Search

Abstract Autoimmune disease is characterized by the proliferation of harmful immune cells, inducing tissue inflammation and ultimately causing organ damage. Current treatments often lack specificity, necessitating high doses, prolonged usage, and high recurrence rates. Therefore, the identification of innovative and safe therapeutic strategies is urgently required. Recent preclinical studies and clinical trials on inflammatory and autoimmune diseases have evidenced the immunosuppressive properties of mesenchymal stromal cells (MSCs). Studies have demonstrated that extracellular vesicles (EV) derived from MSCs can mitigate abnormal autoinflammation while maintaining safety within the diseased microenvironment. This study conducted a systematic review to elucidate the crucial role of MSC‐EVs in alleviating autoimmune diseases, particularly focusing on their impact on the underlying mechanisms of autoimmune conditions such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD). By specifically examining the regulatory functions of microRNAs (miRNAs) derived from MSC‐EVs, the comprehensive study aimed to enhance the understanding related to disease mechanisms and identify potential diagnostic markers and therapeutic targets for these diseases.

Abstract Background T cell receptor (TCR) signaling and T cell activation are tightly regulated by gatekeepers to maintain immune tolerance and avoid autoimmunity. The TRAIL receptor (TRAIL-R) is a TNF-family death receptor that transduces apoptotic signals to induce cell death. Recent studies have indicated that TRAIL-R regulates T cell-mediated immune responses by directly inhibiting T cell activation without inducing apoptosis; however, the distinct signaling pathway that regulates T cell activation remains unclear. In this study, we screened for intracellular TRAIL-R-binding proteins within T cells to explore the novel signaling pathway transduced by TRAIL-R that directly inhibits T cell activation. Methods Whole-transcriptome RNA sequencing was used to identify gene expression signatures associated with TRAIL-R signaling during T cell activation. High-throughput screening with mass spectrometry was used to identify the novel TRAIL-R binding proteins within T cells. Co-immunoprecipitation, lipid raft isolation, and confocal microscopic analyses were conducted to verify the association between TRAIL-R and the identified binding proteins within T cells. Results TRAIL engagement downregulated gene signatures in TCR signaling pathways and profoundly suppressed phosphorylation of TCR proximal tyrosine kinases without inducing cell death. The tyrosine phosphatase SHP-1 was identified as the major TRAIL-R binding protein within T cells, using high throughput mass spectrometry-based proteomics analysis. Furthermore, Lck was co-immunoprecipitated with the TRAIL-R/SHP-1 complex in the activated T cells. TRAIL engagement profoundly inhibited phosphorylation of Lck (Y394) and suppressed the recruitment of Lck into lipid rafts in the activated T cells, leading to the interruption of proximal TCR signaling and subsequent T cell activation. Conclusions TRAIL-R associates with phosphatase SHP-1 and transduces a unique and distinct immune gatekeeper signal to repress TCR signaling and T cell activation via inactivating Lck. Thus, our results define TRAIL-R as a new class of immune checkpoint receptors for restraining T cell activation, and TRAIL-R/SHP-1 axis can serve as a potential therapeutic target for immune-mediated diseases.

Background/Purpose: Chronic periodontitis (CP) and rheumatoid arthritis (RA) are the most common chronic inflammatory diseases and their immunopathogenesis is similar. The aim of this study was to evaluate the effect of non-surgical periodontal treatment on the serum levels of RA-related inflammatory markers in patients with chronic periodontitis. Methods: Thirty-one Taiwanese adults with CP were included. Demographics and periodontal parameters, including probing depth, clinical attachment level, and number of remaining teeth in the oral cavity, were recorded. All subjects received non-surgical periodontal treatment such as scaling and subgingival root planing. Serum samples were collected before and after the treatment. Serum levels of anti-citrullinated protein antibodies (ACPA), rheumatoid factor, tumor necrosis factor-α (TNF-α), C-reactive protein, interleukin-1β (IL-1β), and Interleukin-6 (IL-6) were measured using an enzyme-linked immunosorbent assay. Results: Non-surgical periodontal treatment significantly reduced the serum ACPA (p = 0.015) and TNF-α levels (p = 0.026) in CP patients, particularly in patients with generalized CP. Furthermore, there was a significant and positive correlation between the number of extracted teeth and the reduction in the serum ACPA (p = 0.05) and IL-1β levels (p = 0.029) after non-surgical periodontal treatment. Conclusion: Non-surgical periodontal therapy may aid in the control of RA-related inflammatory markers in patients with CP. A large-scale study with well-defined populations is needed to clarify the benefit of non-surgical periodontal therapy. Keywords: Periodontitis, Anti-citrullinated protein antibodies, Tumor necrosis factor-α, Non-surgical periodontal treatment

