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关键词： HLA sensitization   regulatory T cells   B cells   antibody production   transplantation   engineered immune receptors   human immunology   transplant rejection  

摘要： Organ transplantation is a lifesaving procedure, with 50,000 transplants happening every year in the United States. However, many patients harbor antibodies and B cells directed against allogeneic human leukocyte antigen (HLA) molecules, notably HLA-A2, greatly decreasing their likelihood of receiving a compatible organ. Moreover, antibody-mediated rejection is a significant contributor to chronic transplant rejection. Current strategies to desensitize patients non-specifically target circulating antibodies and B cells, resulting in poor efficacy and complications. Regulatory T cells (Tregs) are immune cells dedicated to suppressing specific immune responses by interacting with both innate and adaptive immune cells. Here, we genetically modified human Tregs with a chimeric anti-HLA antibody receptor (CHAR) consisting of an extracellular HLA-A2 protein fused to a CD28-CD3zeta intracellular signaling domain, driving Treg activation upon recognition of anti-HLA-A2 antibodies on the surface of alloreactive B cells. We find that HLA-A2 CHAR Tregs get activated specifically by anti-HLA-A2 antibody-producing cells. Of note, HLA-A2 CHAR activation does not negatively affect Treg stability, as measured by expression of the Treg lineage transcription factors FOXP3 and HELIOS. Interestingly, HLA-A2 CHAR Tregs are not cytotoxic towards anti-HLA-A2 antibody-producing cells, unlike HLA-A2 CHAR modified conventional CD4+ T cells. Importantly, HLA-A2 CHAR Tregs recognize and significantly suppress high affinity IgG antibody production by B cells from HLA-A2 sensitized patients. Altogether, our results provide proof-of-concept of a new strategy to specifically inhibit alloreactive B cells to desensitize transplant recipients.

关键词： 牛嵴病毒   结构蛋白   单克隆抗体   双抗体夹心ELISA  

摘要： 本研究旨在制备牛嵴病毒（bovine kobuvirus，BKV）单克隆抗体，并建立一种双抗体夹心ELISA检测方法。利用pET-30a(+)载体，原核表达BKV结构蛋白VP0，VP3和VP1，纯化后分别免疫BALB/c小鼠，三次免疫后分离小鼠脾细胞，与SP2/0细胞融合制备杂交瘤细胞，通过间接ELISA方法筛选，以制备的单克隆抗体为捕获抗体和检测抗体，优化抗体浓度和孵育时间等条件，建立特异性检测BKV的双抗体夹心ELISA方法。结果显示：获得2株稳定分泌单克隆抗体的杂交瘤细胞，分别命名为2A12和5E11，均为抗VP1蛋白抗体；叠加ELISA及抗体可变区序列分析结果表明其识别不同的抗原位点，单抗特异性检测结果显示，2株单抗特异性结合BKV，不与其它牛腹泻病毒结合；分别用RT-PCR方法和本研究建立的双抗体夹心ELISA方法，对107份临床样品进行检测，结果显示双抗体夹心ELISA方法与RT-PCR方法的阳性符合率为92.2%，阴性符合率为95.3%，总符合率为93.5%。综上，本研究制备了2株BKV单克隆抗体，并建立BKV的双抗体夹心ELISA方法，该方法特异性、重复性和敏感性良好，为BKV的快速诊断与防控奠定了基础。

