Search Results (521)

Autoantibodies have long been regarded as passive reflections of immune dysregulation in connective tissue diseases (CTDs). Recent advances in systems immunology and molecular pathology have fundamentally redefined them as active molecular fingerprints that delineate distinct disease endophenotypes with predictive power for clinical trajectories and therapeutic responses. Rather than mere epiphenomena, autoantibodies encode precise information about dominant immune pathways, organ tropism, and pathogenic mechanisms. This review synthesizes emerging evidence that autoantibody repertoires—defined by specificity, structural properties, and functional characteristics—stratify patients beyond traditional clinical taxonomy into discrete pathobiological subsets. Specific signatures such as anti-MDA5 in rapidly progressive interstitial lung disease, anti-RNA polymerase III in scleroderma renal crisis, and anti-Ro52/TRIM21 in systemic overlap syndromes illustrate how serological profiles predict outcomes with remarkable precision. Mechanistically, autoantibody pathogenicity is modulated by immunoglobulin isotype distribution, Fc glycosylation patterns, and tissue-specific receptor expression—variables that determine whether an antibody functions as a biomarker or pathogenic effector. The structural heterogeneity of autoantibodies, shaped by cytokine microenvironments and B-cell subset imprinting, creates a dynamic continuum between pro-inflammatory and regulatory states. The integration of serological, transcriptomic, and imaging data establishes a precision medicine framework: autoantibodies function simultaneously as disease classifiers and therapeutic guides. This endophenotype-driven approach is already influencing trial design and patient stratification in systemic lupus erythematosus, systemic sclerosis, and inflammatory myopathies, and is reshaping both clinical practice and scientific taxonomy in CTDs. Recognizing autoantibodies as endophenotypic determinants aligns disease classification with pathogenic mechanism and supports the transition towards immunologically informed therapeutic strategies. Full article

B-cells and plasmablasts have emerged as central organizers of autoimmune pathogenesis, extending far beyond their classical role as antibody-producing cells to orchestrate immune circuits, tissue microenvironments, and therapeutic trajectories. Advances in single-cell technologies, high-dimensional cytometry, and B-cell receptor sequencing have uncovered a dynamic continuum of B-cell differentiation programs that drive clinical heterogeneity across systemic autoimmune diseases. Plasmablasts, in particular, have gained recognition as highly responsive sensors of immune activation: they expand during flares, encode interferon-driven and extrafollicular responses, and correlate with disease severity. Autoantibody profiles, long viewed as static diagnostic signatures, are now understood as durable molecular footprints of distinct B-cell pathways. In this review, we propose an endotype-based framework integrating B-cell circuits with clinical phenotypes, illustrate therapeutic decision-making through mechanistic case vignettes, and outline future strategies combining immunomonitoring, multi-omics, and precision therapeutics. We further address translational challenges and discuss complementary approaches, including T-cell modulation, FcRn inhibition, and antigen-specific tolerization. Full article

Acne vulgaris is a prevalent chronic inflammatory skin disorder affecting over 85% of adolescents. Emerging evidence indicates that Cutibacterium acnes phylotype IA₁ contributes to acne initiation and progression, yet its precise mechanisms in epidermal keratinocytes remain unclear. This study investigated C. acnes IA1’s effects on keratinocyte behavior using an in vitro HaCaT cell model. Cells were co-cultured with live C. acnes IA₁ (CICC 10864) for 24 h. Transcriptomic profiling identified 769 differentially expressed genes (DEGs; adjusted p < 0.05, |log2FC| > 1), including 392 upregulated and 377 downregulated. The protein–protein interaction network analysis via Cytoscape revealed key hub genes (HNRNPA2B1, HNRNPM, RBM39). Enrichment analyses (GO, KEGG, Reactome, DO) highlighted significant involvement of the C-type lectin receptor (CLR) signaling pathway. Validation experiments showed cellular morphological changes, altered structure, and markedly elevated interleukin-6 (IL-6; p < 0.01), underscoring its role in inflammation. These findings suggest C. acnes IA₁ drives acne pathogenesis by regulating hub genes that influence sebaceous gland inflammation, immune activity, and keratinocyte proliferation, positioning them as potential biomarkers for microbiome-targeted therapies. Limitations include the in vitro model’s lack of in vivo skin microenvironment complexity and use of only one representative IA₁ strain. Full article

