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关键词： TNF-alpha   Aptamers   Aptasensors   Aptamer therapeutics   Biosensors  

摘要： Tumor necrosis factor-alpha (TNF-alpha) is a pivotal cytokine in the pathogenesis of numerous inflammatory and autoimmune diseases. Precise and sensitive detection of TNF-alpha is essential for both clinical applications and research endeavors. In the realm of cytokine detection, particularly TNF-alpha, the development of highly sensitive and specific biosensors has become a focal point. The biosensing landscape encompasses a variety of biorecognition elements, each with its unique set of characteristics. TNF inhibitors come with a significant price tag and, notably, do not yield positive responses in all patients. Despite the availability of numerous FDA-approved biologic agents (e.g., infliximab, adalimumab, certolizumab pegol, etc.) and monoclonal antibodies (e.g., adalimumab) targeting TNF-alpha, aptamers tailored for blocking TNF-alpha activities have yet to receive approval. Aptamers have rapidly gained recognition as readily available, versatile, and highly effective molecular tools for both therapeutic and diagnostic purposes in the context of TNF-alpha. In this manuscript, we explore the potential of short single-stranded DNA or RNA sequences known as aptamers as biorecognition elements in biosensors designed for the detection of TNF-alpha. We delve into the progress made in the development of aptamerbased TNF-alpha inhibitors and shed light on successful studies in this burgeoning field.

关键词： Lentinan   IL-22   ILC3s   Fucosylation   Macrophages   Barrier function   Ulcerative colitis  

摘要： Ulcerative colitis (UC) involves chronic, complex pathology of the intestinal mucosa. Current treatments are limited in efficacy and associated with adverse effects, highlighting the urgent need for improved therapeutic options. Lentinan (LNT), a polysaccharide drug commonly used in clinical immune modulation therapies, shows potential for UC treatment, though its specific targets and mechanisms remain unclear. In this study, LNT administration effectively mitigated DSS-induced colitis in mice, enhanced mucosal barrier function and antimicrobial defense. Specifically, LNT modulated the balance between tissue-resident and infiltrating macrophages, thereby improving pathogen clearance and enhancing the immunological barrier. Notably, we identified a novel effect of LNT in regulating the macrophage Dectin-1-ILC3 axis to increase IL-22 secretion. This led to the modulation of epithelial O-glycan fucosylation, antimicrobial peptides, and epithelial stem cells, thereby strengthening antimicrobial defenses and the physicochemical barrier. Neutralization with anti-IL-22 antibodies diminished the therapeutic effect of LNT in UC, underscoring the critical role of IL-22 in LNT-mediated treatment. Overall, this study highlights the potential of LNT as a novel therapeutic agent for UC, offering new insights into its molecular mechanisms and clinical application.

关键词： Human leukocyte antigen   Micropolymorphism   Crystallography   HIV   Psoriasis  

摘要： Micropolymorphisms drastically shape the antigen presentation characteristics of human leukocyte antigen class I (HLA-I) molecules, with profound implications for immune responses and disease susceptibility. HLA-C*12:02 and HLA-C*12:03 are closely related HLA-I allotypes that differ by a single amino acid substitution (R97W) but exhibit distinct associations with disease. HLA-C*12:02 has been shown to provide protective effects against HIV infection, playing a crucial role in controlling viral replication and slowing disease progression, whereas HLAC*12:03 is associated with increased susceptibility to psoriasis. We determined the X-ray crystal structures of the two allotypes presenting MARELHPEY (MY9) and RAFPGLRYV (RV9). Peptide residues that function as anchors, as well as those accessible for T-cell antigen receptor (TCR) contact, were identified. Our results, combined with those of biochemical studies, demonstrated that the R97W variation alters the peptide-binding groove (PBG) volume and charge, leading to conformational and stability changes in pHLA-C*12 complexes and ultimately affecting peptide-binding preferences for the two HLA-C*12 allotypes. This research not only advances our understanding of the impact of HLA-I micropolymorphisms but also offers clues for the use of structure-guided therapeutics to interfere with peptide binding.

关键词： Viruses   Epstein-Barr virus (EBV) BSRF1   Cellular moleculars   Antiviral response   Protein-protein interaction   NF-kappa B signaling pathway  

摘要： The Epstein-Barr virus (EBV) encoded tegument protein BSRF1 plays a significant role in the processes of viral maturation and release, however, it's not clear whether BSRF1 is involved in the modulation of host innate immunity. In this study, we demonstrated that BSRF1 can inhibit interferon beta (IFN-beta) production by down- regulating nuclear factor kappa B (NF-kappa B) activity and subsequently reducing the yield of inflammatory cytokines, thereby facilitating viral replication. Dual luciferase reporter assays indicated that BSRF1 may inhibit NF kappa B signaling at the level of IKK or between IKK and p65, while co-immunoprecipitation experiments revealed its association with multiple critical host adaptor proteins. Mechanistically, BSRF1 hinders the phosphorylation of I kappa B alpha at Ser32/36 and K48-linked polyubiquitination, thereby preventing proteasome-mediated degradation of I kappa B alpha by disrupting the assembly of the regulatory subunits within the IKK complex. Although BSRF1 interacts with p65 and its N-terminal domain, it does not alter the formation of the p65/p50 heterodimer. Instead, it prevents the nuclear translocation of p65 by inhibiting the dissociation of I kappa B alpha from the NF-kappa B dimer. Collectively, these findings suggested that BSRF1 assists EBV's evasion of host innate immune system by inhibiting the antiviral response to IFN-beta through the NF-kappa B signaling pathway, potentially contributing to the virus's ability to establish persistent infection and its association with tumorigenesis.

