A more mature phenotype of blood mononuclear phagocytes is induced by fluvastatin treatment in hypercholesterolemic patients with coronary heart disease.

Monocytes are recruited as the principal inflammatory cells into the atherosclerotic lesion. In a previous study we demonstrated that a low HDL-cholesterol and the apo E4 allele are associated with an increased proportion of blood monocytes that are characterized by a high expression of Fcgamma-RIIIa (CD16), a dim expression of the lipopolysaccharide (LPS) receptor (CD14) and a high expression of beta1- and beta2-integrins (Rothe et al. Arterioscler Thromb Vasc Cell Biol 1996;16:1437-1447). In this study, 79 hypercholesterolemic patients were treated either with the HMG CoA reductase inhibitor fluvastatin in combination with diet or with placebo and diet in a double-blind and randomized multicenter study, and monitored for the potential effects on the phenotype of peripheral blood monocytes. At baseline, in the whole group of hypercholesterolemic patients the population size of these more mature monocytes (CD14dimCD16+) was positively correlated to triglyceride (P = 0.003) and total serum cholesterol levels (P = 0.012) confirming our previous study. Fluvastatin treatment for 52 weeks was associated with a 24.2% reduction in LDL-cholesterol (P < 0.001) as well as a 40.7% decrease in the expression density of CD14 on all monocytes (P = 0.027). A 24.5% decrease (P < 0.001) of the population of less differentiated CD14brightCD16- monocytes and an 83.1% increase (P = 0.029) of the population of more differentiated CD14dimCD16+ monocytes further confirmed this modification of the phenotype of peripheral blood monocytes. The positive pre-study correlation of the CD14dimCD16+ monocyte subset to the serum cholesterol concentration, but inverse changes of both parameters under fluvastatin therapy, in conclusion indicate that fluvastatin exerts an as yet uncharacterized immunomodulatory effect on either monocyte maturation and differentiation, or extravasation which may also depend on the endothelial phenotype that is independent of the change in serum lipids.     

Inhibition of immune activation by a novel nuclear factor-kappa B inhibitor in HTLV-I-associated neurologic disease

The human T-lymphotropic virus type I (HTLV-I) causes a chronic inflammatory disorder of the central nervous system termed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-I encodes a protein known to activate several host-signaling pathways involved in inflammation, such as the nuclear factor-κB (NF-κB). The contribution of the NF-κB pathway to the pathogenesis of HAM/TSP, however, has not been fully defined. We show evidence of canonical NF-κB activation in short-term cultures of peripheral blood mononuclear cells (PBMCs) from subjects with HAM/TSP. NF-κB activation was closely linked to HTLV-I viral protein expression. The NF-κB activation in HAM/TSP PBMCs was reversed by a novel small-molecule inhibitor that demonstrates potent and selective NF-κB antagonist activity. Inhibition of NF-κB activation led to a reduction in the expression of lymphocyte activation markers and resulted in reduced cytokine signaling in HAM/TSP PBMCs. Furthermore, NF-κB inhibition led to a reduction in spontaneous lymphoproliferation, a key ex vivo correlate of the immune activation associated with HAM/TSP. These results indicate that NF-κB activation plays a critical upstream role in the immune activation of HAM/TSP, and identify the NF-κB pathway as a potential target for immunomodulation in HAM/TSP.     

Different expression of integrins by mononuclear phagocytes in peripheral blood and bronchoalveolar lavage fluid

Alveolar macrophages (AM) originate from blood monocytes and, during the maturation process, undergo functional and morphological changes which are also reflected in their phenotypic pattern. Among the macrophage membrane antigens, adhesion molecules of the integrin family are particularly important for effector functions and cell-cell interactions. The aim of this study was to analyse the membrane expression of selected integrins by AM recovered from bronchoalveolar lavage (BAL) as compared to their precursors, peripheral blood monocytes (PBM). The cells were stained using a sensitive immunoperoxidase assay with 10 different monoclonal antibodies. The data showed a higher expression by AM than PBM of all but one of the studied adhesion molecules. The only exception was CD11b (Mac-1, CR3) which showed a higher expression in PBM than in AM. Several molecules, for example, CD49d (VLA-4), CD51 (vitronectin receptor), and CD54 (intercellular adhesion molecule-1, ICAM-1) were found to be upregulated by AM in patients with a lymphocytic pattern of BAL. In contrast, the phenotype of PBM does not show any changes in these patients. In conclusion, we have demonstrated differences in the expression of integrins between AM and PBM which can be partially responsible for some of their functional differences.     