Background: Venezuelan equine encephalitis virus (VEEV) poses a significant public health and biodefense threat due to periodic epidemics of severe neurological disease in the Americas, yet no licensed human vaccines or specific antiviral therapies exist. Methods: We comprehensively reviewed the current literature across three core domains: structural biology, vaccine development, and therapeutic antibodies. Results: First, we detail the complex viral structural proteome (including E1/E2 glycoproteins and Capsid), focusing on the LDLRAD3 entry receptor interaction. Second, we overview vaccine strategies, covering live-attenuated, VLP, and nucleic acid platforms designed to induce robust neutralizing antibodies. Finally, we examine the evolution of therapeutic antibodies, highlighting that optimal protection often relies on both neutralization and Fc effector functions, particularly for antibodies targeting the fusion loop or receptor-binding sites. Conclusions: Integrating structural insights with advanced antibody and vaccine engineering is essential for establishing effective clinical interventions capable of preventing future outbreaks and treating infected individuals. Full article

West Nile fever is an infectious disease caused by the West Nile virus (WNV), which is transmitted by mosquitoes. Epidemiological surveillance confirms the potential risk of WNV infection in human populations. The lack of specific antiviral therapeutics and vaccines against WNV underscores the urgent need to develop effective therapeutic approaches. In this study, a recombinant chimeric monoclonal antibody (mAb) 900 was generated based on the broadly neutralizing and protective murine mAb 9E2. The antigen-binding regions of the murine mAb were fused with the constant domains (CH2–CH3) of human IgG1. Two key amino acid clusters, M252/S254/T256 and H433/N434, were introduced into the CH2–CH3 domains to enhance the affinity of mAb 900 for the neonatal Fc receptor (FcRn). The engineered mAb 900 was produced in CHO cells and purified to high homogeneity. Biophysical characterization confirmed its stability and correct dimeric assembly. Comparative analysis demonstrated that mAb 900 retained the high antigen-binding affinity and potent virus-neutralizing activity of its murine predecessor. Most importantly, mAb 900 demonstrated significant protective efficacy in a lethal mouse model of WNV infection. These results establish the proof of concept for mAb 900 as a promising candidate for further preclinical development against WNV infection. Full article

Background: Dulaglutide, a GLP-1-IgG4 Fc fusion, is a long-acting GLP-1 receptor agonist used for type 2 diabetes therapy and other emerging indications. It is produced commercially in Chinese hamster ovary (CHO) cells. The supply of the original drug is now limited in some regions, so creation of highly productive biosimilar manufacturing platforms is important. Methods: Two expression plasmids (p1.1-Tr2-Dul, p1.2-GS-Dul) encoding dulaglutide were sequentially transfected into apoptosis-resistant CHO 4BGD cells. Two-step transgene amplifications with methotrexate (MTX), followed by methionine sulfoximine (MSX) selection and subsequent cell cloning pipeline, were employed. Candidate clonal cell lines were selected using fed-batch culturing and long-term productivity testing. Results: Transfection with a second plasmid encoding glutamine synthetase (p1.2-GS-Dul) and selection with MSX resulted in a further ~30% increase titer in polyclonal population even after MTX-driven amplification. Top clone 4BGD/Dul #73 reached 1.05 g/L product titer in fed-batch culture (qP up to 22 pg·cell⁻¹·day⁻¹) and remained stable for 69 days in medium without MTX/MSX. Size exclusion-high-performance liquid chromatography showed ≥95% monomer; EC₅₀ of the purified GLP-1-Fc in a GLP-1R/CRE-Luc assay was 52 pM for the obtained product versus 76 pM for the original reference drug. Conclusions: The sequential transfection and dual-marker selection approach enables the efficient generation of a robust, high-yield, and glutamine-independent CHO producer, representing a productive strategy suitable for industrial biosimilar development. Full article

