isotypes and assessed their capacity to mediate pathomechanisms. RESULTS: Efgartigimod decreased all detectable AChR-specific IgG subclasses. At baseline, AChR autoantibody-mediated C3b deposition, AChR internalisation and ACh-binding site blockade were detected in 42 (84%), 41 (82%) and 10 (20%) patients, respectively. After 4-weekly infusions of efgartigimod, the magnitude of all three pathomechanisms was significantly decreased. However, the extent of this reduction varied across individuals. Double responders on both MG-activities of daily living and quantitative MG scores demonstrated a greater reduction in complement activity and AChR internalisation compared with patients who responded on only one score or were double non-responders. In addition, efgartigimod reduced IgG-dependent IgM binding to AChR. CONCLUSIONS: These findings suggest that clinical efficacy may be more closely associated with functional modulation of the AChR-specific autoantibodies than with their absolute quantity alone. These results support the evaluation of mechanistic pathway monitoring as a potential strategy to predict or guide efgartigimod treatment response.

Humans↗

PubMed2025

High-affinity CD16A polymorphism associated with reduced risk ofsevere COVID-19.

CD16A is an activating Fc receptor on NK cells that mediates antibody-dependent cellular cytotoxicity (ADCC), a key mechanism in antiviral immunity. However, the role of NK cell-mediated ADCC in SARS-CoV-2 infection remains unclear, particularly whether it limits viral spread and disease severity or contributes to the immunopathogenesis of COVID-19. We hypothesized that the high-affinity CD16AV176 polymorphism influences these outcomes. Using an in vitro reporter system, we demonstrated that CD16AV176 is a more potent and sensitive activator than the common CD16AF176 allele. To assess its clinical relevance, we analyzed 1,027 patients hospitalized with COVID-19 from the Immunophenotyping Assessment in a COVID-19 cohort (IMPACC), a comprehensive longitudinal dataset with extensive transcriptomic, proteomic, and clinical data. The high-affinity CD16AV176 allele was associated with a significantly reduced risk of ICU admission, mechanical ventilation, and severe disease trajectories. Lower anti-SARS-CoV-2 IgG titers were correlated to CD16AV176; however, there was no difference in viral load across CD16A genotypes. Proteomic analysis revealed that participants homozygous for CD16AV176 had lower levels of inflammatory mediators. These findings suggest that CD16AV176 enhances early NK cell-mediated immune responses, limiting severe respiratory complications in COVID-19. This study identifies a protective genetic factor against severe COVID-19, informing future host-directed therapeutic strategies.

Humans↗

PubMed2026

Development of a High-Sensitivity Glycoproteomics Approach for Fc-Specific Quantification of IgG Core Fucosylation in Traumatic Brain Injury.

Traumatic brain injury (TBI) triggers complex neuroinflammatory cascades that involve sustained immune activation and dysregulated antibody effector functions. Immunoglobulin G (IgG) Fc N-glycosylation, particularly core fucosylation, critically modulates immune signaling through altered Fcγ receptor (FcγR) interactions; however, its role in TBI remains unexplored. Here, we developed a high-sensitivity, mass spectrometry-based glycoproteomics method for the systematic analysis of IgG Fc core fucosylation dynamics following TBI. The approach integrates Fc-specific enzymatic truncation with GlycINATOR (EndoS2) and tryptic digestion, followed by high-resolution LC-MS/MS profiling, enabling confident identification of truncated Fc glycopeptides. Furthermore, a targeted parallel reaction monitoring (PRM) strategy allowed direct quantification of core fucosylated and afucosylated glycopeptides from 10 μg of crude serum protein, eliminating the need for IgG purification. Our results reveal time-dependent and subclass-specific remodeling of IgG Fc fucosylation postinjury, characterized by an overall reduction in fucosylated species and a relative increase in afucosylation. Collectively, this study establishes a scalable analytical platform for Fc-specific glycosylation profiling and identifies IgG core fucosylation as a candidate molecular indicator of immune dysregulation in TBI, providing new insights into post-traumatic immune regulation.

Brain Injuries, Traumatic↗

PubMed2025

Serum proteomics reveals high-affinity and convergent antibodies by tracking SARS-CoV-2 hybrid immunity to emerging variants of concern.