关键词： Rheumatoid arthritis   Autoimmune disease   Monocyte subsets   Classical monocytes   Intermediate monocytes   FIL1Z(IL-37)   FCGR1A(CD64)   In silico analysis  

摘要： Rheumatoid arthritis (RA) is one of the most common chronic autoimmune diseases. Chronic joint inflammation and bone destruction were shown to be caused by expanded monocytes in RA affected individuals. Interleukin-37 which known as FIL1Z(IL-37) is a well-known anti-inflammatory cytokine that plays a negative regulatory role of inflammation in RA. A total of 48 RA patients were divided equally into active RA group and stable RA group using the Disease Activity score (DAS)-28 score. Twenty-four age-and sex-matched healthy subjects were enrolled as controls. The expression level of Fc gamma receptor IA (FCGR1A(CD64)) on monocytes and their subsets in peripheral blood were assessed by flow cytometry (FC) and serum levels of FIL1Z(IL-37) were measured by ELISA. The mean fluorescence intensity (MFI) of FCGR1A(CD64) expressing classical and intermediate monocyte subsets and serum levels of FIL1Z(IL-37) were significantly elevated in RA patients compared to the control and positively correlated with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) and DAS-28 scores. The MFI of FCGR1A(CD64) expressing classical monocyte and serum levels of FIL1Z(IL-37) were significantly elevated in the active RA group compared to the stable RA group. The serum concentration of FIL1Z(IL-37) revealed very high specificity but limited sensitivity in discriminating between active and stable RA patients. Our results demonstrate a strong correlation between serum levels of FIL1Z (IL-37) and FCGR1A(CD64) expression on activated monocytes and their subsets in peripheral blood of RA patients. The results also depict that activated monocytes and their subsets may contribute to the elevated levels of FIL1Z(IL37) during an active disease status to counter-act the inflammatory process.

关键词： xMAP technology   CDC   Anti-HLA antibodies   Waiting list   Kidney transplant outcomes  

摘要： Background: Differences in sensitivity and specificity between the techniques used for the detection of anti-HLA antibodies before kidney transplantation (KT) can lead to contradictory results that influence patients' management. Our aim is to analyse whether the technique used, based on complement-mediated-cytotoxicity (CDC) or on microsphere fluorimetry (xMAP), conditions the waiting time until transplantation and its results. Methods: We performed a retrospective cohort study of the KT performed in our centre from 2006 to 2018 whose pre-transplant anti-HLA specificity determination and definition of prohibited antigens was performed by CDC (2006-2011) or by xMAP (2012-2018). Living donor KT recipients were excluded. The influence of each technique on the time on the waiting list and on the outcome of kidney transplantation was analysed, using as indicators the initial function of the graft, the rate of humoral rejection and graft survival. Results: During the period of the study, 622 patients were included (264 were studied by CDC and 358 by xMAP). Recipient and donor age was higher in the xMAP group (p < 0.001). Additionally, most sensitised patients were in the xMAP group (p < 0.001). However, they received a KT earlier. There were no differences in the rate of acute humoral rejection between groups. Nevertheless, graft survival was better in the xMAP group. Conclusions: The introduction of the xMAP technique in our centre has meant an improvement in terms of accessibility to transplantation and the initial management of the patient. However, it does not ameliorate the indicators of graft rejection.

关键词： B cell   IL‐12   autoimmunity   extrafollicular   germinal center   infection  

摘要： Upon activation, B cells undergo either the germinal center (GC) or extrafollicular (EF) response. While GC are known to generate high-affinity memory B cells and long-lived plasma cells, the role of the EF response is less well understood. Initially, it was thought to be limited to that of a source of fast but lower-quality antibodies until the GC can form. However, recent evidence strongly supports the EF response as an important component of the humoral response to infection. EF responses are now also recognized as a source of pathogenic B cells in autoimmune diseases. The EF response itself is dynamic and regulated by pathways that are only recently being uncovered. We have identified that the cytokine IL-12 acts as a molecular switch, enhancing the EF response and suppressing GC through multiple mechanisms. These include direct effects on both B cells themselves and the coordinated differentiation of helper CD4 T cells. Here, we explore this pathway in relation to other recent advancements in our understanding of the EF response's role and highlight areas for future research. A better understanding of how the EF response forms and is regulated is essential for advancing treatments for many disease states.

