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Viruses pose a significant threat to humans by causing numerous infectious and potentially fatal diseases. Understanding how the host's innate immune system recognizes viruses is essential to understanding pathogenesis and ways to control viral infection. Innate immunity also plays a critical role in shaping adaptive immune responses induced by vaccines. Recently developed adjuvants often include nucleic acids that stimulate pattern recognition receptors which are essential components of innate immunity necessary for activating antigen-presentation cells and thereby bridging innate and adaptive immunity. Therefore, understanding viral nucleic acid sensing by cytosolic sensors is essential, as it provides the potential means for developing new vaccine strategies, including effective adjuvants. [ABSTRACT FROM AUTHOR]

B-lymphocyte-induced maturation protein 1 (Blimp-1) is a transcription factor that, among other functions, modulates metabolism and helps to regulate antioxidant pathways, which is important in the context of chronic inflammatory diseases like diabetes, cardiovascular disease, and autoimmune disease. In immune cell function, Blimp-1 has a modulatory role in the orchestration of metabolic reprogramming and as a promoter of anti-inflammatory cytokines, including IL-10, responsible for modulating oxidative stress and immune homeostasis. Moreover, Blimp-1 also modulates key metabolic aspects, such as glycolysis and fatty acid oxidation, which regulate reactive oxygen species levels, as well as tissue protection. This review depicts Blimp-1 as an important regulator of antioxidant defenses and anti-inflammation and suggests that the protein could serve as a therapeutic target in chronic inflammatory and metabolic dysregulation conditions. The modulation of Blimp-1 in diseases such as diabetic coronary heart disease and atherosclerosis could alleviate oxidative stress, augment the protection of tissues, and improve disease outcomes. The therapeutic potential for the development of new treatments for these chronic conditions lies in the synergy between the regulation of Blimp-1 and antioxidant therapies, which are future directions that may be pursued. This review emphasizes Blimp-1's emerging importance as a novel regulator in the pathogenesis of inflammatory diseases, providing new opportunities for therapeutic intervention. [ABSTRACT FROM AUTHOR]

We reported that an acquired miR-142 deficit transforms chronic phase (CP) chronic myeloid leukemia (CML) leukemic stem cells (LSCs) into blast crisis (BC) LSCs. Given the role of miR-142 in the development and activity of the immune system, we postulated that this deficit also promotes LSC immune escape. Herein, we report on IL-6-driven miR-142 deficit occurring in T cells during BC transformation. In CML murine models, miR-142 deficit impairs thymic differentiation of lymphoid-primed multipotent progenitors (LMPP) into T cells and prevents T cells' metabolic reprogramming, thereby leading to loss of T cells and leukemia immune escape. Correcting miR-142 deficit with a miR-142 mimic compound (M-miR-142), alone or in combination with immune checkpoint antibodies, restores T cell number and immune activity, leading to LSC elimination and prolonged survival of BC CML murine and patient-derived xenograft models. These observations may open new therapeutic opportunities for BC CML and other myeloid malignancies. Acquired miR-142 deficit in leukemic stem cells has been associated with chronic myeloid leukemia blast crisis. Here the authors show that acquired miR-142 deficit in T cells further enables leukemic stem cells to escape immune surveillance and supports disease growth. [ABSTRACT FROM AUTHOR]

Small fiber neuropathy (SFN) belongs to a heterogeneous group of disorders in which thinly myelinated Aδ and unmyelinated C-fibers are primarily affected, leading to neuropathic pain and autonomic symptoms. SFN can be associated with systemic conditions such as diabetes, autoimmune diseases, exposure to drugs and toxins, and infection, with the list of associated diseases continuing to expand. Variants in the SCN9A, SCN10A, and SCN11A genes encoding Nav 1.7, Nav 1.8, and Nav 1.9 sodium channel subunits, as well as in the TRPA1 gene, have been found in SFN patients, expanding the spectrum of underlying conditions and enhancing our understanding of pathophysiological mechanisms. There is also growing interest in immune-mediated forms that could help identify potentially treatable subgroups. According to international criteria, diagnosis is established through clinical examination, the assessment of intraepidermal nerve fiber density, and/or quantitative sensory testing. Autonomic functional tests allow for a better characterization of dysautonomia in SFN, which can be subclinical. Other tests can support the diagnosis. Currently, the management of SFN prioritizes treating the underlying condition, if identified, within a multidisciplinary approach that combines symptomatic pain therapy, lifestyle changes, and biopsychological interventions. Emerging insights from the molecular characterization of SFN channelopathies hold promise for improving diagnosis, potentially leading to the discovery of new drugs and refining trial designs in the future. This article reviews the clinical presentation, diagnostic workup, and advancing knowledge of associated conditions and interventional management of SFN. [ABSTRACT FROM AUTHOR]

Introduction: TNFα inhibitor (TNFi) immunogenicity in rheumatoid arthritis (RA) is a major obstacle to its therapeutic effectiveness. Although methotrexate (MTX) can mitigate TNFi immunogenicity, its adverse effects necessitate alternative strategies. Targeting nuclear factor of activated T cells (NFAT) transcription factors may protect against biologic immunogenicity. Therefore, developing a potent NFAT inhibitor to suppress this immunogenicity may offer an alternative to MTX. Methods: We performed a structure-based virtual screen of the NFATC2 crystal structure to identify potential small molecules that could interact with NFATC2. For validation, we investigated the effect of the identified compound on NFAT transcriptional activity, nuclear localization, and binding to the NFAT consensus sequence. In vivo studies assessed the ability of the compound to protect against TNFi immunogenicity, while ex vivo studies evaluated its effect on CD4+ T cell proliferation and B cell antibody secretion. Results: We identified duvelisib (DV) as a novel NFATC2 and NFATC1 inhibitor that attenuates NFAT transcriptional activity without inhibiting calcineurin or NFAT nuclear localization. Our results suggest that DV inhibits NFAT independently of PI3K by interfering with nuclear NFAT binding to the NFAT consensus promoter sequence. DV significantly protected mice from adalimumab immunogenicity and attenuated ex vivo CD4+ T cell proliferation and B cell antibody secretion. Discussion: DV is a promising NFAT inhibitor that can protect against TNFi immunogenicity without inhibiting calcineurin phosphatase activity. Our results suggest that the future development of DV analogs may be of interest as agents to attenuate unwanted immune responses. [ABSTRACT FROM AUTHOR]

