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摘要： Neutralizing anti-interferon-gamma (IFN-gamma) autoantibodies (nAIGAs) impair IFN-gamma-mediated immunity, predisposing patients with nAIGAs to infection by nontuberculous mycobacteria, Talaromyces marneffei, and other intracellular pathogens. Current clinical management relies on continuous antimicrobial therapy, with no treatment offering sustained benefits. Here, we developed human chimeric autoantibody receptor (CAAR) T cells targeting autoreactive B cells expressing nAIGA B cell receptors (BCRs) using an IFN-gamma receptor-irresponsive IFN-gamma variant as bait. By exploiting a mouse model of nAIGA BCR-expressing B cell leukemia, we found that IFN-gamma CAAR T cells lack off-target toxicity, including IFN-gamma receptor cross-reactive toxicity and Fc-redirected toxicity. IFN-gamma CAAR T cells substantially reduced circulating AIGAs secreted from target cells in vivo. Further, IFN-gamma CAAR T cells effectively eliminated autoreactive B cells in ex vivo cultures of peripheral blood mononuclear cells from patients with nAIGAs. Together, these results demonstrate that IFN-gamma CAAR T cells may be a promising strategy to ameliorate nAIGA-associated infections by eliminating autoreactive B cells.

关键词： rheumatoid arthritis   exosome   C22:6   TLR4   IL-1 beta  

摘要： Introduction: Rheumatoid arthritis (RA) is an autoimmune disorder characterized by significant disability and teratogenic effects, for which there are few effective curative therapies. Exosomes derived from mesenchymal stem cells (MSCs) exhibit anti-inflammatory and tissue regenerative properties. This study aimed to investigate the therapeutic potential of exosomes derived from human classical interscapular brown adipocytes (hcBAC-exos) in alleviating symptoms of RA in a mouse model. Methods: We established a mouse model of collagen-induced arthritis (CIA) to evaluate the efficacy of hcBAC-exos. Specifically, we assessed the degree of RA remission by applying vitamin E emulsion, as well as a mixture of vitamin E emulsion and hcBAC-exos, to the foot paws of CIA mice. Additionally, the effects of hcBAC-exos on pro-inflammatory cytokines in macrophages (RAW264.7 cells) were investigated at the cellular level. The active components of hcBAC-exos were analyzed via lipidomics, and the mechanism of their ability to inhibit inflammation was explored. Results: Administration of hcBAC-exos significantly reduced the expression of pro-inflammatory cytokines in macrophages. In the CIA mouse model, transdermal application of hcBAC-exos led to notable decreases in ankle swelling and the serum levels of IL-1 beta and TNF alpha (P < 0.5). Mechanistically, lipidomic analysis showed that Docosahexaenoic acid (C22:6) is highly enriched in hcBAC-exos. Furthermore, we found that C22:6 specifically inhibits IL-1 beta expression by binding to the amino acids Y183, S210, E265, S182, and R223 of TLR4, mutating these amino acids results in the loss of C22:6 binding activity to TLR4. Discussion: Our findings suggest that the hcBAC-exos-C22:6-TLR4-IL-1 beta signaling pathway plays a crucial role in the context of RA, indicating the potential clinical applications of hcBAC-exos in the treatment of inflammatory conditions such as rheumatoid arthritis.

关键词： gypenosides   ferroptosis   chronic stress   lipid peroxidation   iron homeostasis  

摘要： Chronic stress can lead to nervous system dysfunction and depression-like behaviors in animals. Gypenosides can improve chronic stress-induced neuronal damage, but the protective mechanism remains poorly understood. This study aims to investigate the effect and mechanism of gypenosides on chronic stress-induced neuronal ferroptosis. Therefore, we established a chronic stress-induced neuronal damage model in vitro using corticosterone to induce PC12 cell injury. We demonstrated that ferroptosis inhibitors DFO and Ferrostatin-1 alleviated corticosterone-induced cell death in PC12 cells by reducing iron accumulation, lipid peroxidation, and increasing cell viability. Meanwhile, gypenosides attenuated ferroptosis agonist Erastin-induced ferroptosis in PC12 cells. Then, gypenosides ameliorated corticosterone-induced ferroptosis in PC12 cells. In terms of molecular mechanisms, gypenosides decreased the expression of Hepcidin and DMT1, and increased the expression of Ferritin and FPN1, thereby improving corticosterone-induced iron homeostasis disorders and iron accumulation. Moreover, gypenosides improved corticosterone-induced lipid peroxidation by inhibiting GLS2 expression, upregulating the expression of SLC7A11 and glutathione peroxidase 4, and reducing glutamate accumulation and GSH depletion. Gypenosides also reduced corticosterone-induced release of inflammatory cytokines, the expression of TNFR1, and the phosphorylation of NF-kappa B and p53 in PC12 cells. These findings indicate that gypenosides attenuate corticosterone-induced ferroptosis by inhibiting TNF-alpha/NF-kappa B signaling pathway in PC12 cells.

