FK506对BXSB狼疮性肾炎小鼠的治疗作用及其机制初步探讨

目的观察FK506对BXSB狼疮性肾炎小鼠治疗作用,初步探讨其作用机制。方法 6只12周龄雄性C57BL/6小鼠为正常对照组,12只12周龄雄性BXSB小鼠随机分为LN治疗组和LN未治疗组。治疗组予FK506 2 mg/kg隔日腹腔注射,未治疗组、正常对照组予NS 0.2 ml隔日腹腔注射,治疗至20周龄。PASM染色法观察肾组织病理变化,直接免疫荧光法观察肾组织IgG沉积,ELISA法检测血清抗-dsDNA抗体和IL-18水平,RT-PCR法检测肾组织IL-18 mRNA表达水平,免疫组化法检测肾组织IL-18表达水平。结果治疗组小鼠肾脏病理学改变明显好转,肾组织免疫球蛋白沉积减少,血清抗-dsDNA抗体和IL-18水平、肾组织IL-18mRNA和蛋白表达水平均低于未治疗组。结论 FK506对BXSB小鼠肾损害具有良好的治疗作用,抑制IL-18 mRNA的表达可能是FK506治疗LN的作用机制之一。     

Abrogation of ICOS/ICOS ligand costimulation in NOD mice results in autoimmune deviation toward the neuromuscular system

NOD mice spontaneously develop insulin‐dependent diabetes around 10–40 wk of age. Numerous immune gene variants contribute to the autoimmune process. However, genes that direct the autoimmune response toward β cells remain ill defined. In this study, we provide evidence that the Icos and Icosl genes contribute to the diabetes process. Protection from diabetes in ICOS^?/? and ICOSL^?/? NOD mice was unexpectedly associated with the development of an autoimmune disorder of the neuro‐muscular system, characterized by myositis, sensory ganglionitis and, to a reduced extent, inflammatory infiltrates in the CNS. This syndrome was reproduced upon adoptive transfer of CD4⁺ and CD8⁺ T cells from diseased donors to naïve NOD.scid recipients. Our data further show that protection from diabetes results from defective activation of autoimmune diabetogenic effector T cells in ICOS^?/? NOD mice, whereas acceleration of diabetes in BDC2.5 ICOS^?/? NOD mice is induced by a dominant defect in Treg. Taken together, our findings indicate that costimulation signals play a key role in regulating immune tolerance in peripheral tissues and that the ICOS/ICOSL costimulatory pathway influences the balance between Treg and diabetogenic effector T cells.     

The expression of PD-1 and level of CXCL10 in patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is known tobe a chronic and complicated rheumatic diseasewith an autoimmune etiology.SLEis also a proto-type of autoimmune disease due to a substantialoverlapinits clinical symptoms withother autoim-mune diseases . The immune systemof SLElosesbalance of auto-tolerance ,in which lymphocytesare activated excessively,contributingto SLE de-velopment .It has been well established that effi-cient T cell-mediated immune responses requirenot only the TCR-mediat…     

中药狼疮方对狼疮样BXSB小鼠脾脏免疫系统和淋巴细胞亚群的影响

目的：研究中药狼疮方对狼疮样BXSB小鼠免疫系统和淋巴细胞亚群的影响，探讨狼疮方治疗SLE的免疫学机制。 方法： 采用BXSB小鼠模型，随机分为3组：狼疮方治疗组（每天0.5 mL狼疮方药液灌胃）、强的松治疗组（每天prednisone 0.173 mg/20 g BW溶于0.5 mL生理盐水灌胃），未治疗组（每天0.5 mL生理盐水灌胃），每组6只，疗程10周。另设与BXSB小鼠同基因的正常C57BL/6小鼠6只为正常对照组。分别采集上述各组小鼠外周血和脾组织进行检测。 结果： （1）未治疗组BXSB小鼠血清IgG和抗ds-DNA抗体水平及脾组织CD3、CD4、CD8、CD19、CD23阳性细胞百分比都显著高于正常对照组、狼疮方治疗组、强的松治疗组（P＜0.05或P＜0.01）。（2）经狼疮方或强的松治疗后，BXSB小鼠血清IgG、抗ds-DNA抗体水平及脾组织CD4、CD8、CD19、CD23阳性细胞百分比显著低于未治疗组（与未治疗组相比，P＜0.05或P＜0.01），且接近正常水平（与正常对照组比较，P＞0.05）。 结论： 狼疮样BXSB小鼠T、B细胞免疫功能上调。中药狼疮方可抑制狼疮样小鼠T、B淋巴细胞活化，减轻其高丙种球蛋白血症，减少体内自身抗体产生。     