关键词： 急性荨麻疹   过敏原检测   免疫球蛋白E   特异性免疫球蛋白E   白细胞介素6   C反应蛋白   临床价值  

摘要： 目的 探究急性荨麻疹患者血清免疫球蛋白（immunoglobulin E,IgE）、特异性免疫球蛋白（specific immunoglobulin e,s IgE）、白细胞介素-6(interleukin-6,IL-6)、C反应蛋白（C-reactive protein,CRP）水平表达及临床价值。方法 选取2023年3月至2024年3月驻马店市中心医院收治的120例急性荨麻疹患者资料行回顾性研究，并按1∶1比例选取同期体检健康者120例行病例对照研究，比较两组血清IgE、sIgE、IL-6、CRP水平的差异，通过ROC曲线分析血清IgE、sIgE、IL-6、CRP水平诊断急性荨麻疹的价值，以及IgE、s IgE、IL-6、CRP水平的相关性。结果 相较于对照组，研究组吸入性过敏原总检测率、食入性过敏原总检测率更高（P <0.05）；研究组总IgE抗体、过敏原s IgE抗体、CRP、IL-6水平也更高（P <0.05）。ROC曲线分析显示，血清IgE、s IgE、IL-6、CRP水平诊断急性荨麻疹的AUC分别为0.783、0.733、0.784、0.748；敏感度分别为0.492、0.508、0.492、0.500，特异度均为1.000。将上述因素纳入Logistic回归模型，通过回归系数（β值分别为0.028、2.167、0.681、0.257）统计分析得出联合数据（联合数据=0.028×IgE+2.167×sIgE+0.681×IL-6+0.257×CRP）。联合数据诊断急性荨麻疹的AUC为0.865，敏感度、特异度为0.850、0.883。Pearson相关性显示，血清IgE、sIgE、IL-6、CRP水平均呈正相关（r=0.494、0.568、0.576、0.461、0.403,P <0.05）。结论 急性荨麻疹患者血清存在多种过敏原，IgE、s IgE、IL-6、CRP水平表达可作为临床诊断急性荨麻疹的有效指标，且联合数据诊断价值更好。

摘要： Interleukin (IL)-23 is the master pathogenic cytokine in psoriasis and neutralization of IL-23 alleviates psoriasis. Psoriasis relapses after the withdrawal of anti-IL-23 antibodies, and the persistence of IL-23-producing cells potentially contributes to such recurrence, but the cellular source of IL-23 is unclear. Here we show that IL4I1+CD200+CCR7+ dendritic cells (CCR7+ DC) are the main producer of IL-23 by concomitantly expressing the IL-23A and IL-12B subunits in human psoriatic skin. Deletion of CCR7+ DC completely abrogates IL-23 production in a mouse model of psoriasis, while enforced expression of IL-23a in CCR7+ DC elicits not only alpha beta T cell-driven psoriasis-like skin disease, but also arthritis. CCR7+ DC co-localize with CD161+ IL-17-producing T cells and KRT17+ keratinocytes, which are located in the outermost layers of psoriatic epidermis and exhibit IL-17 downstream signatures. Our data thus identify CCR7+ DC as the source of IL-23 in psoriasis, and paves the way for IL-23-targeting therapy for suppressing the relapse of chronic inflammatory disorders like psoriasis.

关键词： Anti-IL-6 receptor antibody   Glucocorticoid   Osteoporosis   Aquaporin-4   IL-6   NMOSD  

摘要： Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease characterized by the production of autoantibodies against aquaporin-4 (AQP4). Treatment with prednisolone (PSL) or anti-IL-6 receptor (IL-6R) antibody can reduce the frequency of relapse in patients with AQP4 antibody-positive NMOSD. We previously established a mouse model of paralysis induced by intradermal immunization with AQP4 peptide. In this study, we investigated the effects of PSL and anti-IL-6R antibody treatment on paralysis and on bone fragility in this NMOSD mouse model. Prednisolone and anti-IL-6R antibody treatment each suppressed the clinical scores and incidence of paralytic symptoms in AQP4 peptide-immunized mice. High-PSL treatment induced thinning of cortical bone and reduction of tissue mineral density in the femoral shaft and a decrease in femoral bone strength, although it increased bone volume/tissue volume in the trabecular bone of the distal femur. In contrast, anti-IL-6R treatment showed no significant differences in bone strength or cortical thickness compared to the non-immunized naive group. Bone morphometric analysis showed that high-PSL treatment reduced the bone formation rate in both cortical and trabecular bone, with a predominance of bone resorption, whereas anti-IL-6R treatment demonstrated no notable effect on bone metabolism. These results suggest that anti-IL-6R antibody can prevent the development of paralytic symptoms in AQP4 peptide-immunized mice without reducing bone strength.

关键词： DQB1 mismatch   HLA matched unrelated donor   MMUD   MUD   PTCy   donor age   mismatched unrelated donor  