The rapid spread of SARS-CoV-2 and its continuing impact on human health has prompted the need for effective and rapid development of monoclonal antibody therapeutics. In this study, we investigate polyclonal antibodies in serum and B cells from the whole blood of three donors with SARS-CoV-2 immunity to find high-affinity anti-SARS-CoV-2 antibodies to escape variants. Serum IgG antibodies were selected by their affinity to the receptor-binding domain (RBD) and non-RBD sites on the spike protein of Omicron subvariant B.1.1.529 from each donor. Antibodies were analyzed by bottom-up mass spectrometry, and matched to single- and bulk-cell sequenced repertoires for each donor. The antibodies observed in serum were recombinantly expressed, and characterized to assess domain binding, cross-reactivity between different variants, and capacity to inhibit RBD binding to host protein. Donors infected with early Omicron subvariants had serum antibodies with subnanomolar affinity to RBD that also showed binding activity to a newer Omicron subvariant BQ.1.1. The donors also showed a convergent immune response. Serum antibodies and other single- and bulk-cell sequences were similar to publicly reported anti-SARS-CoV-2 antibodies, and the characterized serum antibodies had the same variant-binding and neutralization profiles as their reported public sequences. The serum antibodies analyzed were a subset of anti-SARS-CoV-2 antibodies in the B cell repertoire, which demonstrates significant dynamics between the B cells and circulating antibodies in peripheral blood.

Humans↗

PubMed2026

Localized PD-1 CAR T therapy reprograms neuroinflammation.

B cell-depleting therapies are effective in multiple sclerosis (MS), yet some patients relapse, underscoring the need for more precise interventions. To identify new therapeutic targets, we generated a single-cell RNA sequencing (scRNA-seq) atlas of cerebrospinal fluid (CSF), brain, and blood from non-inflammatory controls and patients with MS or other neuroinflammatory diseases. We found disease-associated enrichment of class-switched immunoglobulin G+ (IgG+) B cells and plasma cells in MS CSF. Unbiased analysis identified a rare disease-enriched subset of activated, T cell receptor (TCR)-restricted, PD-1+ T follicular helper-like cells with B cell-recruiting features. To target this population, we developed PD-1-directed chimeric antigen receptor (CAR) T cells that selectively depleted pathogenic PD-1+ CD4 T cells and locally released IL-10. This strategy attenuated central nervous system (CNS) inflammation, reprogrammed the local immune milieu, and improved clinical outcomes across murine neuroinflammation models. These findings define a CNS-localized adaptive immune circuit in MS and nominate programmable PD-1 CAR T cells as a strategy to disrupt it.

Animals↗

PubMed2026

FPR2/ALX stimulation modulates microglia and natural killer cells to restrict autoimmune astrocytopathy.

Autoantibody- and complement-mediated cytotoxicity can cause autoimmune astrocytopathy that leads to CNS inflammatory demyelination. Formyl peptide receptor 2 (FPR2/ALX) governs the activation and propagation of immune response. However, the precise role of FPR2/ALX in neuroinflammation and the effect of FPR2/ALX stimulation on autoimmune astrocytopathy are poorly understood. Using a mouse model of autoimmune astrocytopathy induced by AQP4-IgG- and complement-mediated cytotoxicity, we found that the stimulation of FPR2/ALX with the small-molecule agonist Quin-C1 led to reduced brain lesion volume, astrocyte loss and demyelination. This was accompanied by enhanced anti-inflammatory activity of microglia and reduced infiltration of lymphocytes in the brain. FPR2/ALX stimulation also led to increased phosphorylation of SYK and AKT in mice with autoimmune astrocytopathy. Notably, the benefits of FPR2/ALX stimulation were attenuated in mice with autoimmune astrocytopathy after microglial depletion using the CSF1R inhibitor PLX5622 or natural killer (NK) cell depletion using an anti-NK1.1 monoclonal antibody. Additionally, the protective effects of FPR2/ALX stimulation were diminished in mice with autoimmune astrocytopathy that received the SYK inhibitor R406. Collectively, our findings demonstrate that FPR2/ALX stimulation may represent a promising therapeutic strategy to attenuate detrimental neuroinflammation in autoimmune astrocytopathy by modulating microglia and NK cells. FPR2/ALX stimulation suppresses autoimmune astrocytopathy: Using a mouse model of autoimmune astrocytopathy, we demonstrated that FPR2/ALX stimulation with the small molecule Quin-C1 reduces the CNS infiltration of lymphocytes and augments the anti-inflammatory activity of microglia, leading to attenuated astrocyte pathology induced by AQP4-IgG and complement-mediated attacks. Mechanistically, the benefits of FPR2/ALX stimulation using Quin-C1 involve microglia, natural killer (NK) cells, and SYK-AKT signaling.

Animals↗

PubMed2026

Nipocalimab Phase 3 Dose Selection for Severe Hemolytic Disease of the Fetus and Newborn.

