Use of synthetic data, a novel paradigm for immunopathology.

Metabolic traits of T cells and the implications in autoimmune diseases.

The immune system depends on ion channels to control activation and maintain cellular homeostasis. The role of voltage-dependent potassium channels (Kv) in immune cells has been well studied in recent decades, with a special interest in the role of Kv1.3 in cell physiology and its implications in autoimmune diseases. However, native K+ currents in leukocytes result not only from the assembly of pore-forming α-subunits but are also shaped by regulatory β-subunits that fine-tune gating, trafficking, and pharmacology. Immune cells express members of the Kvβ, KCNE, and KChIP families, but the contribution of these regulatory subunits to immune physiology remains largely underexplored. In this review, we synthesize evidence for regulatory subunit expression and function in leukocytes, focusing on how these partners modify Kv channel behavior and downstream signaling. We highlight Kv1.3-Kvβ2.1-KCNE4 as a promising immunoregulatory complex, and we discuss the role of KChIPs in shaping gene expression as well as a Kv regulatory subunit. Despite gaps in the expression of regulatory subunits in immune cells, increasing evidence highlights the importance of further studies addressing the role of Kvβ-subunits in the immune context. Understanding how Kv channels are regulated in leukocytes could lead to new ways to control immune responses and develop new targeted therapies.

Structure-based virtual screening identifies potent CD28 inhibitors that suppress T cell co-stimulation in cellular and mucosal models.

Dopamine is a neuromodulator molecule that is involved in several systems in the human body. As a neurotransmitter, it plays a role in regulating reward, pleasure, and motor control in the brain. Beyond its well-known central nervous system functions it significantly influences peripheral systems including kidneys, circulatory system, and notably, immune system. It increases glomerular filtration rate and renal blood flow in the kidneys, while it increases aortic pressure and cardiac output in the circulatory system. Crucially, dopamine and its receptors have been identified on various immune cells, playing a significant immunomodulatory role that contributes to balanced immune responses and has implications in autoimmune diseases and conditions like sepsis. Moreover, in the respiratory system, dopamine plays a significant role in the pathophysiology of major respiratory disorders such as asthma, cystic fibrosis, chronic obstructive pulmonary disease, and lung cancer. Depending on the type of receptor, dopaminergic receptors contribute to the pathophysiology of lung disease. As part of the narrative review, we have identified dopaminergic receptors in the respiratory system, their anatomic locations, and their specific mechanisms of action in the pathophysiology of major respiratory disorders. We have also identified and summarized molecular therapy protocols that can be used in the treatment of these disorders, considering the evolving understanding of dopamine's broad systemic effects.

Serum Amyloid A (SAA) proteins are critical mediators of immune activation and metabolic regulation, bridging the acute-phase response with long-term disease dynamics. Once considered mere biomarkers of inflammation, emerging research has revealed their central role in orchestrating immune responses, lipid metabolism, and tissue remodeling. SAA proteins display context-dependent functions: they promote immune defense and tissue regeneration in some conditions, while exacerbating chronic inflammation and disease progression in others. Recent studies highlight the intricate interplay between SAA isoforms, pattern recognition receptors, and metabolic pathways, with implications for autoimmune diseases, metabolic disorders, and inflammatory pathologies. Despite their well-documented role in acute inflammation, the therapeutic potential of SAA proteins remains underexplored. Ongoing research aims to dissect their multifaceted functions and isoform-specific effects, paving the way for novel diagnostic and therapeutic strategies in immune-mediated diseases.