NOD-like receptors are significant contributors to the immune response of fish against different types of pathogen invasion. NOD1 and NOD2 genes of yellow catfish (Tachysurus fulvidraco) were identified and characterized in this study. Yellow catfish NOD1 and NOD2 have open reading frames (ORFs) of 2841 and 2949 bp, encoding 946 and 982 amino acids, respectively. Both NOD1 and NOD2 are intracellular proteins lacking transmembrane regions and signal peptides. Sequence homology analysis revealed that the protein sequences of NOD1 and NOD2 of yellow catfish are highly similar to those of channel catfish. Both NOD1 and NOD2 showed high expression in the head kidney, and spleen. Following challenge with Flavobacterium columnare, NOD1 expression obviously increased in the liver, spleen, midgut, and hindgut, whereas NOD2 clearly increased in head kidney, and gut. Microscopic observation of gill tissues revealed evident epithelial hyperplasia in the secondary gill filaments at 3 and 6 hpi, with a notable decrease in the aspect ratio in comparison with the control group, followed by a return to baseline levels. These findings indicate a potential involvement of NOD1 and NOD2 genes in defense against F. columnare invasion. The findings of this study contribute valuable insights into NOD1 and NOD2's functions in the innate immune response of yellow catfish and other fish species to bacterial infection., (© 2025 Fisheries Society of the British Isles.)

We performed a systems vaccinology analysis to investigate immune responses in humans to an H5N1 influenza vaccine, with and without the AS03 adjuvant, to identify factors influencing antibody response magnitude and durability. Our findings revealed a platelet and adhesion-related blood transcriptional signature on day 7 that predicted the longevity of the antibody response, suggesting a potential role for platelets in modulating antibody response durability. As platelets originate from megakaryocytes, we explored the effect of thrombopoietin (TPO)-mediated megakaryocyte activation on antibody response longevity. We found that TPO administration enhanced the durability of vaccine-induced antibody responses. TPO-activated megakaryocytes also promoted survival of human bone-marrow plasma cells through integrin β1/β2-mediated cell-cell interactions, along with survival factors APRIL and the MIF-CD74 axis. Using machine learning, we developed a classifier based on this platelet-associated signature, which predicted antibody response longevity across six vaccines from seven independent trials, highlighting a conserved mechanism for vaccine durability., Competing Interests: Competing interests: R.v.d.M., M. Cortese and M. Coccia are or were employees of GSK. B.P. serves or has served on the External Immunology Board of GSK and on the Scientific Advisory Board of Sanofi, Medicago, Boehringer Ingelheim, Pharmajet, Icosavax, Imu Biosciences and Ed-Jen, and holds shares at CircBio and Orbital Therapeutics. R.v.d.M. and T.H. hold shares in the GSK group of companies. The other authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.)

We present a single-arm, phase II, neoadjuvant trial with the oncolytic virus talimogene laherparepvec (T-VEC) in 18 patients with difficult-to-resect cutaneous basal cell carcinomas. The primary end point, defined as the proportion of patients, who after six cycles of T-VEC (13 weeks), become resectable without the need for plastic reconstructive surgery, was already achieved after stage I (9 of 18 patients; 50.0%); thus the study was discontinued for early success. The objective response rate was 55.6% and the complete pathological response rate was 33.3%. Secondary end points included safety, relapse-free survival and overall survival, time to occurrence of new basal cell carcinomas and biological read outs. Only mild adverse events occurred. The 6-month relapse-free survival and overall survival rates were 100%. In two patients a new basal cell carcinoma was diagnosed. T-VEC led to a significant increase in cytotoxic T cells (P = 0.0092), B cells (P = 0.0004) and myeloid cells (P = 0.0042) and a decrease in regulatory T cells (P = 0.0290) within the tumor microenvironment. Together, neoadjuvant T-VEC represents a viable treatment option for patients with difficult-to-resect basal cell carcinomas (EudraCT no. 2018-002165-19)., Competing Interests: Competing interests: J.M.R. received speaker honoraria from Bristol-Myers Squibb, Roche, Amgen and Novartis and travel support by Sanofi, Roche and Bristol-Myers Squibb through the institution. P.T. received honoraria from Silverchair, unrestricted grants for education projects from Lilly, and honoraria for lectures from AbbVie, Lilly, FotoFinder and Novartis. J.T. reports an unrestricted grant from Lilly, consulting fees from Lilly, speaker honoraria from Lilly and Novartis, all outside the submitted work, as well as travel support from Almirall, AbbVie and Bristol-Myers Squibb through institution. C.H. reports speaker honoraria from Amgen, BMS, MSD, Novartis, Roche, participation in advisory Boards: Amgen, Astra Zeneca, BMS, Incyte, MSD, Novartis, Pierre Fabre, Roche and research funding by Amgen to the institution. The other authors declare no competing interests., (© 2025. The Author(s).)