摘要：

关键词： SHP2   SHP099   IL-6   osteoclasts   growth plate injury  

摘要： Introduction Disruption of growth plate cartilage often leads to severe bone growth defects in children, necessitating novel therapeutic strategies. Following growth plate injury, an inflammatory response is rapidly initiated, resulting in the release of pro-inflammatory cytokines such as IL-6 into the injured tissue, which subsequently induce and enhance osteoclast generation and differentiation. This study investigates the role of SHP2 in regulating IL-6-driven osteoclastogenesis during growth plate injury *** Tibial drill-hole injuries were induced in C57BL/6 mice (n=9), with SHP099 (30 mg/kg, intra-articular) administered to intervention groups and tissues were harvested for qPCR/histology. RAW 264.7 cells were treated with RANKL (100 ng/ml) +/- IL-6 (100 ng/ml) +/- SHP099 (15 mu M). Osteoclast differentiation, expression level of pro-inflammatory cytokines and the associated signaling pathway were assessed via TRAP staining, Western blot, qPCR and *** SHP2/PTPN11, osteoclast markers (CTSK/OSCAR) and pro-inflammatory cytokines (IL-6, IL-1 beta, TNF-alpha) was upregulated and could be inhibited by SHP099 at injury sites. IL-6 enhanced p-SHP2/p-TAK1 expression, osteoclastogenesis and inflammatory response in vitro, while SHP099 effectively reduced osteoclast numbers, downregulating CTSK/OSCAR and pro-inflammatory cytokines (IL-6, IL-1 beta, TNF-alpha). Furthermore, the NF-kappa B pathway remained unaffected by SHP099, indicating a distinct signaling mechanism through which SHP2 regulates *** Our findings underscore the pivotal role of SHP2 as a downstream signaling molecule of IL-6 in mediating inflammatory responses during bone repair, suggesting that SHP2 inhibition may present a novel therapeutic approach to prevent pathological bone remodeling and enhance recovery following growth plate injuries. Future investigations should focus on the translational potential of SHP2 inhibitors in pediatric orthopedics.

关键词： Rheumatoid arthritis   autoimmune disease   erythrocyte sedimentation rate   disease activity score   tumor necrosis factor alpha   seronegative rheumatoid arthritis   seropositive rheumatoid arthritis  

摘要： Introduction: 14-3-3 eta (eta), an intracellular chaperonin, is elevated in the serum of patients with Rheumatoid Arthritis, a progressive inflammatory "autoimmune" disease that impacts joint function and daily activities. This study aimed to assess 14-3-3 eta levels in DMARD-na & iuml;ve Rheumatoid Arthritis patients and analyze their association with TNF-alpha, MMP-1, RA factor, ACCP, and disease activity. Methods: A cross-sectional study was conducted on 90 DMARD-na & iuml;ve RA patients. The clinical evaluation included the Health Assessment Questionnaire-Disability Index (HAQ-DI) and the Disease Activity Score of 28 joints using ESR (DAS28-ESR). Serum levels of RF, ACCP, 14-3-3 eta, TNF-alpha, and MMP-1 were measured using ELISA. Mann-Whitney and Spearman correlation tests were applied, with p < 0.05 considered statistically significant. Results: Among 90 RA patients (76 females, 14 males), 68(75.6%) were seropositive. Serum levels of 14-3-3 eta and TNF-alpha differed significantly between seropositive and seronegative groups. TNF- alpha correlated positively with both 14-3-3 eta (r = 0.397, p < 0.001) and MMP-1 (r = 0.284, p = 0.007). Discussion: The correlation between 14-3-3 eta and TNF-alpha suggests a possible role for 14-3-3 eta as an adjunctive biomarker in early RA. While findings are promising, the small sample size and lack of follow-up warrant cautious interpretation. Further longitudinal studies are needed to confirm its clinical utility and integration within composite biomarker models. Conclusion: Serum 14-3-3 eta may serve as a supportive biomarker for the diagnosis of early rheumatoid arthritis and assessment of disease activity. Its correlation with TNF-alpha reflects a potential link to inflammatory burden. Further large-scale, longitudinal studies are needed to confirm its clinical utility.

关键词： T -helper cell 9   Interleukin-9   Autoimmune disease   Rheumatoid arthritis   Multiple sclerosis   Systemic lupus erythematosus  

摘要： Autoimmune diseases (AIDs), such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, are caused by abnormal immune response that targets the body's own tissues. T-helper cell 9 (Th9) is a recently discovered subpopulation of T cells that primarily participates in inflammatory responses and immune regulation by secreting interleukin-9 (IL-9). IL-9 is a multifunctional cytokine that regulates the function of T and B cells, and also affects the activation and response of mast cells, macrophages, and other cells. Studies have shown that Th9 cells significantly affect the development of autoimmune diseases and are closely related to disease activity and pathological processes. Exploring drugs targeting Th9 cells or IL-9 and elucidating the regulatory mechanisms of Th9 and IL-9 in various AIDs will provide important insights for the development of novel therapeutic strategies.

关键词： Microenvironment   Immune response   Cancer  

摘要：