慢性乙型肝炎患者血清中sICOS和sPD-1升高及意义

目的 检测慢性乙型肝炎(CHB)患者血清中可溶性可诱导共刺激分子(sICOS)和可溶性程序性死亡蛋白1(sPD-1)的蛋白水平,并初步探讨其意义.方法 收集80例CHB患者和30例健康对照者外周血单个核细胞(PB-MCs)和血液上清.根据HBsAg和HBeAg测定值,将CHB患者分为HBeAg(-)和HBeAg(+)两组;并将HBeAg(+)组分为免疫耐受期和免疫清除期.用ELISA法检测以上研究对象外周血上清中sICOS和sPD-1蛋白浓度.用实时荧光定量PCR检测PBMCs中ICOS、PD-1和PD-1△ex3的表达.结果 与对照相比,sICOS在CHB患者中均增高(P＜0.05);而sPD-1仅在HBeAg(+)组显著增高(P＜0.01),其中免疫清除期比免疫耐受期患者增高更明显(P＜0.05).CHB患者的sPD-1与AST呈正相关(P＜0.01);且HBeAg(+)组的sPD-1与ALT呈正相关(P＜0.01);CHB患者的sICOS与HBV-DNA呈弱的负相关性(P＜0.05).活化前,两组CHB患者的ICOS mRNA表达水平均降低(P＜0.05).结论 sICOS和sPD-1在CHB患者的血清中均异常增高,提示sICOS和sPD-1可能参与了CHB的发生发展.     

Beneficial effect of polyclonal immunoglobulins from malaria-infected BALB/c mice on the lupus-like syndrome of (NZB × NZW)F1 mice

We previously reported that infection of BALB/c mice with the parasite Plasmodium chabaudi induces high production of natural autoantibodies. Here we demonstrate that such an infection of lupus-prone (NZB × NZW)F1 (B/W) mice retards the development of their autoimmune disease. Survival and disease hallmarks (high-grade proteinuria and IgG anti-DNA antibodies) were delayed for 6 months when parasite inoculation was given at either 3 or 7 months of age, i.e. before or after the onset of the clinical symptoms. Similar beneficial effects, although less pronounced, were obtained when mice were treated with a total of 800 m?g of IgG (P-IgG) or IgM (P-IgM) or 300 m?g of cryoglobulin preparations isolated from P. chabaudi-infected BALB/c mice while similarly prepared fractions from uninfected mice had little effect. Compared to these fractions, P-IgG and P-IgM contained higher levels of natural antibodies bearing the D23 idiotype characteristic of polyreactive natural autoantibodies with enhanced activity against Fab and Fc fragments of IgG. In surviving mice, the level of anti-DNA antibodies, particularly those of IgG1 isotype, were significantly decreased. Flow cytometric analysis of various T cell subsets showed that the number of cells expressing γδ T cell receptor (TcR) antigens which did not vary with age was not modified after P-IgG or P-IgM treatment. In contrast, the number of T cells expressing Vβ8.1,2, Vβ10 and Vβ14 TcR antigens, which increased with age, were significantly reduced. Taken together, these results indicate that parasite infection of mice induces the synthesis of populations of IgM and IgG natural autoantibodies with immunoregulatory properties and that these antibodies attempt, at least transitorily, to rescue a natural autoantibody network that is deficient in B/W mice.     