IL-15表达质粒联合HPV基因疫苗诱导细胞免疫应答的实验研究

目的研究白细胞介素15(IL-15)真核表达质粒,对人乳头瘤病毒(HPV)16E7基因疫苗所诱导的小鼠特异性细胞免疫应答的影响。方法构建含IL-15的真核表达质粒pcDNA3.1-IL-15。将该质粒与HPV16 E7基因疫苗通过肌肉注射方式免疫雌性BALB/c小鼠。基因免疫后测定其血清γ-干扰素(IFN-γ)水平;并制备脾淋巴细胞悬液,经体外E7蛋白再刺激后用MTT法检测其T淋巴细胞增殖情况。结果pcDNA3.1-IL-15与pcD-NA3.1-E7共同注射,可以提高免疫小鼠血清中IFN-γ水平至414.1pg/ml,与E7 空质粒组、E7组比较差异有统计学意义(P<0.01)。pcDNA3-1-IL-15与pcDNA3.1-E7共同注射,可以增强特异性T细胞增殖反应,OD570差值为1.313,与其他各组比较差异均有统计学意义(P<0.01)。结论IL-15真核表达质粒可以提高HPV16 E7基因疫苗的免疫原性,增强小鼠细胞免疫应答。     

Comparison of phenotype expression by mononuclear phagocytes within subcutaneous gouty tophi and rheumatoid nodules

Summary The mononuclear phagocyte infiltrate which occupies the gout tophus has been compared with that of the subcutaneous rheumatoid nodule. In the gout tophus, macrophage migration appears to be at a relatively low level and effectively terminates once these cells have been recruited into the corona. In the nodule the evidence suggests that both macrophage and granulocyte populations continuously migrate towards, and are progressively incorporated into, the necrotic centres. These observations indicate that chemotactic activity in rheumatoid nodules is at a higher level than in gout tophi, or that the rheumatoid mononuclear phagocyte is more responsive to such stimuli.     

血清GDF-15和IL-12表达与老年患者ICU机械通气后肺部感染的相关性

目的 观察生长分化因子15(GDF-15)和白细胞介素12(IL-12)在重症监护室(ICU)行机械通气后肺部感染老年患者血清中的表达水平,并探讨血清GDF-15、IL-12水平与ICU机械通气术后肺部感染的相关性.方法 选取2016年7月至2019年8月于哈尔滨医科大学附属第一医院ICU行机械通气术的老年患者169例...     

Impaired microbicidal capacity of mononuclear phagocytes from patients with type I Gaucher disease: partial correction by enzyme replacement therapy

The higher susceptibility to serious bacterial infections in patients with Gaucher disease (GD) may be due in part to defective function of phagocytic cells. We studied five patients with GD (type I) and examined the ability of granulocytes and mononuclear phagocytes from these patients to phagocytose and kill Staphylococcus aureus and to generate superoxide anion (O2-) on stimulation with fully opsonized bacteria. Serum-opsonized staphylococci were ingested equally by phagocytic cells from patients and controls. In the presence of normal serum, the extent of killing of S aureus and the release of O2- by granulocytes over incubation periods of 60 minutes and 30 minutes, respectively, were also equivalent for patients and controls. However, we found that killing of viable bacteria and release of O2- by the patients' monocytes was significantly lower than that in cells from controls (P < .05 for both). The magnitude of differences in killing and O2- release between patients' cells and those from controls was even more profound with monocyte-derived macrophages. Enzyme augmentation with macrophage-targeted glucocerebrosidase preparation for 6 months at doses from 7.5 to 10 U/kg/wk resulted in significant increases of functional activities and O2- generation of monocytes and macrophages along with hematologic and hepatosplenic improvements. These data suggest that mononuclear phagocytes from GD patients are defective in their ability to kill bacteria and to generate reactive oxygen intermediates. Our data also suggest that enzyme substitution may improve functions of monocytes and macrophages in patients with GD that should make them more resistant to severe bacterial infection.     