Abstract Immune checkpoints or coinhibitory receptors, such as cytotoxic T lymphocyte antigen (CTLA)-4 and programmed death (PD)-1, play important roles in regulating T cell responses, and they were proven to be effective targets in treating cancer. In chronic viral infections and cancer, T cells are chronically exposed to persistent antigen stimulation. This is often associated with deterioration of T cell function with constitutive activation of immune checkpoints, a state called ‘exhaustion’, which is commonly associated with inefficient control of tumors and persistent viral infections. Immune checkpoint blockade can reinvigorate dysfunctional/exhausted T cells by restoring immunity to eliminate cancer or virus-infected cells. These immune checkpoint blocking antibodies have moved immunotherapy into a new era, and they represent paradigm-shifting therapeutic strategies for cancer treatment. A clearer understanding of the regulatory roles of these receptors and elucidation of the mechanisms of T cell dysfunction will provide more insights for rational design and development of cancer therapies that target immune checkpoints. This article reviews recent advance(s) in molecular understanding of T cell dysfunction in tumor microenvironments. In addition, we also discuss new immune checkpoint targets in cancer therapy.

Immune checkpoints play critical roles in the regulation of T-cell effector function, and the effectiveness of their inhibitors in cancer therapy has been established. Immune checkpoint inhibitors (ICIs) constitute a paradigm shift in cancer therapy in general and cancer immunotherapy in particular. Immunotherapy has been indicated to reinvigorate antitumor T-cell activity and dynamically modulate anticancer immune responses. However, despite the promising results in the use of immunotherapy in some cancers, numerous patients do not respond to ICIs without the existence of a clear predictive biomarker. Overall, immunotherapy involves a certain degree of uncertainty and complexity. Research on the exploration of cellular and molecular factors within the tumor microenvironment (TME) aims to identify possible mechanisms of immunotherapy resistance, as well as to develop novel combination strategies involving the specific targeting of the TME for cancer immunotherapy. The combination of this approach with other types of treatment, including immune checkpoint blockade therapy involving multiple agents, most of the responses and effects in cancer therapy could be significantly enhanced, but the appropriate combinations have yet to be established. Moreover, the in-depth exploration of complexity within the TME allows for the exploration of pathways of immune dysfunction. It may also aid in the identification of new therapeutic targets. This paper reviews recent advances in the improvement of therapeutic efficacy on the immune context of the TME and highlights its contribution to cancer immunotherapy.

ObjectiveTumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell apoptosis by transducing apoptosis signals after interacting with its receptor (TRAIL-R). Although the actual biological role of TRAIL remains to be elucidated, recent accumulating evidence implies that TRAIL regulates immune responses and immune cell homeostasis via an apoptosis-independent pathway, suggesting a novel immune-regulatory role of TRAIL in autoimmune diseases. The purpose of this study is to address the immune-regulatory role and molecular mechanism of TRAIL in regulating T cell activation in autoimmune diseases.DesignTRAIL was administered to mice to induce experimental autoimmune encephalomyelitis (EAE), and to evaluate its impact on neuroinflammation and disease activity. The effects of TRAIL on neuroantigen [myelin oligodendrocyte glycoprotein (MOG)35–55]-activated T cell proliferation and cytokine production were investigated. TRAIL-treated MOG35–55-activated splenic Th17 cells were further adoptively transferred into Rag1 KO mice to induce passive EAE. Gene expression profiles of CD4+ T cells from EAE mice treated with TRAIL were analyzed by RNA sequencing and transcriptome analysis.ResultsTRAIL suppressed autoimmune encephalomyelitis and inhibited T cell reactivity to neuro-antigen in murine EAE, and the effects were dependent on TRAIL-R signaling. Moreover, TRAIL directly inhibited activation of MOG35–55-activated CD4+ T cells, resulting in suppression of neuroinflammation and reduced disease activity in adoptive transfer-induced EAE. Furthermore, TRAIL-R signaling inhibited phosphorylation of proximal T cell receptor (TCR)-associated tyrosine kinases in activated CD4+ T cells. Importantly, TRAIL/TRAIL-R interaction downregulated TCR downstream signaling genes in RNA sequencing and transcriptome analysis.ConclusionTRAIL/TRAIL-R interaction regulates CD4+ T cell activation in autoimmune inflammation and directly suppresses T cell activation via inhibiting TCR signaling, suggesting that TRAIL-R serves as a novel immune checkpoint in T cell responses.

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is the most common subtype of gastric lymphoma. Most gastric MALT lymphomas are characterized by their association with the Helicobacter pylori (HP) infection and are cured by first-line HP eradication therapy (HPE). Several studies have been conducted to investigate why most gastric MALT lymphomas remain localized, are dependent on HP infection, and show HP-specific intratumoral T-cells (e.g., CD40-mediated signaling, T-helper-2 (Th2)-type cytokines, chemokines, costimulatory molecules, and FOXP3+ regulatory T-cells) and their communication with B-cells. Furthermore, the reason why the antigen stimuli of these intratumoral T-cells with tonic B-cell receptor signaling promote lymphomagenesis of gastric MALT lymphoma has also been investigated. In addition to the aforementioned mechanisms, it has been demonstrated that the translocated HP cytotoxin-associated gene A (CagA) can promote B-cell proliferation through the activation of Src homology-2 domain-containing phosphatase (SHP-2) phosphorylation-dependent signaling, extracellular-signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), B-cell lymphoma (Bcl)-2, and Bcl-xL. Furthermore, the expression of CagA and these CagA-signaling molecules is closely associated with the HP-dependence of gastric MALT lymphomas (completely respond to first-line HPE). In this article, we summarize evidence of the classical theory of HP-reactive T-cells and the new paradigm of direct interaction between HP and B-cells that contributes to the HP-dependent lymphomagenesis of gastric MALT lymphomas. Although the role of first-line HPE in the treatment of HP-negative gastric MALT lymphoma remains uncertain, several case series suggest that a proportion of HP-negative gastric MALT lymphomas remains antibiotic-responsive and is cured by HPE. Considering the complicated interaction between microbiomes and the genome/epigenome, further studies on the precise mechanisms of HP- and other bacteria-directed lymphomagenesis in antibiotic-responsive gastric MALT lymphomas are warranted.

Discovertebral erosion with pseudoarthrosis is a well-known complication in ankylosing spondylitis but it is seldom mentioned in psoriatic arthritis. We report a 53-year-old woman with an 8-year history of pso-riatic arthritis who developed severe low back pain followed by sudden onset of numbness in the lower limbs, weakness and dysesthesia. Abnormal contour of L1 and L2 vertebrae and intervertebral disc space was noted during radiologic examination. Pseudoarthrosis was suspected based on extensive osseous re-sorption and reactive sclerosis about the discovertebral junction on magnetic resonance imaging study. She underwent emergency operation due to spinal instability with neurologic deficit. Pseudoarthrosis was confirmed intraoperatively. No evidence of infection or neoplasms was found. This case shows that pseudoarthrosis can be complicated in patients with psoriatic arthritis, and this possibility should be considered in patients with previously quiescent disease.

