Objective To investigate the correlation between anemia and rheumatoid arthritis (RA), and to analyze the potential impact and causal relationship between them. Methods Using data from the National Health and Nutrition Examination Survey (NHANES) database, a logistic regression model was constructed to assess the association between anemia and RA; subgroup analysis was performed to verify the stability of the results. Subsequently, a two-sample mendelian randomization (MR) analysis was conducted to explore the bidirectional causal relationship between anemia and RA. Results Multivariate logistic regression analysis revealed a positive correlation between anemia and RA (OR=1.21, 95%CI: 1.05-1.40), and subgroup analysis further confirmed the stability of these results. Furthermore, MR analysis indicated a bidirectional causal relationship between anemia and RA, with no observed evidence of horizontal pleiotropy or heterogeneity. Conclusion Anemia and RA demonstrate a significant correlation and a bidirectional causal relationship at multiple levels.

Rheumatoid arthritis (RA) is a common systemic autoimmune disease characterized by progressive deterioration of bone and cartilage. Sex hormone-binding globulin (SHBG), a glycoprotein integral to the regulation of sex hormone bioavailability, may have a pivotal role in the pathogenesis of RA. This study aims to investigate the relationship between SHBG concentrations and the risk of RA, as well as the occurrence of related cardiovascular complications. The analysis included 25,051 adult participants from the National Health and Nutrition Examination Survey (NHANES) conducted between 2013 and 2023. Frailty was assessed using a 49-item frailty index, while medical conditions were self-reported via questionnaire. Logistic regression and mediation analyses were employed to evaluate these associations. Additionally, Kaplan–Meier survival curves were constructed to compare survival probabilities across different subgroups. Elevated SHBG levels were identified as a significant risk factor for RA. Both the frailty index and C-reactive protein (CRP) levels demonstrated positive correlations with RA. Importantly, the frailty index partially mediated the association between SHBG and RA, accounting for approximately 24.47

CD147 is a T cell activation-associated molecule which is closely involved in the formation of the immune synapse (IS). However, the precise role of CD147 in T cell activation and IS formation remains unclear. In the present study, we demonstrated that CD147 translocated to the IS upon T cell activation and was primarily distributed in the peripheral super molecular cluster (p-SMAC). The knock down of CD147 expression in T cells, but not in B cells, impaired IS formation. CD147 participated in IS formation between T cells and different types of antigen-presenting cells (APCs), including macrophages and dendritic cells. Ligation of CD147 with its monoclonal antibody (mAb) HAb18 effectively inhibited T cell activation and IL-2 secretion. CD98, a critical molecule interacting with CD147, was distributed in IS in a CD147-dependent way. Phosphorylation levels of T cell receptor (TCR) related molecules, like ZAP-70, ERK, and cJun, were down-regulated by CD147 ligation, which is crucial for the interaction of CD147 and TCR signaling transduction. CD147 is indispensable for the formation of immune synapses and plays an important role in the regulation of its function.

目的 本研究旨在探讨巨噬细胞亚型在类风湿关节炎相关间质性肺疾病(RA-ILD)患者外周血中的意义.方法 选取2017年1月至2021年12月在医院随访的158例RA-ILD患者入组本研究.RA-ILD患者分为活动组(n=63)和非活动组(n=65).活动组中,包括新诊断的RA-ILD和未治疗的受试者;非活动组中,符合缓解期的RA-ILD患者.30例单纯类风湿关节炎(RA)作为对照组.所有患者均采集外周血.流式细胞术检测巨噬细胞亚型:M1(CD14+CD86+CD80+)、M2a(CD14+CD206+CD301+)、M2b(CD14+CD206+CD86+)和 M2c(CD14+CD206+CD163+),还检测了细胞因子淋巴细胞亚群含量,包括白细胞介素(IL)(IL-1 β、IL-2、IL-4、IL-5、IL-6、IL-8、IL-10和IL-17)、干扰素(IFN)-α、IFN-γ和肿瘤坏死因子(TNF)-α.结果 M1标记CD80和M2标记CD163、CD301在活动性RA-ILD患者中高表达.活动组巨噬细胞以M1和M2a为主(P＜0.05).在非活动组中,M2倾向于极化为M2b和M2c(P＜0.05).与对照组相比,活动组IL-6显著升高(P＜0.05),非活动组IL-10、IL-4和IL-17显著升高(P＜0.05).结论 在活动的RA-ILD中,M1激活促进炎症,而M2a快速反应抑制炎症;在非活动组RA-ILD中,M2b和M2c在抑制炎症中起主要作用.