Expression of leukocyte adhesion molecules by mucosal mononuclear phagocytes in inflammatory bowel disease.

Leukocyte adhesion molecules are important in cell-cell interactions of the immune system. Lymphocyte function-associated antigen 1 (cluster designation 11a) mediates interactions between T cells and mononuclear phagocytes through its ligand, the intercellular adhesion molecule 1 (CD54), whereas complement receptors 3 (CD 11b) and 4 (CD11c) are involved in complement-mediated phagocytosis. Expression of CD11 molecules and intercellular adhesion molecule 1 was studied in colonic biopsy specimens from 20 patients with inflammatory bowel disease and 10 normal controls. In normal colon, few mononuclear phagocytes expressed lymphocyte function-associated antigen 1 and intercellular adhesion molecule 1 at high densities. The major adhesion molecule was CD11c. Thus, the largest population of normal colonic mononuclear phagocytes was represented by quiescent, resident macrophages with likely phagocytic function. In inflammatory bowel disease, mononuclear phagocytes showed only a slight increase in CD11a expression and no significant change in expression of CD11b and CD11c. By contrast, the percentage of mononuclear phagocytes expressing intercellular adhesion molecule 1 was increased from 6.9% +/- 3.9% in controls to 69.2% +/- 12.8% in ulcerative colitis (P less than 0.001) and to 45.7% +/- 22.8% in Crohn's disease (P less than 0.01), showing a close relationship with histological activity. The increased expression of intercellular adhesion molecule 1 in inflammatory bowel disease indicates a state of immunological activation induced by local release of inflammatory cytokines. Such induction of intercellular adhesion molecule 1 on mononuclear phagocytes may be important in the maintenance of chronic inflammation by facilitating interactions with T cells and T-cell antigen recognition.     

Differential effects of IL-21 and IL-15 on perforin expression, lysosomal degranulation, and proliferation in CD8 T cells of patients with human immunodeficiency virus-1 (HIV)

An urgent need exists to devise strategies to augment antiviral immune responses in patients with HIV who are virologically well controlled and immunologically stable on highly active antiretroviral therapy (HAART). The objective of this study was to compare the immunomodulatory effects of the cytokines interleukin (IL)-21 with IL-15 on CD8 T cells in patients with HIV RNA of less than 50 copies/mL and CD4 counts greater than 200 cells/mm.(3) Patient CD8 T cells displayed skewed maturation and decreased perforin expression compared with healthy controls. Culture of freshly isolated patient peripheral-blood mononuclear cells (PBMCs) for 5 hours to 5 days with IL-21 resulted in up-regulation of perforin in CD8 T cells, including memory and effector subsets and virus-specific T cells. IL-21 did not induce T-cell activation or proliferation, nor did it augment T-cell receptor (TCR)-induced degranulation. Treatment of patient PBMCs with IL-15 resulted in induction of perforin in association with lymphocyte proliferation and augmentation of TCR-induced degranulation. Patient CD8 T cells were more responsive to cytokine effects than the cells of healthy volunteers. We conclude that CD8 T cells of patients with HIV can be modulated by IL-21 to increase perforin expression without undergoing overt cellular activation. IL-21 could potentially be useful for its perforin-enhancing properties in anti-HIV immunotherapy.     

