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摘要： Over the past three decades, the Hunt laboratory has developed advancements in mass spectrometry-based technologies to enable the identification of peptides bound to major histocompatibility complex (MHC) molecules. The MHC class I processing pathway is responsible for presenting these peptides to circulating cytotoxic T cells, allowing them to recognize and eliminate malignant cells, many of which have aberrant signaling. Professor Hunt hypothesized that due to the dysregulation in phosphorylation in cancer, that abnormal phosphopeptides are likely presented by this pathway, and went on to discover the first phosphopeptide presented by the MHC processing pathway. Thereafter, the laboratory continued to sequence MHC-associated phosphopeptides and contributed several improved methods for their enrichment, detection, and sequencing. This manuscript summarizes the most recent advancements in identification of modified MHC-associated peptides and includes the cumulative list of phosphopeptides sequenced by the Hunt lab. Further, many other post-translational modifications (PTMs) were found to modify MHC peptides, including O-GlcNAcylation, methylation, and kynurenine; in total, we present here a list of 2,450 MHC-associated PTM peptides. Many of these were disease specific and found across several patients, thus highlighting their potential as cancer immunotherapy targets. We are sharing this list with the field in hopes that it might be used in investigating this potential. Overall, the Hunt lab's contributions have significantly advanced our understanding of antigen presentation and dysregulation of PTMs, supporting modern immunotherapy and vaccine development efforts.

关键词： 慢性中性粒细胞白血病   意义未明的单克隆免疫球蛋白血症   临床相关性   发病机制   治疗   预后  

摘要： 慢性中性粒细胞白血病是一种罕见的不伴有BCR-ABL1融合基因突变的骨髓增殖性疾病（myeloproliferative neoplasms， MPN）[1]，多见于老年群体，其主要的临床特征包括外周血中性粒细胞计数的显著升高，以及骨髓中粒系的过度增殖，不伴有髓系细胞形态学发育的异常。此外，患者常常伴有肝脏和脾脏的肿大。另一方面，意义未明的单克隆免疫球蛋白血症（MGUS）是一种与浆细胞产生的M蛋白相关的疾病，常是多发性骨髓瘤发展过程中的一个早期阶段，可伴有肾脏、心脏等多器官功能障碍。

关键词： Autoimmunity   Neuroinflammation  

摘要： In chronic inflammatory disorders of the central nervous system (CNS), tissue-resident self-reactive T cells perpetuate disease. The specific tissue factors governing the persistence and continuous differentiation of these cells remain undefined but could represent attractive therapeutic targets. In a model of chronic CNS autoimmunity, we find that oligodendrocyte-derived IL-33, an alarmin, is key for locally regulating the pathogenicity of self-reactive CD8+ T cells. The selective ablation of IL-33 from neo-self-antigen-expressing oligodendrocytes mitigates CNS disease. In this context, fewer self-reactive CD8+ T cells persist in the inflamed CNS, and the remaining cells are impaired in generating TCF-1low effector cells. Importantly, interventional IL-33 blockade by locally administered somatic gene therapy reduces T cell infiltrates and improves the disease course. Our study identifies oligodendrocyte-derived IL-33 as a druggable tissue factor regulating the differentiation and survival of self-reactive CD8+ T cells in the inflamed CNS. This finding introduces tissue factors as a novel category of immune targets for treating chronic CNS autoimmune diseases.

关键词： 猪伪狂犬病病毒   US9蛋白   US2蛋白   原核表达   多克隆抗体  

摘要： 多种商品化猪伪狂犬病病毒(PRV)疫苗毒株基因组缺失US9和US2基因。为探究US9和US2蛋白在鉴别PRV野毒株感染及疫苗毒株免疫猪的血清，以及抗US9和US2蛋白多克隆抗体在鉴别PRV野毒株及疫苗毒株感染细胞的可行性，本研究通过原核表达系统表达PRV US9和US2蛋白，纯化后免疫小鼠制备多克隆抗体。研究结果表明，经纯化处理的US9和US2蛋白在间接酶联免疫吸附试验(ELISA)中表现出特异性识别能力，能够与感染野毒株PRV CD22的猪血清产生免疫反应，但与接种疫苗毒株PRV Bartha-K61的猪血清不反应。此外，试验制备的小鼠抗US9和US2蛋白多克隆抗体在蛋白质印迹试验(Western-blot)和间接免疫荧光试验(IFA)中均能特异性识别PRV CD22感染的细胞，而不与疫苗毒株PRV Bartha-K61感染的细胞发生反应。本研究成功获得了具有鉴别诊断价值的PRV US9和US2蛋白及其多克隆抗体，为深入探索PRV US9和US2蛋白的功能特性，以及开发基于PRV疫苗毒株的新型诊断试剂奠定了重要基础。