致敏小鼠树突状细胞和T细胞PD-1配体/受体的表达

目的 探讨致敏小鼠PD-1信号通路是否有改变.方法 RT-PCR法分别检测致敏及正常小鼠树突状细胞PD-1配体PD-L1、PD-L2及T细胞PD-1受体的mRNA表达情况,流式细胞检测PD-1和配体PD-LI、PD-12的表达.结果 [1]致敏小鼠树突状细胞PD-L1和PD-L2的mRNA表达均显著低于正常小鼠,致敏小鼠T细胞PD-1的mRNA表达也显著低于正常小鼠(P＜0.05).[2]流式细胞检测致敏小鼠树突状细胞PD-L1、PD-L2表达和T细胞PD-1的表达也显著低于正常小鼠.结论 致敏小鼠PD-1信号表达缺陷.     

The role of Stim1 in the progression of lupus nephritis in mice

Objective: To investigate the expression of Stim1 in the kidneys of mice with lupus, and the effect of Stim1 on the progression of renal interstitial fibrosis. Methods: Mice (MRL/lpr) with spontaneous lupus nephritis (LN) and normal control mice (C57/BL) were selected. Immunohistochemistry and Masson staining were used to determine the degree of renal interstitial fibrosis in kidney tissues. The expression of Stim1 and fibronectin in tissues was measured by qRT-PCR, western blotting, and immunohistochemistry. Urine protein, blood urea nitrogen, and serum creatinine levels in the mice were analyzed, and Spearman analysis was conducted to determine the correlation with Stim1 expression levels. Mouse renal tubular epithelial cells (mRTECs) were chosen as the experimental objects. After various treatments, the cells were divided into the blank control group, lipopolysaccharide (LPS) treatment group, LPS+siRNA-NC group and LPS+siRNA-Stim1 group. Western blotting and immunofluorescence were used to measure epithelial-mesenchymal transition (EMT)-related protein levels. Results: There was significant interstitial fibrosis in the kidneys of LN mice. Compared with that in normal mice, the expression of Stim1 in the kidney tissues of LN mice was significantly increased, and Stim1 expression was positively correlated with fibronectin, urine protein, blood urea nitrogen and serum creatinine levels. LPS induced the expression of Stim1, fibronectin, and α-SMA in mRTECs and decreased the protein level of E-CA, while silencing Stim1 effectively alleviated the effects of LPS. Conclusion: Stim1 is significantly increased in the kidneys of lupus mice, and it is possible to promote EMT in renal tubular epithelial cells and renal interstitial fibrosis by elevating fibronectin, which ultimately contributes to renal damage.     

High mortality rate of (NZW x BXSB)F1 mice induced by administration of lipopolysaccharide attributes to high production of tumour necrosis factor-alpha by increased numbers of dendritic cells

(NZW × BXSB)F1 mice (W/BF1 mice) have been reported to be a type of autoimmune‐prone mice, showing symptoms of proteinuria, anti‐DNA antibodies and anti‐platelet antibodies. In this paper, we report that W/BF1 mice show hyperproduction of tumour necrosis factor (TNF)‐α, responding to lipopolysaccharide (LPS) in comparison with normal mice, resulting in induction of death. In normal mice, monocytes/macrophages (Mo/MØ) are the main producer of TNF‐α, while both Mo/MØ and dendritic cells (DCs) produce TNF‐α in W/BF1 mice. Because the number of DCs is higher in W/BF1 mice, the main producers of TNF‐α in W/BF1 mice are thought to be DCs. Moreover, administration of anti‐TNF‐α antibodies rescued the W/BF1 mice from death induced by LPS, suggesting that TNF‐α is crucial for the effect of LPS. Although there is no significant difference in the expression of Toll‐like receptor‐4 (TLR‐4) on DCs between B6 and W/BF1 mice, nuclear factor kappa b activity of DCs from W/BF1 mice is augmented under stimulation of LPS in comparison with that of normal mice. These results suggest that the signal transduction from TLR‐4 is augmented in W/BF1 mice in comparison with normal mice, resulting in the hyperproduction of TNF‐α and reduced survival rate. The results also suggest that not only the quantity of endotoxin, but also the host conditions, the facility to translate signal from TLR, and so on, could reflect the degree of bacterial infections and prognosis.     