关键词： 单克隆抗体   抗体制备   杂交瘤技术   单个B细胞技术   AI辅助技术   联合应用   技术进展   应用研究  

摘要： 基因工程(Genetic engineering)与人工智能(Artificial Intelligence,AI)的发展极大推动了单克隆抗体制备技术的革新与优化,但当前如何利用这些前沿技术高效制备单克隆抗体仍亟待解决。本文将对比传统与现代单克隆抗体制备技术,深入探讨单个B细胞制备技术与AI辅助单抗制备技术这两大创新领域。通过解析单抗的结构特点,重点阐述两种技术的作用机理,并讨论单B测序技术与AI预测技术在单抗制备、疾病治疗等方面的最新研究进展。对这两种技术的协同应用进行前瞻性展望,期望通过它们的整合,实现单克隆抗体制备过程的全面自动化与个性化医疗发展,加速商业化进程。

关键词： IL-21   Radiotherapy   Melanoma   Anti-tumor  

摘要： Melanoma, known for its aggressive behavior and tendency to metastasize to the brain and lungs, is a formidable challenge in oncology. Radiotherapy is a potent treatment for localized solid tumors, effective against both intracranial and extracranial metastases. Yet, some melanoma patients exhibit substantial resistance to radiotherapy, with the underlying mechanisms of this resistance remaining elusive. While radiotherapy can stimulate the infiltration of immune cells, thereby triggering a range of immunostimulatory effects, it can also suppress the tumor microenvironment (TME), limiting its effectiveness. In physiological conditions, cytokines inhibit the activity of immunosuppressive cells through paracrine and autocrine signaling, while also activating immune cells to boost antitumor responses. Here, we found that Interleukin (IL)-21 expression was higher in the mice with good radiotherapy response to melanoma than in the mice with poor radiotherapy response. Interestingly, we also observed the higher infiltration of M2 TAMs and lower CD8+ T cells in the group with poor radiotherapy response. To tackle this issue, we explored the therapeutic potential of a plasmid encoding IL-21, delivered via attenuated Salmonella, in mice bearing melanomas. Our findings revealed that IL-21 administration significantly reduced M2 TAMs infiltration and enhanced CD8+ T cells infiltration and granzyme B (GZMB) expression within melanoma tumors. Most importantly, the combination of IL-21 with radiotherapy led to markedly tumor reduction compared to either treatment alone. This research highlights the potential of IL-21 as a valuable adjunct to radiotherapy in the treatment of melanoma, presenting a promising strategy for enhancing antitumor immune responses and optimizing patient outcomes.

关键词： alopecia areata   brodalumab   erythroderma   IL-17C   pityriasis rubra pilaris  

关键词： Cancer   Cytokines   Hematology   Immunotherapy   Transplantation  

摘要： BACKGROUND. The graft-versus-leukemia (GVL) effect contributes to the efficacy of allogeneic stem cell transplantation (alloSCT). However, relapse, indicative of GVL failure, is the greatest single cause of treatment failure. Based on preclinical data showing that IFN-gamma is important to sensitize myeloblasts to alloreactive T cells, we performed a phase I trial of IFN-gamma combined with donor leukocyte infusions (DLIs) in myeloblastic malignancies that relapsed after HLA-matched alloSCT. METHODS. Patients with relapsed acute myeloid leukemia or myelodysplastic syndrome after alloSCT were eligible. Patients self-administered IFN-gamma for 4 weeks (cohort 1) or 1 week (cohort 2), followed by DLI and concurrent IFN-gamma for a total of 12 weeks. Bone marrow samples were analyzed by single-cell RNA sequencing (scRNA-Seq) to assess in vivo responses to IFN-gamma by malignant myeloblasts. RESULTS. IFN-gamma monotherapy was well tolerated by all participants (n = 7). Treatment-related toxicities after DLI included grade I-II graft-versus-host disease (n = 5), immune effector cell-associated neurotoxicity syndrome (n = 2), and idiopathic pulmonary syndrome (n = 1), all of which resolved with corticosteroids. Four of 6 DLI recipients achieved minimal residual disease-negative complete remissions and full donor hematopoietic recovery. Median overall survival was 579 days (range, 97-906) in responders. scRNA-Seq validated in vivo activation of the IFN-gamma response pathway in hematopoietic stem cell-like or myeloid progenitor cells after IFN-gamma in analyzed samples. CONCLUSION. IFN-gamma was safe and well tolerated in this phase I study of IFN-gamma for relapsed acute myeloid leukemia and myelodysplastic syndrome after alloSCT, with a promising efficacy signal when combined with DLI. Larger studies are needed to formally test the efficacy of this approach. TRIAL REGISTRATION. *** NCT04628338.