T cell acute lymphoblastic leukemia (T-ALL) is invasive and heterogeneous, and existing therapies are sometimes unsuccessful. Chimeric antigen receptor (CAR) T cell therapy is a breakthrough tumor treatment method, particularly for B cell acute lymphoblastic leukemia. We found that CD147 was highly expressed in tumor T cells of T-ALL patients and T cell lymphoma. Therefore, CD147-CAR T cells that contain a humanized single-chain variable fragment targeting human CD147 and a second-generation CAR frame were constructed for treating T-ALL. CD147-CAR T cells were able to maintain a healthy proliferation rate, preserving a subset of CD62L+/ CCR7+ memory T cells. CD147-CAR T cells showed a potent anti-tumor activity against human T-ALL cell line and T-ALL blasts, releasing high level of cytokines in the process. However, CD147-CAR T cells exhibited potential safety toward human normal cells and CD147-deficent cells. NOD/ShiLtJGpt-Prkd(cem26Cd52)Il2rg(em26Cd22)/ Gpt mice were used to establish a T-ALL xenograft model and CD147-CAR T cells conferred robust protection against T-ALL progression and significantly improved survival in mice. Overall, we found that CD147 is a potential antigen target of CAR T cell therapy for T-ALL.

目的:比较传统的以授课为主的教学方法(lecture based learning,LBL)模式和以问题为基础的教学法(problems based learning,PBL)联合LBL教学模式对肿瘤免疫教学效果的影响,以期提高教学质量.方法:在2016年肿瘤免疫教学中,选取空军军医大学临床医学专业两个班级共1 12名本科生,并将两个班级分别作为对照组(LBL)和实验组(LBL联合PBL),通过书面考试与调查问卷评估教学效果.结果:在理论考试中,实验组的考核总成绩显著高于对照组(P＜0.05),进一步分析发现,两组之间的客观题成绩无显著差异(P＞0.05),而实验组的理解应用题成绩显著高于对照组(P＜0.05).实验组中调查问卷的结果显示,91.7%的学生认为PBL模式优于传统LBL模式,且86.7%学生认为PBL联合LBL优于单一的PBL模式.结论:PBL联合LBL教学模式可提高肿瘤免疫课程的教学质量,并有利于培养高素质的医学人才,值得推广.

Rheumatoid arthritis (RA) is a common autoimmune disease in which T helper-type 17 (Th17) cells have been critically involved. CD147 is a T cell activation-associated molecule and is involved in T cell development. However, it remains unclear whether CD147 participates in Th17 responses in RA patients. In this study, we demonstrated that in both the RA and healthy controls (HC) groups, CD147 expression on CD4+ T cells was increased in CCR6+ and CD161+ subsets, and was associated with IL-17 production. Ligation of CD147 with its monoclonal antibody (mAb) strongly inhibited Th17 responses, and knock down of CD147 expression on CD4+ Tm cells specifically enhanced Th17 responses, triggered by coculture with in vitro activated monocytes from HC. Further functional studies showed that anti-CD147 mAb decreased the activation of AKT, mTORC1 and STAT3 signaling, which is known to enhance Th17 responses. Ligation of CD147 with its mAb on CD4+ Tm cells specifically reduced Th17 responses induced by in vitro or in vivo activated monocytes from RA patients. In collagen-induced arthritis model, anti-CD147 mAb treatment reduced the Th17 levels and severity of arthritis in vivo. These data suggest that CD147 plays a negative role in regulating human Th17 responses. Anti-CD147 mAb can limit the extraordinary proliferation of Th17 cells and may be a new therapeutic option in RA.

Objective Rheumatoid arthritis (RA) is a chronic inflammatory and angiogenic disease. This study aimed to explore the profiles of circulating angiogenic T cells (Tang cells) and the role of CD147 in Tang cell activation function in RA. Methods Samples were obtained from patients with RA and health controls (HC). Then, Tang cells were quantified by flow cytometry (FCM) in the samples from 87 patients with RA and 29 HC. Tang cells were purified by magnetic cell sorting in cell culture-conditioned media, and the phosphorylation signals were determined by FCM. In addition, cytokine levels were assessed by enzyme-linked immunosorbent assay. Results The percentage of circulating Tang cells increased and positively correlated with the number of endothelial progenitor cells in the RA group. Further, the percentage of Tang cells was closely related to disease activity, autoantibody positivity, and proangiogenic cytokine levels. Meanwhile, the expression of CD147 on Tang cells increased in patients with RA. CD147 participated in the Akt phosphorylation and VEGF level of the activated Tang cells. Conclusions CD147 may play a critical role in regulating VEGF production of activated Tang cells by affecting Akt signaling, which in turn may serve an essential function in angiogenesis and RA pathogenesis.