Excessive activation of toll-like receptor 7 and 8 (TLR7/8) plays a role in the pathogenesis of autoimmune diseases and is associated with negative outcomes from viral infections. Neutrophil activation is highly inflammatory and mediates tissue damage. We explored the effects of TLR7/8 activation in neutrophils to better understand neutrophil biology and evaluate the therapeutic utility of TLR7/8 inhibitors in indications where neutrophils contribute to disease pathogenesis. We found that TLR8, but not TLR7, is active in human neutrophils. TLR8 activation led to increased interleukin-8 (IL-8) secretion and resulted in significant changes in gene expression, as determined by RNA sequencing, with increased expression of genes encoding cytokines and other inflammatory mediators. Type I interferon (IFN) also induced gene expression changes distinct from those induced by TLR8. Additionally, neutrophil extracellular traps (NET) formation and DNA release, or NETosis, was induced by TLR8 activation in IFN-primed neutrophils. Treatment with a TLR7/8 inhibitor (CMPD2) effectively blocked IL-8 secretion and NETosis. In a Phase II clinical trial in COVID-19 pneumonia, TLR7/8 inhibition with enpatoran affected neutrophil counts. Expression of NFKBIZ was induced by TLR8 in neutrophils in vitro and found to also be reduced by enpatoran in patients with COVID-19, suggesting it may be useful as a marker for TLR8-activated neutrophils and for identifying candidate diseases and patients that may benefit from treatment with a TLR7/8 inhibitor. Overall, our findings provide new insights into TLR8 and neutrophil biology that have therapeutic implications in autoimmune diseases and immune-mediated inflammation.

The gut microbiome has emerged as a powerful regulator of immune function, profoundly influencing both autoimmune diseases and cancer therapies. Recent advances in microbiome research have unveiled the dynamic interplay between microbial communities and host immunity, revealing how microbial metabolites, bacterial surface molecules, and host-microbe interactions shape immune responses. This review explores the intricate mechanisms by which gut microbiota modulate immune tolerance, inflammation, and cancer immunosurveillance, highlighting the potential of microbiome-targeted interventions. Emerging therapeutic strategies, including fecal microbiota transplantation, engineered probiotics, and microbiome-derived metabolites, offer novel avenues for modulating immune dysfunction and enhancing treatment efficacy. Furthermore, artificial intelligence-driven microbiome profiling and CRISPR-based microbiome engineering hold promise for precision medicine, allowing personalized modulation of microbial ecosystems. Despite these breakthroughs, challenges such as interindividual microbiome variability, mechanistic gaps, and regulatory hurdles continue to impede clinical translation. Addressing these barriers will be crucial to unlocking the full potential of microbiome-based therapies in immune modulation, autoimmunity, and oncology. By integrating multi-omics approaches and advancing microbial therapeutics, the gut microbiome may soon transition from an adjunct to a cornerstone of precision medicine.

This review article examines the role of B-lymphocyte activating factor (BAFF) in immune regulation and its implications for autoimmune diseases. BAFF, a member of the TNF superfamily, is crucial for B-cell survival, maturation, and differentiation. We detail the mechanisms by which BAFF interacts with its receptors—BAFF receptor, TNFRSF13B, and BCMA—impacting various signaling pathways essential for humoral immunity. Elevated BAFF levels are associated with autoimmune conditions such as systemic lupus erythematosus, rheumatoid arthritis, and primary Sjögren’s syndrome, where it contributes to B-cell dysregulation and autoinflammatory responses. We discuss how therapies targeting BAFF and associated signaling pathways, such as belimumab and atacicept, show promise in modulating immune responses and offering new treatment avenues. This review synthesizes current findings to highlight the potential of BAFF as a therapeutic target and emphasizes the need for additional studies to clarify its role in the pathogenesis and treatment of autoimmune disorders.

Epstein-Barr virus (EBV), a member of the γ-herpesvirus family, is one of the most prevalent and persistent human viruses, infecting up to 90% of the adult population globally. EBV's life cycle includes primary infection, latency, and lytic reactivation, with the virus primarily infecting B cells and epithelial cells. This virus has evolved sophisticated strategies to evade both innate and adaptive immune responses, thereby maintaining a lifelong presence within the host. This persistence is facilitated by the expression of latent genes such as EBV nuclear antigens (EBNAs) and latent membrane proteins (LMPs), which play crucial roles in viral latency and oncogenesis. In addition to their well-known roles in several types of cancer, including nasopharyngeal carcinoma and B-cell lymphomas, recent studies have identified the pathogenic roles of EBV in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. This review highlights the intricate interactions between EBV and the host immune system, underscoring the need for further research to develop effective therapeutic and preventive strategies against EBV-associated diseases.