Upregulation of PD-1 follows tumour development in the AOM/DSS model of inflammation-induced colorectal cancer in mice

Chronic inflammation may drive development of cancer as observed in inflammation-induced colorectal cancer (CRC). Though immune cells can infiltrate the tumour microenvironment, cancer cells seem to evade anti-tumour responses, which is one of the established hallmarks of cancer. Targeting the programmed cell death protein-1 (PD-1)/PD-L1 signalling pathway is currently at the forefront in the development of anti-tumour immunity-based therapies for multiple malignancies. By blocking the immune-checkpoint of activated T-cells, it is possible to rewire the adaptive resistance induced by the PD-1 ligands expressed in the tumour microenvironment. However, adverse immunotherapy-modulated events could complicate the treatment of individuals with preexisting chronic inflammatory conditions. In this study, we investigated the expression of different systemic and mucosal T-cell subsets during the course of azoxymethane (AOM)/dextran sulphate sodium (DSS)-induced colitis and colitis-associated CRC. In addition, we examined the expression of PD-1 and its ligands PD-L1 and PD-L2 as well as other molecular targets related to T-cell exhaustion. We found a significant increase in PD-1 expression on all examined mucosal T-cell subsets of the colon and the ileum, which correlated with disease progression. We also observed an upregulation of PD-L1 and PD-L2 mRNA expression throughout the AOM/DSS regime. Blocking PD-1 signalling with an anti-PD1 antibody did not affect the tumour burden in the AOM/DSS-treated mice, but did potentiate the weight loss in the third DSS cycle, indicating possible immune-mediated toxicity. This raises a concern for patients with colitis-associated CRCs and should be further investigated.     

Intrahepatic PD-1/PD-L1 Up-regulation Closely Correlates with Inflammation and Virus Replication in Patients with Chronic HBV Infection

Chronic hepatitis B was characterized by fluctuant immune response to infected hepatocytes resulting in hepatic inflammation and virus persistence. Recently, Programmed Death-1 (PD-1) and its ligand PD-L1 have been demonstrated to play an essential role in balancing antiviral immunity and inflammation in the livers of acute hepatitis B patients, significantly influencing disease outcome. PD-1 up-regulation in peripheral T cells is associated with immune dysfunction in chronic hepatitis B patients. However, the effect of PD-1/PD-L1 on hepatic damage and chronic infective status is still unknown in patients with chronic HBV infection. Here, we report up-regulation of PD-1 and PD-L1 in liver biopsies from 32 chronic HBV patients compared to 4 healthy donors. PD-1/PD-L1 up-regulation was significantly associated with hepatic inflammation and ALT elevation. Moreover, appropriate up-regulation but not overexpression of PD-L1 in the active phase of chronic hepatitis B as well as lower expression of PD-L1 in the inactive phase in liver residential antigen presenting cells (including Kupffer cells and sinusoidal endothelial cells) may contribute to viral inhibition. Our data suggest that the intrahepatic interaction of PD-1 and PD-L1 might play an important role in balancing the immune response to HBV and immune-mediated liver damage in chronic HBV infection.     

Soluble PD-1 is Associated with Aberrant Regulation of T Cells Activation in Aplastic Anemia

Engagement of the membrane program death-1 (PD-1) receptor by its ligands suppresses T cell proliferation and cytokine production. Aberrant over-expression of costimulatory molecules, including PD-1, has been associated with persistent activation of self-reactive T cells in autoimmune diseases. However, the mechanism underlying the dysfunction of PD-1 in the regulation of T-cell activation in such diseases remains unclear. Here, we report the overexpression of CD4⁺ and CD8⁺ T cell PD-1 and elevated serum levels of soluble PD-1 in aplastic anemia (AA) patients. Detailed characterization of soluble PD-1 revealed that it corresponded to an alternative splice variant PD-1Δex3, which lacks the transmembrane domain but has a soluble extracellular domain of the PD-1 molecule. In a further study, PD-1 fusion protein displayed the ability of increasing the proliferation of T cells in vitro, which suggested that soluble PD-1 might serve as an autoimmune antibody to block the function of membrane-bound PD-1 on T cells and lead to aberrant T cell proliferation. Our study revealed a novel pathogenic pathway in which the function of overexpressed PD-1 to restrict over-self-reaction is counteracted by the excessive production of soluble PD-1.     