关键词： IL-6   IL-6R   thyroid eye disease (TED)   Graves' ophthalmopathy   Graves' orbitopathy   Graves' disease   thyroid-associated orbitopathy (TAO)  

摘要： Elevated serum interleukin-6 (IL-6) levels have been shown to correlate with disease activity in patients with thyroid eye disease (TED), a complex, heterogeneous, autoimmune disease affecting thousands of people worldwide. IL-6 plays a pivotal role in the pathogenesis of TED through three key mechanisms that together may contribute to inflammation, tissue expansion, remodeling, and fibrosis within the orbit. First, IL-6 drives an autoimmune response targeting the thyroid-stimulating hormone receptor (TSHR) by promoting the production of autoantibodies (i.e. TSHR-Ab, TSI), thereby triggering TSHR-dependent immune pathways. Second, IL-6 stimulates the activation and differentiation of orbital fibroblasts, which contributes to the inflammatory process and increase adipogenesis. Finally, IL-6 stimulates T-cell-mediated inflammation, amplifying the immune response within orbital tissues. Although corticosteroids and surgery have served as mainstays of TED treatment, a multimodal approach is often required due to the disease's heterogeneous presentation and response to current treatment options. TED is a chronic, lifelong condition characterized by periods of exacerbation and remission, with inflammation playing a central role in disease progression and severity. Because inflammation can flare intermittently throughout a patient's life, there is growing interest in targeting specific components of the immune system to reduce disease activity and severity. This review focuses on the current evidence supporting IL-6 as a key mediator of TED pathogenesis and explores its potential as a diagnostic biomarker and therapeutic target of the disease.

关键词： COVID-19   Vaccination   GWAS   MHC locus   Common side effects   HLA  

摘要： Individual differences have been observed in side effects after vaccination for COVID-19, and host genetic factors have been suggested as a contributing factor. Here, we conducted a genome-wide association study (GWAS) involving 2,554 Japanese corporate employees who received a third booster dose of BNT162b2/Pfizer or mRNA-1273/Moderna vaccine. Although no genome-wide significant association was found for the presence of adverse symptoms, the GWAS for severity revealed six associated loci. The most significant association was observed between the severity of swelling of lymph nodes and chromosome 2q12 locus, including the IL1RL1, IL18R1, and IL18RAP genes (lead variant: rs76152249;P = 1.46 x 10-9). Pathway analysis suggested associations between immune pathways related to the MHC locus, including HLA genes, and the occurrence and severity of fever, and the NF-kappa B binding pathway and those of itching at the injection site. In addition, a meta-analysis of previous GWAS studies for the primary first or second dose of COVID-19 vaccine revealed 818 variants from 72 loci that demonstrated genome-wide significant associations with any of 12 symptoms, and pathway analysis identified immune pathways related to the MHC locus, suggesting shared genetic risks among primary and booster vaccinations. These results may help control side effects following COVID-19 vaccination.

关键词： Pancreatic Cancer   Immunosuppression   MHC   Prognosis   Biomarker  

摘要： The low immunogenicity of pancreatic cancer inhibits effective antitumor immune responses, primarily due to the immune evasion mediated by low expression of the major histocompatibility complex (MHC). Through comprehensive analysis, our study identifies UPK3B as a gene closely associated with low MHC expression and low immunogenicity in pancreatic cancer. UPK3B has been reported as a marker of primary mesothelial cells, mature epicardium and promotes extracellular matrix signaling. However, the role of UPK3B in pancreatic cancer remain unclear. We found that UPK3B is highly predictive of overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC) and is significantly related to clinical features, immune cell infiltration, and response to immune checkpoint inhibitor (ICI) therapy. Gene enrichment analysis revealed significant downregulation of immune regulatory and BCR signaling pathways in the UPK3B high-expression group. Additionally, UPK3B is positively correlated with immunosuppressive cells, suggesting that high UPK3B expression may inhibit antitumor immune responses by promoting low MHC expression. UPK3B is also positively correlated with immune checkpoints, indicating that tumors with high UPK3B expression may not benefit from ICI therapy. Therefore, UPK3B may serve as a novel biomarker and therapeutic target for pancreatic cancer.