Objective Pain management is a huge challenge in the treatment of rheumatoid arthritis (RA), and central sensitization is reportedly involved in the development of pain. The current study was undertaken to explore the possible role of N-methyl-D-aspartate receptors (NMDARs) in the spinal mechanism of central sensitization in RA using a collagen-induced arthritis (CIA) model. Methods Mechanical hypersensitivity was assessed in C57BL/6 mice, before and after the induction of CIA via administration of chick type II collagen. Analgesic drugs, receptor antagonist, and kinase inhibitor were administrated intrathecally in the spinal cord. Protein expression and phosphorylation changes were detected via immunoblotting. Results CIA mice developed significant mechanical hypersensitivity, and spinal administration of the NMDAR antagonist D-2-amino-5-phosphonovaleric acid (D-APV) effectively attenuated peripheral pain hypersensitivity. There was specific enhancement of synaptic NR2B-containing NMDAR (NR2BR) expression in the spinal dorsal horns of the mice. Both the increased total protein expression of NR2B subunit and the enhanced total phosphorylation level of NR2B subunit at 1472 tyrosine promoted the synaptic expression of NMDAR in the mice. Intrathecal injection of tramadol suppressed synaptic NMDAR expression mainly by changing the synaptic phosphorylation state of NR2B subunit at Tyr1472. Extracellular signal-regulated protein kinases 2 (ERK2) activity synchronized with the synaptic expression of NR2BR, which was downregulated by the action of tramadol. Conclusion Specific enhancement of NR2BR in the spinal dorsal horn may be vital for central sensitization in the CIA model of RA. The NR2BR/ERK2 pathway may be a promising target for pain management in RA patients.

Background: The reduction of -aminobutyric acid (GABA) type A receptor-mediated inhibition has long been implicated in spinal sensitization of nociceptive responses. However, it is largely unknown which signaling cascades in spinal dorsal horn neurons are initiated by the reduced inhibition to trigger pain hypersensitivity.Methods: GABAergic inhibition was manipulated by intrathecal application of GABA type A receptor antagonist bicuculline in intact mice or by GABA type A receptor agonist muscimol in complete Freund's adjuvant-injected mice. Immunoblotting, coimmunoprecipitation, immunohistochemistry, and behavioral tests were used to explore the signaling pathways downstream of the altered GABAergic tone.Results: The study data revealed that the 61-kD isoform of striatal-enriched protein phosphatase (STEP61) was a key molecule that relayed the signals from GABAergic neurotransmission. The authors found that STEP61 was highly expressed in dorsal horn neurons. Under physiological conditions, STEP61 tonically interacted with and negatively controlled the activities of extracellular signal-regulated kinase and Src-family protein tyrosine kinases member Fyn, two critical kinases involved in spinal sensitization. Once GABAergic inhibition was impaired, STEP61 interaction with its substrates was substantially disturbed, allowing for activation of extracellular signal-regulated kinase and Fyn (n = 4 to 6). The hyperactivities of extracellular signal-regulated kinase and Fyn, along with STEP61 dysregulation, caused the tyrosine phosphorylation and synaptic accumulation of GluN2B subunit-containing N-methyl-d-aspartate subtype of glutamate receptors (n = 6), leading to GluN2B receptor-dependent pain hypersensitivity. Overexpression of wild-type STEP61 to resume its enzymatic activity significantly blocked the mechanical allodynia evoked by bicuculline and more importantly, alleviated chronic inflammatory pain (n = 6 in each group).Conclusion: These data identified STEP61 as a key intermediary for GABAergic inhibition to regulate pain sensitization.

Intrathecal application of α2 noradrenergic receptor agonists effectively alleviates the pathological pain induced by peripheral tissue injury. However, the spinal antinociceptive mechanisms of α2 noradrenergic receptors remain to be characterized. The present study performed immunohistochemistry and western blot to elucidate the signaling pathway initiated by α2 noradrenergic receptors in spinal dorsal horn of mice, and identified calcium/calmodulin-dependent protein kinase II (CaMKII) as an important target for noradrenergic suppression of inflammatory pain. Our data showed that intraplantar injection of Complete Freund's Adjuvant (CFA) substantially enhanced CaMKII autophosphorylation at Threonine 286, which could be abolished by intrathecal administration of α2 noradrenergic receptor agonist clonidine. Gi protein-coupled α2 noradrenergic receptor might inhibit cAMP-dependent protein kinase (PKA) to disturb CaMKII signaling. We found that pharmacological activation of PKA in intact mice also enhanced spinal CaMKII autophosphorylation level, which was completely antagonized by clonidine. Moreover, direct PKA inhibition in CFA-injected mice mimicked the suppressive effect of α2 noradrenergic receptors on CaMKII. PKA inhibition has been shown to downregulate CaMKII by enhancing protein phosphatase activity. Consistent with this notion, spinal treatment with protein phosphatase inhibitor okadaic acid ruled out clonidine-mediated CaMKII dephosphorylation in CFA-injected mice. Through PKA/protein phosphatase/CaMKII pathway, clonidine noticeably decreased CFA-evoked phosphorylation of N-methyl-d-aspartate subtype glutamate receptor GluN1 and GluN2B subunit as well as α-amino-3-hydroxy-5-methylisoxazole-4-propionic Acid subtype glutamate receptor GluA1 subunit. These data suggested that interference with CaMKII signaling might represent an important mechanism underlying noradrenergic suppression of inflammatory pain.