Experimental autoimmune thyroiditis in nonobese diabetic mice lacking interferon regulatory factor-1

Interferon regulatory factor-1 (IRF-1) is pivotal in the regulation of interferon (IFN)-mediated immune reactions, and studies suggest that IRF-1 is involved in the development of autoimmune diseases. IRF-1+/+, +/-, and -/- nonobese diabetic (NOD) mice were immunized with mouse thyroglobulin (mTg) to determine whether IRF-1 is required in experimental autoimmune thyroiditis (EAT), a murine model for Hashimoto's thyroiditis (HT). IRF-1-deficient mice developed EAT and anti-mTg antibodies comparable to IRF-1+/+ and +/- mice. Whereas both CD4+ and CD8+ T cells were found in thyroids of IRF-1+/+ mice, the latter was not in IRF-1-/- mice. Major histocompatibility complex class II antigen was comparably expressed in thyroids of IRF-1+/+ and -/- mice. Lack of IRF-1 resulted in decreased CD8+ T cell number in the spleen and reduced IFNgamma production by splenocytes. Our results suggest that IRF-1 is not pivotal in EAT in NOD mice.     

Vaccination with autoreactive CD4Th1 clones in lupus-prone MRL/Mp-Fas mice

We studied the efficacy of T cell vaccination with CD4⁺αβTh1 clones in lupus-prone MRL/Mp-Fas^lpr/lpr (MRL/lpr) mice. CD4⁺αβ Th1 clones, dna51 (Vβ8.3) and rnp2 (Vβ14), which stimulated anti-dsDNA or U1 ribonucleoprotein (U1RNP) antibody (Ab) production respectively, were isolated from splenocytes of MRL/lpr mice. Antinuclear Ab kinetics, renal function, renal histology, survival rate, and lymphocyte subpopulations in the spleen were monitored after intravenous adoptive transfer of IL-2-stimulated (s-) or irradiated (i-) clones to 3 week-old female MRL/lpr mice. Anti-idiotypic humoral and T cell responses against the transferred autoreactive Th1 clones were determined in parallel. Compared with PBS-treated MRL/lpr mice, anti-dsDNA Ab titers, and the activity index for lupus nephritis were all decreased in MRL/lpr mice vaccinated with i-dna51 cells, whereas survival rate was not improved. The numbers of CD4⁺Vβ8.3 T cells in the spleen were also significantly decreased in these mice. Anti-idiotypic Abs recognizing a 12 amino acid sequence of clone dna51 T cell receptor Vβ8.3-complementarity-determining region (CDR) 3 were detected in the MRL/lpr mice that received i-dna51 or s-dna51 cells. These Abs suppressed dna51 cell proliferation, as well as cytotoxicity of CD8⁺T cells against dna51. The present study suggests that vaccination with CD4⁺αβTh1 clone, dna51, elicits anti-idiotypic T cell and humoral responses against dna51 in MRL/lpr mice, although the immunoregulatory effects on lupus may be limited.     

应用基因芯片筛选慢性乙型肝炎患者PD-1/PD-L通路基因差异表达

目的 应用基因芯片技术筛选慢乙肝病人PD-1/PD-L通路差异性表达的基因.方法 应用基因芯片技术筛选4例慢乙肝病人与2例健康人外周血,获得差异性表达的基因,结合初步构建的PD-1/PD-L信号通路,挑选出一致的转录因子或调控蛋白,并应用Western blot方法检测CD 40L、Bcl-10、GATA-3、NFAT蛋白的水平的表达.结果 与健康人相比,慢乙肝患者有838个异常表达的基因,其中高表达的基因有150个,低表达的基因有688个.在这些异常表达基因中,有13个基因属于所构建的PD-1/PD-L信号通路中的转录因子或调控蛋白,其中表达上调的6个分别是BCL-10、AP、SRY、MYOD1、ELK4、NFAT,表达下调的7个分别是CD 40L、GADS、PDK1、IL-4、GATA3、CREB、RARG.Westem blotting法证实慢乙肝组高表达BCL-10,低表达CD 40L、GATA3,NFAT但与病毒载量不相关.结论 CD40L、BCL-10、GATA3、NFAT在慢性乙型肝炎患者PD-1/PD-L信号传导通路中可能有重要的调控作用,可以做深入的功能分析研究.     