关键词： Palmoplantar pustulosis   IL-23 inhibitors   guselkumab   risankizumab   small-molecule inhibitors   apremilast   clinical trials  

摘要： Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disease characterized by recurrent pustules, erythema, and scaling on the palms and soles, leading to a significantly reduced quality of life. Although PPP shares some immunopathological features with psoriasis vulgaris, it is distinguished by unique genetic predispositions, including a higher prevalence in East Asian populations, and a complex immune profile, particularly dysregulation of the IL-23/Th17 axis and IL-36 cytokines. Recent advances in psoriasis treatment have highlighted IL-23 inhibitors, which target the p19 subunit to suppress Th17 activation and inflammatory cytokines. Clinical trials show that IL-23 inhibitors significantly improve disease severity and patient-reported outcomes in PPP while maintaining favorable safety profiles. Notably, guselkumab and risankizumab have recently been approved for PPP treatment in Japan and Korea. In contrast, IL-17 inhibitors and IL-36 blockers have yielded mixed results. A recent phase 3 trial in Japan demonstrated the significant efficacy of apremilast in treating PPP, with a favorable safety profile, suggesting that apremilast may be a promising treatment option for PPP. Due to PPP's lower prevalence compared with psoriasis vulgaris, clinical trials remain limited. Further large-scale, controlled studies are needed to clarify the efficacy and long-term safety of these therapies in diverse populations. This review summarizes emerging evidence on IL-23 inhibitors and other treatments for PPP, detailing their mechanisms of action, clinical efficacy, safety profiles, current challenges, and future perspectives in optimizing therapy.

关键词： MHC class I   tapasin   TAPBPR   peptide editing   peptide selection   immunopeptidome  

摘要： Major Histocompatibility Complex class I (MHC-I) molecules bind and present peptides to cytotoxic T cells, protecting against pathogens and cancer. MHC-I is highly polymorphic and each allotype is promiscuous, and capable of binding a unique and diverse repertoire of peptide ligands. The peptide editing chaperone tapasin optimizes this allotype specific repertoire of peptides, resulting in the selection of high affinity peptides. MHC-I allotypes differ in the extent they engage tapasin. This suggests that tapasin-dependent MHC-I allotypes should present a less diverse repertoire that is enriched in higher-affinity peptides, and which are present in higher abundance, than tapasin independent MHC-I allotypes, which should present a broader repertoire containing peptides with a lower average affinity. Experimental verification of this hypothesis has been confounded by the different peptide binding specificities of MHC-I allotypes. Here, we independently investigated the peptide focusing function of tapasin by introducing a point mutation into a tapasin independent MHC-I allotype that dramatically increased its tapasin dependence without substantially altering its peptide binding specificity. This allowed us to demonstrate ligand focusing by tapasin at both the repertoire level in cellulo, and by using an in vitro system in which tapasin was artificially tethered to MHC-I, at the individual peptide level. We found that tapasin had a greater influence on tapasin dependent MHC-I molecules, and that tapasin modulated peptide selection according to peptide-MHC-I complex stability, disfavoring short-lived peptide-MHC-I complexes. Thus, tapasin dependent MHC-I molecules experience greater tapasin filtering, resulting in less diverse MHC-I immunopeptidomes that are enriched in high affinity peptide-MHC-I complexes.

摘要： The JAK-STAT signaling pathway is fundamental for immune system regulation. It involves phosphorylation of several types of STAT proteins in response to binding of cytokines to immune cell receptors. Traditionally, the immune signaling studies focus on measuring the levels of phosphorylated STATs (pSTATs) following individual cytokine application. We developed an experimental approach, based on multiparametric flow cytometry, to simultaneously measure the levels of five pSTATs after 15 minutes of cell treatment with high doses of individual cytokines and their paired combinations. Analysis of our experimental data involving peripheral blood mononuclear cells from healthy donors reveals systematic suppression of IL-10R, IL-6R, and IL-2Rβγ signaling in T cells, B cells, NK cells, and monocytes. This suppression is mediated by at least all tested cytokines that do not induce relevant pSTATs by themselves. Remarkably, the cytokines with negligible own signaling do act as prominent selective signaling suppressors. In contrast, the signaling of IFNAR, IFNGR, IL-4R, and IL-2Rαβγ remains largely unaffected by co-application of other cytokines. We propose that this pattern of signaling suppression represents an evolutionary developed mechanism enhancing the promptness, specialization, and efficiency of the immune response, while increased concentration of cytokines serves as a danger signal of inefficient response. We hypothesize that selective signaling suppression arises from the differential sensitivity of conformations of cytokine-receptor complexes to the increase of cell surface tension and stiffness, which is caused by effects following the binding of cytokines to membrane-associated molecules, including glycocalyx elements. While the rewiring of immune cell signaling should represent a powerful evolutionary tool for augmentation of adaptive response, it should also lead to the prolonged suppression of counteracting signaling pathways, culminating in cytokine release