T helper 17 (TH17) cells are implicated in autoimmune diseases, and several metabolic processes are shown to be important for their development and function. In this study, we report an essential role for sphingolipids synthesized through the de novo pathway in TH17 cell development. Deficiency of SPTLC1, a major subunit of serine palmitoyl transferase enzyme complex that catalyzes the first and rate-limiting step of de novo sphingolipid synthesis, impaired glycolysis in differentiating TH17 cells by increasing intracellular reactive oxygen species (ROS) through enhancement of nicotinamide adenine dinucleotide phosphate oxidase 2 activity. Increased ROS leads to impaired activation of mammalian target of rapamycin C1 and reduced expression of hypoxia-inducible factor 1-alpha and c-Myc-induced glycolytic genes. SPTLCI deficiency protected mice from developing experimental autoimmune encephalomyelitis and experimental T cell transfer colitis. Our results thus show a critical role for de novo sphingolipid biosynthetic pathway in shaping adaptive immune responses with implications in autoimmune diseases.

Autoimmune and inflammatory diseases are highly complex, limiting treatment and the development of new therapies. Recent work has shown that cell-free DNA bound to biological microparticles is linked to systemic lupus erythematosus, a prototypic autoimmune disease. However, the heterogeneity and technical challenges associated with the study of biological particles have hindered a mechanistic understanding of their role. Our goal was to develop a well-controlled DNA-particle model system to understand how DNA-particle complexes affect cells. We first characterized the adsorption of DNA on the surface of polystyrene nanoparticles (200 nm and 2 µm) using transmission electron microscopy, dynamic light scattering, and colorimetric DNA concentration assays. We found that DNA adsorbed on the surface of nanoparticles was resistant to degradation by DNase 1. Macrophage cells incubated with the DNA-nanoparticle complexes had increased production of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). We probed two intracellular DNA sensing pathways, toll-like receptor 9 (TLR9) and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), to determine how cells sense the DNA-nanoparticle complexes. We found that the cGAS-STING pathway is the primary route for the interaction between DNA-nanoparticles and macrophages. These studies provide a molecular and cellular-level understanding of DNA-nanoparticle-macrophage interactions. In addition, this work provides the mechanistic information necessary for future in vivo experiments to elucidate the role of DNA-particle interactions in autoimmune diseases, providing a unique experimental framework to develop novel therapeutic approaches.

Autoimmune diseases are characterized by vast alterations in immune responses, but the pathogenesis remains sophisticated and yet to be fully elucidated. Multiple mechanisms regulating cell differentiation, maturation, and death are critical, among which mitochondria-related cellular organelle functions have recently gained accumulating attention. Mitochondria, as a highly preserved organelle in eukaryotes, have crucial roles in the cellular response to both exogenous and endogenous stress beyond their fundamental functions in chemical energy conversion. In this review, we aim to summarize recent findings on the function of mitochondria in the innate immune response and its aberrancy in autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, etc., mainly focusing on its direct impact on cellular metabolism and its machinery on regulating immune response signaling pathways. More importantly, we summarize the status quo of potential therapeutic targets found in the mitochondrial regulation in the setting of autoimmune diseases and wish to shed light on future studies.

Bullous pemphigoid (BP) is an autoimmune blistering disease that targets the haemidesmosomal proteins, mainly BP180. Extracellular vesicles (EVs) have been demonstrated to carry tissue-specific autoantigens in the setting of autoimmune diseases and transplant organ rejection; this phenomenon was demonstrated to have pathogenic implications in autoimmune diseases and to correlate with transplant rejection severity. The purpose of this study was to identify the presence of BP targeted autoantigens in blister fluid derived EVs. We isolated, by size exclusion chromatography, EVs derived from blisters of BP-patients and from suction blisters of healthy donors. EV characterization was performed by flow cytometry and nanoparticle tracking analysis. Western blot analysis was used to investigate the presence of autoantigens. A suspension enriched in EVs was efficiently obtained from blister fluid from patients and healthy donors. EV-enriched fractions were enriched in particles with a size distribution characterizing small-EVs (main peak was present at 94.5 nm). BP180 was found, by western blot analysis, in EVs derived from blister fluid of 3 out 6 BP patients and in none of EVs isolated from suction blister fluid of healthy donors. BP230 and Dsg1 were not detectable in EVs of any of the samples. No specific clinical characteristics seemed to correlate to the presence of BP180 in EVs. The discovery of BP180 in EVs derived from blister fluid might help understanding BP pathogenesis.