Accurate detection of microbial contamination is essential in the assessment of toxicological and immunological responses to various materials, as low-level contaminants can lead to confounding results. Traditional endotoxin testing relies on the Limulus Amebocyte Lysate (LAL) assay, which depends on horseshoe crab blood and raises both ecological and ethical concerns. Sustainable alternatives such as recombinant Factor C (rFC) provide a promising solution, yet validation for the detection of endotoxin in nanomaterials remains incomplete. In this study, we have used rFC alongside Toll-like receptor (TLR) reporter assays to detect both endotoxin and broader microbial contaminants in 31 nanomaterials from diverse classes. Special attention was given to assay interference by nanomaterials to ensure reliable detection. The rFC assay demonstrated a sensitive detection limit of 0.005 EU/mL, equivalent to the LAL assay, and showed that more than 50% of tested nanomaterials contained low-level endotoxin contamination. Additionally, several nanomaterials activated the TLR2 reporter, indicative of microbial contaminants beyond endotoxin. These results suggest that rFC can serve as a sustainable and reliable replacement for LAL in nanomaterial endotoxin testing but also emphasize the limitations of relying solely on endotoxin-specific assays. We recommend that future nanotoxicological evaluations integrate rFC with complementary methods, such as TLR-based approaches, and include thorough interference controls to ensure robust and comprehensive microbial contamination assessment. Full article

Background/Objectives: To evaluate the cost-effectiveness of recombinant tumor necrosis factor receptor Fc fusion protein compared with methotrexate as first-line therapy for active rheumatoid arthritis in China using evidence from a Chinese head-to-head randomized trial. Methods: A Markov model with 6 months per cycle was developed to estimate costs and health utilization in the lifetime of patients with RA from the Chinese healthcare system. The analysis data were derived from the randomized clinical trial in China. The primary cost includes drug and other medical costs. The health utilities quality-adjusted life years (QALYs) were derived using EQ-5D-5L mapping from disease-specific health assessment questionnaire (HAQ) scores obtained in clinical trials. The cost-effectiveness analysis was conducted by calculating the incremental cost-effectiveness ratio (ICER) values for rhTNFR:Fc and MTX. One-way and probabilistic sensitivity analyses were conducted to test the robustness of the base-case result. Results: In the base case, rhTNFR:Fc yielded 8.20 QALYs versus 7.46 with methotrexate, resulting in an ICER of CNY 12,783.56 per QALY. Scenario ICERs for bDMARD group combination treatment were 11,776.31 per QALY. Scenario ICERs were CNY 8079.04 per QALY for the patient perspective and CNY 7630.34 per QALY for the medical insurance perspective. One-way analysis highlighted utility inputs as the main drivers, and probabilistic analysis indicated a high probability of cost-effectiveness across common willingness-to-pay thresholds. Conclusions: The fusion protein strategy achieved an incremental cost-effectiveness ratio far below the 2024 China per capita gross domestic product threshold of CNY 95,749 per quality-adjusted life year. As first-line therapy for active rheumatoid arthritis, it is cost-effective relative to methotrexate in the Chinese setting. Full article

Efgartigimod is a novel neonatal Fc receptor (FcRn) antagonist that reduces pathogenic immunoglobulin G (IgG) autoantibodies, offering a targeted therapeutic approach for generalized myasthenia gravis (gMG) and other antibody-mediated autoimmune diseases. This narrative review synthesizes clinical trial data, pharmacological insights, and real-world evidence to evaluate efgartigimod’s efficacy, safety, and emerging applications. Phase 3 randomized controlled trials and extension studies demonstrate rapid and sustained improvements in muscle strength and patient-reported outcomes with a favorable safety profile, including reduced reliance on corticosteroids and intravenous immunoglobulin (IVIg). Additionally, observational studies highlight its expanding utility in diverse IgG-mediated disorders such as immune thrombocytopenia (ITP) and autoimmune encephalitis. Efgartigimod thus represents a paradigm shift in autoimmune disease management, enabling precision immunomodulation with the potential for broad clinical impact and improved patient quality of life (QOL). Full article