关键词： Intracranial infection   Post-neurosurgery   Cell index   CSF PCT   CSF IL-6  

摘要： This study evaluated the predictive value of cell index (CI), cerebrospinal fluid procalcitonin (CSF PCT), and cerebrospinal fluid interleukin-6 (CSF IL-6) for detecting intracranial infection after neurosurgery. A two-center, prospective study analyzed CSF samples from ICU patients suspected of having intracranial infection following neurosurgery from January 2020 to June 2023. Patients with infection had longer operation times and longer stays in the ICU. The AUCs for single biomarkers ranged from 0.829 to 0.860, with the highest AUC of 0.938 observed for the combined biomarkers CI + CSF PCT + CSF IL-6. CI was most effective in patients with elevated CSF RBC counts, and PCT was most effective for detecting Gram-negative infections. The combined use of these biomarkers enhances early diagnosis of intracranial infection after neurosurgery and warrants further study.

关键词： Antimetabolites   immunosuppression   TNF inhibitor   uveitis  

摘要： Purpose: To compare the corticosteroid sparing efficacy of frequently used antimetabolites to tumor necrosis factor (TNF) inhibitors in the management of noninfectious ocular inflammation. Methods: Retrospective analysis of patients with noninfectious uveitis on conventional antimetabolite (methotrexate, mycophenolate mofetil, azathioprine,or leflunomide, "CONV") or a TNF inhibitor (adalimumab or infliximab, "TNFi") with active inflammation or more than 7.5 mg daily prednisone. Eyes were assessed in three groups: CONV only, TNFi only and combination of both (COMB). Cox regression models compared treatment success, adjusted for age, race, smoking, anatomic location of uveitis, duration of uveitis and visual acuity. Corticosteroid sparing success was defined as: inactive or slightly active uveitis on <=7.5 mg daily oral prednisone and <=2 drops of prednisolone acetate 1%. Results: There were 1475 eligible patients in the analysis. By 6 and 12 months, respectively, the Cox model-predicted, percentage success was 27.6% and 44.9% for the CONV group;34.2% and 53.9% in the TNFi group and 39.9% and 61.1% for the COMB group. COMB was more likely than CONV to achieve success (adjusted HR 1.58 (95% confidence interval (CI), 1.28, 1.95, p < 0.0001). Factors associated with lower success were age under 18 years, smoking, visual acuity worse than 20/50 at cohort entry, over 4-year duration of uveitis and daily baseline prednisone 7.5 mg or higher (all p < 0.05). Conclusion: Our results suggest COMB is more effective than CONV at achieving disease quiescence and corticosteroid sparing success among patients with active noninfectious uveitis. More research is needed to determine if TNFi alone is superior to CONV for uveitic corticosteroid-sparing.

关键词： Aqueous humor   interleukin-6   pentraxin 3   uveitis  

摘要： Purpose: Evidence exists that pentraxin 3 (PTX3) is involved in the pathogenesis of autoimmune diseases. The aim of this study was to analyze the levels of PTX3 in aqueous humor (AH) samples from patients with specific autoimmune uveitic entities. In addition, we correlated PTX3 levels with the levels of proinflammatory cytokines and chemokines and the clinical disease activity. Methods: AH samples from patients with active uveitis associated with human leukocyte antigen (HLA)-B27-related inflammation (n = 12), Beh & ccedil;et's disease (BD) (n = 13), Vogt-Koyanagi-Harada (VKH) disease (n = 12), sarcoidosis (n = 8) and control subjects (n = 9) were measured with the use of multiplex assays. Results: When considering all uveitis patients as one group (n = 45), PTX3 levels were significantly increased compared to controls (p = 0.002). When comparing the four individual disease groups to controls, PTX3 levels were significantly higher in only HLA-B27-associated uveitis (p < 0.001). PTX3 levels were significantly higher in patients with HLA-B27-associated uveitis than in patients with BD (p = 0.034) and VKH disease (p < 0.001). PTX3 levels had a significant correlation with clinical disease activity (r = 0.480;p = 0.001) and strong positive correlations with aqueous humor levels of interferon-gamma (r = 0.749;p < 0.001), interleukin (IL)-1 ss (r = 0.804;p < 0.001), IL-6 (r = 707;p < 0.001), CCL20 (r = 0.691;p < 0.001) and CXCL8 (r = 0.775;p < 0.001). Conclusions: PTX3 is an inflammatory marker and might exert a pathogenic role in HLA-B27-associated uveitis.