Influence of X chromosome in sex-biased autoimmune diseases

An autoimmune disease is an inappropriate response to one's tissues due to a break in immune tolerance and exposure to self-antigens. It often leads to structural and functional damage to organs and systemic disorders. To date, there are no effective interventions to prevent the progression of autoimmune diseases. Hence, there is an urgent need for new treatment targets. TRPM7 is an enzyme-coupled, transient receptor ion channel of the subfamily M that plays a vital role in pathologic and physiologic conditions. While TRPM7 is constitutively activated under certain conditions, it can regulate cell migration, polarization, proliferation and cytokine secretion. However, a growing body of evidence highlights the critical role of TRPM7 in autoimmune diseases, including rheumatoid arthritis, multiple sclerosis and diabetes. Herein, we present (a) a review of the channel kinase properties of TRPM7 and its pharmacological properties, (b) discuss the role of TRPM7 in immune cells (neutrophils, macrophages, lymphocytes and mast cells) and its upstream immunoreactive substances, and (c) highlight TRPM7 as a potential therapeutic target for autoimmune diseases.

Physiological models for in vivo imaging and targeting the lymphatic system: Nanoparticles and extracellular vesicles.

T Follicular helper (Tfh) cells, a unique subset of CD4+ T cells, play an essential role in B cell development and the formation of germinal centers (GCs). Tfh differentiation depends on various factors including cytokines, transcription factors and multiple costimulatory molecules. Given that OX40 signaling is critical for costimulating T cell activation and function, its roles in regulating Tfh cells have attracted widespread attention. Recent data have shown that OX40/OX40L signaling can not only promote Tfh cell differentiation and maintain cell survival, but also enhance the helper function of Tfh for B cells. Moreover, upregulated OX40 signaling is related to abnormal Tfh activity that causes autoimmune diseases. This review describes the roles of OX40/OX40L in Tfh biology, including the mechanisms by which OX40 signaling regulates Tfh cell differentiation and functions, and their close relationship with autoimmune diseases.

We sought to determine whether immune reactivity occurs between anti-SARS-CoV-2 protein antibodies and human tissue antigens, and whether molecular mimicry between COVID-19 viral proteins and human tissues could be the cause. We applied both human monoclonal anti-SARS-Cov-2 antibodies (spike protein, nucleoprotein) and rabbit polyclonal anti-SARS-Cov-2 antibodies (envelope protein, membrane protein) to 55 different tissue antigens. We found that SARS-CoV-2 antibodies had reactions with 28 out of 55 tissue antigens, representing a diversity of tissue groups that included barrier proteins, gastrointestinal, thyroid and neural tissues, and more. We also did selective epitope mapping using BLAST and showed similarities and homology between spike, nucleoprotein, and many other SARS-CoV-2 proteins with the human tissue antigens mitochondria M2, F-actin and TPO. This extensive immune cross-reactivity between SARS-CoV-2 antibodies and different antigen groups may play a role in the multi-system disease process of COVID-19, influence the severity of the disease, precipitate the onset of autoimmunity in susceptible subgroups, and potentially exacerbate autoimmunity in subjects that have pre-existing autoimmune diseases. Very recently, human monoclonal antibodies were approved for use on patients with COVID-19. The human monoclonal antibodies used in this study are almost identical with these approved antibodies. Thus, our results can establish the potential risk for autoimmunity and multi-system disorders with COVID-19 that may come from cross-reactivity between our own human tissues and this dreaded virus, and thus ensure that the badly-needed vaccines and treatments being developed for it are truly safe to use against this disease.

Autoimmune diseases (AIDs) are characterized with aberrant immune responses and their respective signaling pathways controlling cell differentiation, death, and survival. Cell metabolism is also an indispensable biochemical process that provides the very fundamental energy and materials. Accumulating evidences implicate that metabolism pathways have critical roles in determining the function of different immune subsets. Mechanisms of how immunometabolism participate in the pathogenesis of AIDs were also under intensive exploration. Here, in this review, we summarize the metabolic features of immune cells in AIDs and also the individual function of immunometabolism pathways, including glucose metabolism and tricarboxylic acid (TCA) cycle, in the setting of AIDs, mainly focusing on the potential targets for intervention. We also review studies that explore the intervention strategies targeting key molecules of metabolic pathways, such as mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and hypoxia-inducible factor 1a (HIF1a), in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The highlight of this review is to provide a comprehensive summary of the status quo of immunometabolism studies in AIDs and the potential translatable drug targets.