Nipocalimab, a neonatal Fc receptor (FcRn) blocker, is under evaluation for severe hemolytic disease of the fetus and newborn (HDFN). In the Phase 2 UNITY trial, weekly intravenous antenatal treatment with nipocalimab at dose regimens of 30 and 45 mg/kg prevented fetal anemia requiring intrauterine transfusion (IUT) in 54% of high-risk pregnancies and delayed the need for IUTs versus their previous pregnancies in the remaining 46% of pregnancies. This analysis aimed to select a weekly dose regimen of nipocalimab for the Phase 3 study in severe HDFN (NCT05912517) that maintains FcRn blockade throughout antenatal treatment, including with an unplanned dosing delay of up to 3 days. Observed pharmacokinetic/pharmacodynamic (PK/PD) data from UNITY (i.e., nipocalimab concentrations, FcRn occupancy, and serum IgG) were analyzed using a model-based approach. A PK/PD model originally developed in nonpregnant participants was updated to incorporate gestational weight gain. Nipocalimab PK and FcRn occupancy were described by a two-compartment model with nonlinear, dose-dependent PK, which captured longitudinal PK, FcRn occupancy, and IgG profiles during dosing and return toward baseline postpartum after discontinuation. Both 30 and 45 mg/kg achieved ∼80%-85% reductions in maternal IgG; however, 30 mg/kg showed greater variability in predose trough concentrations, increasing the risk of falling below concentrations required for full FcRn occupancy across antenatal treatment. Simulations incorporating PK/PD variability indicated that 45 mg/kg weekly per current weight maintained full FcRn occupancy in >95% of pregnant individuals, even with dosing delays up to 3 days. Exploratory exposure-response analyses supported 45 mg/kg for the Phase 3 HDFN study.

Humans↗

PubMed2024

Adeno-Associated Virus Type 5 Infection via PDGFRα Is Associated With Interstitial Lung Disease in Systemic Sclerosis and Generates Composite Peptides and Epitopes Recognized by the Agonistic Immunoglobulins Present in Patients With Systemic Sclerosis.

OBJECTIVE: The etiopathogenesis of systemic sclerosis (SSc) is unknown. Platelet-derived growth factor receptors (PDGFRs) are overexpressed in patients with SSc. Because PDGFRα is targeted by the adeno-associated virus type 5 (AAV5), we investigated whether AAV5 forms a complex with PDGFRα exposing epitopes that may induce the immune responses to the virus-PDGFRα complex. METHODS: The binding of monomeric human PDGFRα to the AAV5 capsid was analyzed by in silico molecular docking, surface plasmon resonance (SPR), and genome editing of the PDGFRα locus. AAV5 was detected in SSc lungs by in situ hybridization, immunohistochemistry, confocal microscopy, and molecular analysis of bronchoalveolar lavage (BAL) fluid. Immune responses to AAV5 and PDGFRα were evaluated by SPR using SSc monoclonal anti-PDGFRα antibodies and immunoaffinity-purified anti-PDGFRα antibodies from sera of patients with SSc. RESULTS: AAV5 was detected in the BAL fluid of 41 of 66 patients with SSc with interstitial lung disease (62.1%) and in 17 of 66 controls (25.75%) (P < 0.001). In SSc lungs, AAV5 localized in type II pneumocytes and in interstitial cells. A molecular complex formed of spatially contiguous epitopes of the AAV5 capsid and of PDGFRα was identified and characterized. In silico molecular docking analysis and binding to the agonistic anti-PDGFRα antibodies identified spatially contiguous epitopes derived from PDGFRα and AAV5 that interacted with SSc agonistic antibodies to PDGFRα. These peptides were also able to bind total IgG isolated from patients with SSc, not from healthy controls. CONCLUSION: These data link AVV5 with the immune reactivity to endogenous antigens in SSc and provide a novel element in the pathogenesis of SSc.

Humans↗

PubMed2026

Dendritic cells control tertiary lymphoid structure development and maintenance in cancer.

Tertiary lymphoid structures (TLSs) are associated with immunotherapy response, yet the mechanisms controlling their formation and maintenance remain unclear. Using spatial transcriptomics and multiplex imaging across human tumors, we found that CCR7+ mature dendritic cells (DCs) accumulate in TLSs. In a mouse non-small cell lung cancer model that forms mature TLSs, we show that early TLS development requires interferon-γ (IFN-γ)-driven type 1 conventional dendritic cell (cDC1) maturation, migration to tumor-draining lymph nodes (tdLNs), and T cell recruitment. As tumors progress, TLSs persist independently of tdLN T cell egress, coinciding with cDC1 accumulation within intratumoral CCL19 stromal hubs. There, cDC1-major histocompatibility complex class 1 (MHC-I) and -MHC-II concomitant antigen presentation, along with CD40 signaling, sustain TLS, T follicular helper (TFH) cell pool, germinal centers, and tumor-specific immunoglobulin G (IgG). These findings highlight local mature cDC1s as key TLS orchestrators and potential targets to enhance antitumor TLS function.

Animals↗