Multiple myeloma (MM) is a clonal malignancy of terminally differentiated plasma cells characterized by bone marrow infiltration and excessive production of monoclonal immunoglobulins, leading to end-organ damage such as osteolytic bone lesions. Despite substantial therapeutic progress achieved with proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, multiple myeloma remains incurable, and outcomes for triple-class-refractory patients remain dismal, with median survival below one year. Bispecific T cell engaging antibodies (TCEs) have recently emerged as a promising immunotherapeutic approach capable of redirecting cytotoxic T cells to eliminate malignant plasma cells. These engineered antibodies simultaneously engage CD3 on T cells and a tumor-associated antigen such as B cell maturation antigen (BCMA), G protein-coupled receptor family C group 5 member D (GPRC5D), or Fc receptor homolog 5 (FcRH5), thereby forming an immune synapse that triggers T cell activation, cytokine secretion, and perforin–granzyme-mediated apoptosis of the targeted B cell. This review summarizes the molecular design, mechanism of action, and clinical development of TCEs in MM, encompassing early bi-specific T cell engagers (BiTE) constructs such as AMG 420 and next-generation IgG-like molecules including teclistamab. Pivotal clinical trials have demonstrated overall response rates between 43% and 73%, accompanied by durable remissions and manageable safety profiles. Future directions include earlier-line integration, synergistic combinations with immunomodulatory or costimulatory agents, and the development of trispecific formats to overcome antigen escape and T cell exhaustion. Collectively, TCEs represent a paradigm shift toward durable, immune-mediated disease control in multiple myeloma. Full article

Inherited platelet function disorders (IPFDs) are rare diseases caused by defects in platelet surface receptors, enzymes, granules, or signaling proteins. In humans, GPVI and P2Y12 deficiency cause autosomal recessive bleeding disorders, while TBXAS1 deficiency is related to Ghosal hematodiaphyseal dysplasa, a rare autosomal recessive disorder characterized by increased long bone density and platelet dysfunction without bleeding. To date, at least 20 patients have been identified with molecular defects in P2RY12, 12 cases with molecular defects in GP6, and 34 cases with molecular defects in TBXAS1. Here, we report a novel nonsense and missense variants in P2RY12, a novel nonsense variant in GP6, and a novel missense variant in TBXAS1. These variants selectively affect the platelet reactivity to ADP and collagen/CRP, predisposing to bleeding. P2RY12 c.835 G>A [p.Val279Met] variant did not affect receptor expression whereas P2RY12 c.44delG [p.Ser15Ilefs*33] lead to decreased levels of the receptor in one of the patients. This was confirmed both by RT-qPCR and immunoblotting analysis. Decreased expression of both GPVI and FcRγ-chain was detected in patients carrying GPVI nonsense variant in heterozygosis. The deleterious effect of these variants was also confirmed in a transfected cell line model. TBXAS1 variant triggered decreased TxA₂ production using a cell line model. These variants expand the genetic landscape of P2RY12, GPVI and TBXAS1 inherited deficiency. Full article

The interaction of therapeutic antibodies with Fc receptors is an important property that is actively modified to improve pharmacokinetic profiles and optimize antibody-dependent mechanisms of action. Various modifications of the Fc and hinge regions of antibodies, leading to a change in affinity with various Fc receptors, are widely covered in the literature. However, data on changes in antibody and Fc receptor interactions after antibody binding to the target antigen are poorly covered in the literature. In this work, we demonstrated a change in the affinity of the interaction of antibodies with Fc receptors after binding to the target antigen via the method of biolayer interferometry. An interesting result was a significant weakening of the interaction of FcRn and FcγRIIIa with some of the antibodies when the latter bound to the target antigen, which suggests the importance of this effect for the pharmacokinetic properties and effector mechanisms of action necessary in the treatment of oncological diseases. The sensor-based biolayer interferometry methods presented in this paper allow antibody screening to be performed to detect the effects of the reduced affinity of interactions with Fc receptors, and can be a useful tool in the early development of therapeutic antibodies. Full article