HIV-1感染者CD4+CD25nt/hiCD127lo调节性T细胞PD-1表达水平与疾病进展的关系

目的:阐明HIV-1感染者外周血中具有CD4+CD25nt/hiCD127lo特征的调节性T细胞(Treg)表面PD-1的表达水平与疾病进展的关系.方法:选取108名未经治疗的不同进展期的HIV-1感染者和27名健康人对照, 采集静脉血, 用Ficoll-Hypaque密度梯度离心法分离获得PBMC, 加入PerCP-CD4抗体、 FITC-CD25抗体、 PE-CD127抗体和APC-PD-1抗体, 经细胞表面四色染色、流式细胞术(FCM)分析Treg表面PD-1的表达;另将50 L全血加入Trucount绝对计数管, 采用Multitest CD3/CD8/CD45/CD4试剂盒检测CD4+T细胞绝对数;分离静脉血血浆, NucliSens EasyQ测定血浆HIV-1病毒载量;实验数据采用SPSS14.0 统计学软件分析处理.结果:HIV-1感染者Treg表面PD-1表达水平显著高于健康人(5.33%±2.24% vs 1.72%±0.65%, P<0.01);AIDS期(7.87%±2.23%)明显高于进展期(5.21%±1.72%, P<0.05)和新近感染者(3.22%±1.01%, P<0.05);HIV-1感染者Treg表面PD-1表达水平与血浆中的HIV-1病毒载量和CD4+T细胞绝对数密切相关.结论:首次证实HIV-1感染者外周血中Treg表面PD-1表达增加, 且表达水平与病程进展相关.该结果为进一步揭示HIV-1感染中Treg的效应机制、探索新的免疫治疗方案提供了理论及实验依据.     

Association of monocyte chemoattractant protein 1 (MCP-1) gene polymorphism with lupus nephritis in Egyptian patients

Background and study aimMonocyte chemoattractant protein-1 (MCP-1) is a member of CC chemokine that plays an important role in the recruitment of monocytes/macrophages into renal tubulointerstitium. A biallelic A/G polymorphism at position ∼2518 in the MCP-1 gene was found to regulate MCP-1 expression. MCP-1 and its A/G gene polymorphism have been implicated in the pathogenesis of some renal diseases. The aim of the study was to investigate the role of the MCP-1 gene polymorphism as early predictors of the development of glomerulonephropathy in SLE patients. We also aimed to measure the serum and urinary levels of MCP-1 in patients with SLE, to find out its relation to clinical disease activity.Methods140 SLE patients (100 with nephritis and 40 without nephritis) and 80 controls were included in this study. MCP-1 gene polymorphism was analyzed by polymerase chain reaction. Serum and urine MCP-1 level were measured using high-sensitivity enzyme-linked immunosorbent assay.ResultsThe A/A genotype was more common in controls than in SLE patients, whereas both the A/G (P < 0.000) and G/G (P < 0.000) genotypes were more frequent in SLE patients. Carriers of G allele of the MCP-1 ∼2518 polymorphism had more than 7 fold increased risk to develop glomerulo-nephropathy in patients with SLE. High MCP-1 circulating levels production from patients with A/G and G/G genotypes was significantly higher than in A/A genotype. In addition there were significant differences in the mean levels of serum MCP-1 (P < 0.001) and urinary MCP-1 (P < 0.001) between patients and controls.ConclusionThe present study provides a new evidence that the presence of MCP-1 A (-2518) G gene polymorphism and high circulating MCP-1 levels can play an important role in the development of SLE and nephropathy in Egyptians.     