关键词： Children   Complex febrile seizures   Neutrophils/lymphocyte ratio   Interleukin   Viral epidemic  

摘要： This report aimed to analyze the potential effects of cytokines and neutrophils-to-lymphocytes ratio (NLR) on the occurrence of febrile seizures (FS) in children during the epidemic of novel coronavirus and influenza virus. Between July 2022 and April 2023, clinical data of 422 children with FS hospitalized in the Pediatrics, Shaoxing People's Hospital and the First Affiliated Hospital of Shaoxing University, during the epidemic and non-epidemic periods of novel coronavirus and influenza virus were analyzed. By comparing the various clinical characteristics of children with FS at different periods, comparison of variations in peripheral blood cell count, neutrophils, lymphocytes, hypersensitive C-creation protein, NLR, and inflammatory cytokines. Among 422 cases, 130 cases were classified as complex FS (CFS), while 292 cases of simple FS (SFS) were identified. During the time of the viral epidemic, 315 FS cases were observed, among which the incidence of CFS was 33.65%. In the non-viral epidemic period, there were 105 cases of FS. The incidence of CFS accounted for 22.86%. In addition, the levels of IL-4, IL-10, and tumor necrosis factor alpha (TNF-alpha) in children in the viral epidemic period were significantly higher than those in the non-epidemic period (P < 0.05). ROC curve analysis revealed that during the epidemic period, NLR (AUC = 0.724), IL-4 (AUC = 0.826), and IL-10 (AUC = 0.688) exhibited high predictive value for CFS children, and the indexes were statistically significant (P < 0.05). This study suggests that IL-4, IL-10, and NLR may play an important role in the pathogenesis of children with FS, especially those with CFS.

关键词： Rabies virus   Single-chain antibodies   CD9   IL-16   Adeno-associated virus   Cell-penetrating peptide  

摘要： Rabies, caused by the rabies virus (RABV;scientific name Rabies lyssavirus), is invariably fatal, and currently, there is no specific drug for its treatment. Previous studies have demonstrated the relationship between CD9 and the RABV. However, it remains unclear whether CD9 and IL-16 affect the RABV life cycle. To verify the role of CD9 and IL-16 in the life cycle of the RABV and further explore drugs that can inhibit RABV replication. We examined the effects of overexpression or underexpression of CD9 and IL-16 on the RABV replication process. Subsequently, adeno-associated virus (AAV) vector-delivered single-chain antibodies against RABV glycoprotein (RABV-G) or IL-16, were utilized to specifically inhibit RABV replication and explore their therapeutic potential in a mouse model of rabies. Our study revealed that the CD9 protein significantly affected RABV replication in cells. Also, IL-16 could effectively inhibited the RABV replication in vitro and prolonged mouse survival in vivo. Single-chain antibodies against RABV and IL-16, delivered by AAV vectors carrying exocytotic peptides and membrane-penetrating peptides, inhibited RABV proliferation in vitro, and suppressed RABV replication in mice in vivo. The tetraspanin CD9 facilitates RABV infection, and like the RABV-G, it may also be a good therapeutic target for RABV infection. The CD9 ligand molecule IL-16 and single-chain antibodies against RABV carried by AAV delivery system are promising therapeutic approaches for RABV infection.

关键词： Proteinase 3   IL33   Tumor-associated macrophages   Regulatory T cells   Tumor immunotherapy  

摘要： The immunosuppressive tumor microenvironment (TME) shaped by tumor-associated macrophages (TAMs) is essential for lung adenocarcinoma (LUAD) immune tolerance and tumor progression. Here, we first reported that proteinase 3 (PRTN3) promoted the alternative activation (M2) of TAMs and enhanced IL33/regulatory T cells (Tregs)-mediated tumor immunosuppression in LUAD. Firstly, clinical analysis revealed PRTN3 was highly expressed in TAMs and correlated with the tumor progression and poor prognosis in LUAD patients. Meanwhile, by using the myeloid cells-specific Prtn3-knockout mouse model, we demonstrated Prtn3 deficiency in macrophages remolded the immunosuppressive TME and suppressed tumor growth. The mechanism studies uncovered a novel signaling pathway that PRTN3 up-regulated IL33 expression in TAMs by suppressing AKT-mediated ubiquitinated degradation of FOXO1, which subsequently activated Il33 transcription. Furthermore, lack of PRTN3 or FOXO1 in macrophages greatly restrained IL33-induced Treg differentiation. Importantly, selective knockout of Prtn3 in macrophages significantly enhanced the antitumor effect of anti-PD1 therapy in the mouse model of LUAD. Thus, our work demonstrated that PRTN3 in macrophages, served as a key immunoregulator, contributed to impede the antitumor immune response through reinforcing the TAMs/Tregs crosstalk, which provided valuable insights to improve the immunotherapeutic effect by functional remodeling of TAMs to alleviate immunosuppression in LUAD.