Background/Objectives: The neonatal Fc receptor (FcRn) is a heterodimeric protein composed of a heavy α-chain with an MHC class I-like fold and β₂-microglobulin. It plays a crucial role in maintaining the homeostasis and pharmacokinetics of immunoglobulin G (IgG) and albumin through pH-dependent recycling. The production of soluble recombinant FcRn is technically challenging due to its heterodimeric structure and the presence of a transmembrane domain. This study aimed to develop a polycistronic construct enabling the co-expression of FcRn subunits from a single transcript and to evaluate the functional activity of the resulting protein in CHO-K1 cells. Methods: Integration vectors (pComV-FcRn-B2M) were designed to encode FcRn and β₂-microglobulin linked via self-cleaving 2A peptides (P2A, E2A, F2A, T2A). Stable producer cell lines were generated using the Sleeping Beauty transposon system. The purified proteins were characterized by SDS-PAGE, Western blotting, and size-exclusion chromatography (SEC). Functional activity was assessed by ELISA and bio-layer interferometry (BLI). Results: Electrophoretic and chromatographic analyses confirmed the expected subunit composition and demonstrated that over 95% of the recombinant protein was monomeric. Functional assays revealed pH-dependent IgG binding, with strong interaction at pH 6.0 and negligible binding at pH 7.5. BLI measurements showed high affinity consistent with native FcRn function (KD = 3.15 nM at pH 6.0). Conclusions: The developed polycistronic construct containing a P2A peptide with a GSG linker enabled efficient production of functional FcRn in CHO-K1 cells (yield up to 2.23 mg/mL). The P2A variant demonstrated the highest efficiency and can serve as a reference system for screening Fc-engineered antibodies with optimized pharmacokinetic properties. Full article

MicroRNAs (miRNAs) are key post-transcriptional regulators of plant development and stress responses, with many being conserved across diverse plant lineages. In this study, we investigated the expression profiles of miRNAs and their corresponding target genes in Arachis stenosperma, a wild peanut relative that exhibits robust resistance to root-knot nematodes (RKN). Small RNA sequencing of nematode-infected roots identified 107 miRNA loci, of which 93 corresponded to conserved miRNA families and 14 represented novel candidates, designated as miRNOVO. Among these, 18 miRNAs belonging to 11 conserved families were identified as differentially expressed (DEMs). Notably, miR399 and miR319 showed the highest upregulation (logFC = 4.25 and 4.20), while miR393 and miR477 were the most downregulated (logFC = −0.83 and −0.79). Integrated analysis of miRNA and transcriptome data revealed several regulatory interactions involving key defense-related genes. These included NLR genes targeted by miR393 and miR477, hormone signaling components such as the auxin response factor ARF8 targeted by miR167, and the growth regulator GRF2 targeted by miR396. Additionally, miR408 was predicted to target laccase3, a gene involved in the oxidation of phenolic compounds, lignin biosynthesis, copper homeostasis and defense responses. Remarkably, four immune receptor genes belonging to the nucleotide-binding site leucine-rich repeat (NLR) family displayed inverse expression patterns relative to their regulatory miRNAs, suggesting miRNA-mediated post-transcriptional control during the early stages of nematode infection. These findings reveal both conserved and species-specific miRNA–mRNA modules associated with nematode resistance in A. stenosperma, highlighting promising targets for developing RKN-tolerant peanut cultivars through miRNA-based strategies. Full article

The pathogenesis of rheumatoid arthritis involves a complex interplay of genetic predisposition, environmental factors, and autoimmune mechanisms that lead to chronic inflammation of the synovial membrane. Fc-like receptor 3 (FcRL3) is a receptor encoded by the FCRL3 gene, located on the long arm of chromosome 1 at 1q23.1. Polymorphisms in the promoter region of FCRL3, rather than elsewhere in the gene, primarily affect the level of protein expression, which is of clinical significance. Understanding the structure of FcRL3, particularly in the context of genetic variants, is therefore important for elucidating the pathogenesis of autoimmune diseases. Detailed knowledge of the molecular architecture of immune receptors such as FcRL3 is also essential for advancing our understanding of immune function and for guiding the development of targeted therapeutic strategies in autoimmune disease. In this article, we discuss the role of FcRL3 in the pathophysiology and potential therapy of rheumatoid arthritis. Full article