Phase I study of CAR-T cells with PD-1 and TCR disruption in mesothelin-positive solid tumors

Programmed cell death protein-1 (PD-1)-mediated immunosuppression has been proposed to contribute to the limited clinical efficacy of chimeric antigen receptor T (CAR-T) cells in solid tumors. We generated PD-1 and T cell receptor (TCR) deficient mesothelin-specific CAR-T (MPTK-CAR-T) cells using CRISPR-Cas9 technology and evaluated them in a dose-escalation study. A total of 15 patients received one or more infusions of MPTK-CAR-T cells without prior lymphodepletion. No dose-limiting toxicity or unexpected adverse events were observed in any of the 15 patients. The best overall response was stable disease (2/15 patients). Circulating MPTK-CAR-T cells peaked at days 7–14 and became undetectable beyond 1 month. TCR-positive CAR-T cells rather than TCR-negative CAR-T cells were predominantly detected in effusion or peripheral blood from three patients after infusion. We further confirmed the reduced persistence of TCR-deficient CAR-T cells in animal models. Our results establish the preliminary feasibility and safety of CRISPR-engineered CAR-T cells with PD-1 disruption and suggest that the natural TCR plays an important role in the persistence of CAR-T cells when treating solid tumors.     

LncRNA XLOC_003810 promotes T cell activation and inhibits PD-1/PD-L1 expression in patients with myasthenia gravis-related thymoma

This study aimed to investigate the effect of long non-coding RNA XLOC_003810 on the activation of CD4⁺ T cells and expression of PD-1/PD-L1 in patients with myasthenia gravis-related thymoma (MG-T). Thymus specimens and thymic mononuclear cells were obtained from MG and MG-T patients or cardiac surgery patients undergoing thoracotomy who were selected as negative controls (NC). XLOC_003810 expression was examined using quantitative real-time PCR (qRT-PCR). Frequency of CD4⁺ T cells and proportion of CD4⁺PD-1⁺ T cells and CD14⁺PD-L1⁺ monocytes were quantified by flow cytometry. The release of inflammatory cytokines was measured by qRT-PCR and enzyme-linked immunosorbent assay. Compared with the NC group, expression of XLOC_003810, frequency of CD4⁺ T cells and the production of inflammatory cytokines were increased in patients with MG and MG-T. XLOC_003810 overexpression significantly increased the frequency of CD4⁺ T cells, facilitated the production of inflammatory cytokines and decreased the proportion of CD4⁺PD-1⁺ T cells and CD14⁺PD-L1⁺ monocytes in the thymic mononuclear cells. In contrast, XLOC_003810 knockdown exerted the opposite effect. Together, XLOC_003810 promotes T cell activation and inhibits PD-1/PD-L1 pathway in patients with MG-T.     

The Y chromosome from autoimmune BXSB/MpJ mice induces a lupus-like syndrome in (NZW x C57BL/6)F1 male mice, but not in C57BL/6 male mice

The Y chromosome of the BXSB mouse has been shown to be responsible for the acceleration of lupus-like autoimmune syndrome in inbred BXSB mice and in their F1 hybrids with NZB or NZW mice. To further define the role of this as yet unidentified gene linked to the BXSB Y chromosome, designated Yaa (Y chromosome-linked autoimmune acceleration), the Y chromosome was transferred from the BXSB strain to nonautoimmune C57BL/6 (B6) mice. The effect of the Yaa gene on the autoantibody formation and the development of glomerulonephritis was investigated in B6 mice and in their F1 hybrids with NZW mice. The presence of the BXSB Y chromosome was not able to induce significant autoimmune responses in B6 mice. However, (NZW x B6)F1 males bearing the BXSB Y chromosome developed a severe lupus-like autoimmune syndrome, as documented by the production of anti-DNA antibodies and gp70-anti-gp70 immune complexes and the development of lethal lupus nephritis. Both sexes of (NZW x B6)F1 hybrids without the BXSB Y chromosome were essentially normal. Our results suggest that (a) the BXSB Y chromosome by itself is not sufficient to initiate autoimmune responses in nonautoimmune B6 mice, and (b) it is able to induce autoimmune responses in mice potentially capable of developing the disease, but whose autosomal abnormality by itself is not sufficient to develop autoimmune diseases.