OBJECTIVE: To investigate the effect of γ-aminobutyratergic (GABAergic) disinhibition on the activity of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in the spinal dorsal horn and its correlation with nociceptive behavioral sensitization. METHODS: GABAA receptor antagonist bicuculline (50 ng·g-1; 5 μl) was intrathecally (ith) given in intact mice to mimic GABAergic disinhibition. Complete Freund's adjuvant (CFA) was intradermally injected to evoke inflammatory pain, followed by spinal application of GABAA receptor agonist diazepam (0.5 μg·g-1; 5 μl) or ERK1/2 inhibitor PD-98059 (0.25 μg·g-1; 5 μ) to detect the alteration in ERK1/2 activity and the paw withdrawal threshold (PWT). RESULTS: Compared with PWT of normal control group (1.24±0.07)g, bicuculline 50 ng·g-1 in intact mice significantly decreased to (0.42±0.17)g (P < 0.05), which, however, could be reversed by PD-98059 0.25 μg·g-1 to (1.29±0.37)g (P < 0.05). Diazepam 0.5 μg·g-1 or PD-98059 0.25 μg·g-1 dramatically enhanced the PWT values of inflamed mice from (0.28±0.06) g to (0.99±0.12)g and (0.97± 0.17)g (P <0.05), respectively. Compared with saline group, bicuculline specifically increased the phosphorylation level of ERK2 to (152±24) % (P < 0.05). CFA injection also enhanced ERK2 phosphorylation to (163±42)% (P < 0.05) in the spinal dorsal horn of mice, whereas ith GABAA receptor agonist diazepam depressed CFA-induced phosphorylation of ERK2 to (91±34)% (P < 0.05). Meanwhile, both diazepam and PD-98059 effectively alleviated inflammatory pain. CONCLUSION: Inhibitory GABAergic innervation controls the activation of ERK2 in the spinal dorsal horn, which may be involved in the formation of inflammatory pain.

Aim To investigate the effects of peripheral tissue injury on the synaptic contents of AMPA receptor in spinal dorsal horn and its underlying molecular mechanisms.Methods Complete Freund's Adjuvant(CFA) was injected into the plantar surface of mouse hindpaws to induce inflammatory pain.24 h later,PSD-enriched fraction was isolated from L4-L5 spinal dorsal horn for immunoblotting analysis of the synaptic content of GluR2.The role of cAMP-dependent protein kinase(PKA) in the regulation of synaptic GluR2 was also investigated.Results CFA simultaneously induced the mechanical allodynia and the increase in the synaptic amount of GluR2 in spinal dorsal horn.Although PKA inhibitor H-89 generated minimal effects on the Paw Withdrawal Threshold and synaptic GluR2 amount in intact mice,it dramatically repressed GluR2 synaptic concentration in inflamed mice,which was coincident with the alleviation of allodynia.Conclusion Peripheral tissue injury evokes aberrant increase in the synaptic contents of AMPA receptor GluR2 subunits in spinal dorsal horn via PKA signaling,which is closely involved in the induction of chronic inflammatory pain.

Aim To investigate the role of spinal protein tyrosine phosphatases(PTPs) in inflammatory pain and its underlying mechanisms.Methods Complete Freund's Adjuvant(CFA) was intradermally injected into the left hindpaw of male Kunming mice to induce inflammatory pain.PTPs inhibitor sodium orthovanadate was intrathecally given one day after CFA injection to observe the alterations of Paw Withdrawal Threshold(PWT) values and of the phosphorylation of NMDA receptor NR2B subunit at Tyrosine 1472(NR2B-Y1472) in ipsilateral dorsal horn.Results Although intrathecal application of sodium orthovanadate for 30 min had no influence on PWT values in intact mice,it dose-dependently alleviated CFA-induced mechanical allodynia by elevating PWT values from(0.24±0.07) g(n=4) of inflamed mice to(0.17±0.06) g(50 ng,P0.05,n=4),(1.07±0.51) g(100 ng,P0.05,n=4) and(1.38±0.47) g(200 ng,P0.05,n=4) respectively.Meanwhile,CFA-induced phosphorylation of NR2B-Y1472 was also repressed by sodium orthovanadate(100 ng).Conclusions PTPs inhibitor sodium orthovanadate reverses NMDA receptor hyperfunction by suppressing NR2B tyrosine phosphorylation,leading to the amelioration of inflammatory pain.