Persistent hepatitis B viral (HBV) infection results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). An efficient control of virus infections requires the coordinated actions of both innate and adaptive immune responses. In order to define the role of innate immunity effectors against HBV, viral clearance was studied in a panel of immunodeficient mouse strains by the hydrodynamic injection approach. Our results demonstrate that HBV viral clearance is not changed in IFN-α/β receptor (IFNAR), RIG-I, MDA5, MYD88, NLRP3, ASC, and IL-1R knock-out mice, indicating that these innate immunity effectors are not required for HBV clearance. In contrast, HBV persists in the absence of tumor necrosis factor-alpha (TNF-α) or in mice treated with the soluble TNF receptor blocker, Etanercept. In these mice, there was an increase in PD-1-expressing CD8+ T-cells and an increase of serum HBV DNA, HBV core, and surface antigen expression as well as viral replication within the liver. Furthermore, the induction of TNF-α in clearing HBV is dependent on the HBV core, and TNF blockage eliminated HBV core-induced viral clearance effects. Finally, the intra-hepatic leukocytes (IHLs), but not the hepatocytes, are the cell source responsible for TNF-α production induced by HBcAg. These results provide evidences for TNF-α mediated innate immune mechanisms in HBV clearance and explain the mechanism of HBV reactivation during therapy with TNF blockage agents.

Human osteoclast formation from mononuclear phagocyte precursors involves interactions between tumor necrosis factor (TNF) ligand superfamily members and their receptors. Recent evidence indicates that in addition to triggering apoptosis, the TNF-related apoptosis-inducing ligand (TRAIL) induces osteoclast differentiation. To understand TRAIL-mediated signal transduction mechanism in osteoclastogenesis, we demonstrated that TRAIL induces osteoclast differentiation via a Tumor necrosis factor receptor-associated factor 6 (TRAF-6)-dependent signaling pathway. TRAIL-induced osteoclast differentiation was significantly inhibited by treatment with TRAF-6 siRNA and TRAF6 decoy peptides in both human monocytes and murine RAW264.7 macrophage cell lines, as evaluated in terms of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and bone resorption activity. Moreover, TRAIL-induced osteoclast differentiation was also abolished in TRAF6 knockout bone marrow macrophages. In addition to induction of NFATc1, treatment of TRAIL also induced ubiquitination of TRAF6 in osteoclast differentiation. Thus, our data demonstrate that TRAIL induces osteoclastic differentiation via a TRAF-6 dependent signaling pathway. This study suggests TRAF6-dependent signaling may be a central pathway in osteoclast differentiation, and that TNF superfamily molecules other than RANKL may modify RANK signaling by interaction with TRAF6-associated signaling.

Persistent hepatitis B viral (HBV) infection results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Recent studies in animal models of viral infection indicate that the interaction between the inhibitory receptor, programmed death (PD)-1, on lymphocytes and its ligand (PD-L1) play a critical role in T-cell exhaustion by inducing T-cell inactivation. High PD-1 expression levels by peripheral T-lymphocytes and the possibility of improving T-cell function by blocking PD-1-mediated signaling confirm the importance of this inhibitory pathway in inducing T-cell exhaustion. We studied T-cell exhaustion and the effects of PD-1 and PD-L1 blockade on intrahepatic infiltrating T-cells in our recently developed mouse model of HBV persistence. In this mouse animal model, we demonstrated that there were increased intrahepatic PD-1-expressing CD8+ and CD4+ T cells in mice with HBV persistence, but PD-1 upregulation was resolved in mice which had cleared HBV. The Intrahepatic CD8+ T-cells expressed higher levels of PD-1 and lower levels of CD127 in mice with HBV persistence. Blockade of PD-1/PD-L1 interactions increased HBcAg-specific interferon (IFN)-γ production in intrahepatic T lymphocytes. Furthermore, blocking the interaction of PD-1 with PD-L1 by an anti-PD-1 monoclonal antibody (mAb) reversed the exhausted phenotype in intrahepatic T lymphocytes and viral persistence to clearance of HBV in vivo. Our results indicated that PD-1 blockage reverses immune dysfunction and viral persistence of HBV infection in a mouse animal model, suggesting that the anti-PD-1 mAb might be a good therapeutic candidate for chronic HBV infection.