IL-15 and IL-15R in leucocytes from patients with systemic lupus erythematosus

OBJECTIVE: To assess the functional status of the IL-15/IL-15Ralpha cytokine system in different leucocyte subsets from patients with systemic lupus erythematosus (SLE). METHODS: Eighteen patients with SLE (10 with inactive and eight with active disease) and 14 healthy individuals were studied. Serum levels and in vitro production of IL-15 were determined. In addition, the expression of IL-15 receptor alpha (IL-15Ralpha) and membrane-bound IL-15 was assessed and the in vitro effects of IL-15 on CD69 and CD64 expression, interferon-gamma and TNF-alpha synthesis, respiratory burst induction and apoptosis were studied. RESULTS: Serum levels of IL-15 were significantly increased in inactive and active patients with SLE. Accordingly, the in vitro synthesis and release of IL-15 by monocytes in response to IFN-gamma+lipopolysaccharide was significantly enhanced in SLE patients with active disease, as was the percentage of membrane-bound IL-15+ monocytes. On the other hand, enhanced basal expression of IL-15Ralpha was detected in leucocytes from SLE patients, with defective induction upon stimulation with phytohaemagglutinin or phorbol myristate acetate/ionomycin. Furthermore, diminished induction of CD69 expression and interferon-gamma and TNF-alpha synthesis by recombinant human IL-15 was detected in peripheral blood mononuclear cells from SLE, and there was defective induction of CD64 and priming for respiratory burst in neutrophils. The anti-apoptotic effect of IL-15 was diminished in leucocytes from SLE patients. CONCLUSION: Our data indicate that there is enhanced synthesis of IL-15 by immune cells from SLE patients, with a poor response to this cytokine by different leucocyte subsets. This abnormal function of IL-15/IL-15Ralpha may contribute significantly to the pathogenesis of SLE.     

HTLV-I infection of cerebrospinal fluid T cells from patients with chronic neurologic disease

Antibodies reacting with HTLV-I, the etiologic agent of acute T cell leukemia/lymphoma and a transforming agent for T4-positive lymphocytes in vitro, have recently been described in sera of patients with chronic neurologic disease in the absence of lymphoproliferative disorders. The largest number of such cases was described in Japan and in the Caribbean and parts of South America. We report here two cases of patients with chronic neurologic disease whose cerebrospinal fluid (CSF)-derived T cells contain HTLV-I specific RNA sequences and antigens and are expressing retroviral particles. Only one of these patients has demonstrable antibody to HTLV-I in serum or CSF.     

IL-31 expression in HIV-infected patients with different routes of disease transmission

Acquired immunodeficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV). AIDS is characterized by an impaired immune system and low cellular immunity. The main manifestation of AIDS is a reduction in the number of CD4⁺ T cells and alteration in cytokine concentration. The present work aimed to explore the expression of IL-31 in HIV infection and disease progression.Serum samples were collected from HIV-infected patients with different routes of disease transmission. The subjects included 24 patients who were infected with HIV upon blood transmission and 36 patients who had acquired the disease through sexual transmission (21 cases of homosexual transmission and 15 cases of heterosexual transmission). In addition, 20 normal healthy individuals were included to serve as the control group. The levels of IL-31 in the collected serum samples were estimated using the human IL-31 Platinum ELISA kit.The serum analysis results revealed that the concentration of IL-31 in the serum samples for the blood transmission, sexually transmission, and normal group patients was 4.07 ± 1.63 pg/L, 7.43 ± 1.15 pg/L, and 2.87 ± 1.04 pg/L, respectively. The statistical analysis revealed that the concentration of IL-31 in HIV-1 infection was higher than that in the normal control. In addition, the expression of IL-31 was significantly higher in the sexual transmission group compared to the blood transmission group (P < .05).IL-31 could have an important role in HIV infection, although the role of IL-31 in disease progression in HIV-infected individuals requires further research.     

IL-17在COPD患者中的表达

目的探讨白细胞介素(IL)-17在COPD发病机制中的作用。方法取20例正常对照、24例COPD急性加重期及其治疗后的稳定期患者空腹静脉血,采用双抗体酶联免疫吸附测定(ELISA)法测定血清中IL-17。并对COPD患者常规行中性粒细胞(N)百分比(%)及肺功能检查,计算出第1秒用力呼气容积占预计值百分率(FEV1%)。结果 AECOPD组IL-17水平高于稳定期组及正常对照组,有统计学差异(P<0.05),COPD稳定期组IL-17水平也高于正常对照组(P<0.05);COPD急性加重组及稳定期组患者血清IL-17均与外周血N(%)正相关,与FEV1%负相关。结论 IL-17可能在COPD发病中起到重要作用。