Modulatory effect of a serine protease inhibitor on surgical stress: its clinical implications

The relationship between endogenous cytokine antagonists and surgical stress is poorly understood. Surgical stress induces immunosuppression, and the reversed therapy of postoperative immunosuppression has been expected. The aim of the present study was to assess the effect of a serine protease inhibitor on postoperative immune reactivity. Twenty patients with colorectal cancer were randomly separated into experimental and control groups of 10 patients each. The experimental group received perioperative administration of a serine protease inhibitor while the control group did not. Plasma levels of cytokine antagonists, which suppress cell-mediated immunity, such as cortisol, interleukin-1 receptor antagonist, soluble interleukin-2 receptor (sIL-2R) and soluble tumor necrosis factors p55, p75 (sTNF-R55, -R75) were simultaneously measured. Significant reductions of plasma concentration of sIL-2R and sTNF-R55 were observed. Perioperative administration of a serine protease inhibitor may contribute to ameliorating immunosuppression after major surgery.     

Elevated soluble interleukin-2 receptors in young healthy cigarette smokers: lack of association with atopy or airways hyperresponsiveness.

To study the relationship of atopy and nonspecific airways hyperresponsiveness to circulating levels of soluble interleukin-2 receptors (sIL-2R), we measured serum sIL-2R concentrations in 40 young, healthy smokers and non-smokers. Levels of sIL-2R were significantly higher in current smokers than in nonsmokers (median sIL-2R levels 605 vs. 398 U/ml, respectively; p less than 0.05). Serum sIL-2R levels were not related to nonspecific airways hyperresponsiveness to methacholine, allergy skin test reactivity, doctor-diagnosed asthma or hay fever, or respiratory symptoms of wheeze. Among current smokers, a trend toward higher sIL-2R levels (not statistically significant) was observed among subjects reporting symptoms of phlegm production. The increase in sIL-2R levels associated with cigarette smoking was similar in magnitude to that reported for immune-mediated conditions such as collagen vascular diseases and eczema. These data confirm that cigarette smoking is an important determinant of sIL-2R level, even among young healthy subjects. This effect does not appear to be related to atopic status or bronchial responsiveness. Among cigarette smokers, sIL-2R level may be related to the presence of conditions associated with phlegm production.     

Soluble plasma IL-2 receptors and malaria.

Plasma levels of soluble IL-2 receptor (sIL-2R) were measured by immunoassay in 180 individuals, aged 1-70 years, living in a malaria-endemic community in West Africa. sIL-2R levels were compared with age, malaria parasitaemia, malaria-associated morbidity and cellular immune responses to Plasmodium falciparum antigens. Plasma levels of sIL-2R were independently associated with both age and patent malaria parasitaemia. No significant association was observed between IL-2R levels and concurrent malaria morbidity (i.e. fever associated with malaria), but the number of individuals with clinical malaria at the time of sampling was small. Although there was no association between plasma sIL-2R levels and in vitro proliferative responses of peripheral blood mononuclear cells (PBMC) to a number of defined malaria antigens, we did find a significant negative association between sIL-2R and in vitro proliferation of unstimulated PBMC. High levels of sIL-2R (up to 5500 U/ml) were detected in the plasma of malaria-infected individuals; this is indicative of a vigorous cellular immune response to malaria antigens in vivo and does not support the notion that malaria infections are generally immunosuppressive. Indeed, we found that, at the low levels of parasitaemia present in study subjects, there was no significant difference in the mean proliferative response to malaria antigens in infected subjects when compared with uninfected subjects.     

Levels of soluble intercellular adhesion molecule-1, soluble E-selectin, tumor necrosis factor-α, and soluble tumor necrosis factor receptor p55 and p75 in atopic children

During inflammation, membrane expression of adhesion molecules and tumor necrosis factor (TNF)-receptors (TNF-R) are increased, and soluble forms of these molecules are released. This study analyzed plasma levels ofsICAM-1 and sE-selectin as well as TNF-γ, sTNF-R55, and sTNF-R75 in nonallergic (NAA) and allergic asthma patients (AA), atopic dermatitis patients (AD), and healthy children (HC) by ELISA. Plasma levels of sICAM-1. sE-selectin. and sTNF-R, but not TNF-γ, were detectable, but were not significantly different between the patient groups and healthy children. In the AA group, a significant correlation (r_s0.78, P=0.008) was found between sICAM-1 and sE-selectin levels. Furthermore, a significant correlation was found between sTNF-R55 and sTNF-R75 levels in the AA group (r_s=0.70, P=0.025) and in the AD group (r_s=0.69, P=O.O27). In AD patients, a significant correlation was observed between sE-selectin and the disease severity, as measured by the SCORAD index (r_s=0.73. P=0.038). Our data demonstrate that plasma levels of sICAM-1. sE-selectin, TNF-a, sTNF-R55, and sTNF-R75 were not different between atopic and nonatopic children during a stable phase of the disease. In AD patients, levels of sE-selectin seemed to be related to clinical severity of the disease.     

Elevated levels of interleukin-2 receptor and intercellular adhesion molecule 1 in sera from a venezuelan cohort of patients with dengue

Summary This study evaluated the levels of soluble interleukin-2 receptor (sIL-2R) and soluble intercellular adhesion molecule-1 (sICAM-1) in patients with dengue. Sera from 17 patients with dengue fever (DF), 15 with dengue hemorrhagic fever (DHF) and 12 healthy individuals were obtained. Increased levels of sIL-2R and sICAM-1 were found in patients with DF and DHF when compared to normal; those were not correlated with leukocytes, hepatic serum enzyme levels or haemostatic parameters. Levels of sIL-2R were related to the different grades of DHF. These results suggest that increased levels of sIL-2R and sICAM-1 are a common feature of dengue. Correspondence: Nereida Valero, MgSc, Apartado Postal 23, Maracaibo 4001-A, Zulia, Venezuela     

Interferon regulatory factor modulation underlies the bystander suppression of malaria antigen-driven IL-12 and IFN-γ in filaria-malaria co-infection

In areas where polyparasitism is highly prevalent, the impact of multiple parasites on the host response is underestimated. In particular, the presence of helminth infection coincident with malaria profoundly alters the production of malaria-specific IFN-γ, IL-12p70, CXCL9, CXCL10 and CXCL11, cytokines/chemokines known to be critical in mediating malaria-specific immunity. In order to elucidate the mechanisms underlying the suppression of malaria-specific cytokines/chemokines, we assessed the expression of malaria-specific IL-12Rβ1, IL-12Rβ2 and interferon regulatory factor (IRF)-1 in blood obtained from 18 filaria-infected (Fil(+)) and 17 filaria-uninfected (Fil(-)) individuals in a filaria-malaria co-endemic region of Mali. We found that Fil(+) individuals had significantly lower RNA expression of IRF-1 but not IL-12Rβ1 or IL-12Rβ2 in response to malaria antigen stimulation. We also measured the frequency of IL-12-producing DCs from these subjects and found that Fil(+) subjects had lower frequencies of IL-12(+) mDCs after malaria antigen stimulation than did the Fil(-) subjects. Modeling these data in vitro, we found that mDCs pre-exposed to live microfilariae not only produced significantly lower levels of CXCL-9, CXCL-10, IL-12p35, IL-12p40, IL-12p19 and CXCL-11 following stimulation with malaria antigen but also markedly downregulated the expression of IRF-1, IRF-2 and IRF-3 compared with microfilaria-unexposed mDCs. siRNA-inhibition of irf-1 in mDCs downregulated the production of IL-12p70 through repression of IL-12p35. Our data demonstrate that the modulation of IRFs seen in filarial (and presumably other tissue-invasive helminths) infection underlies the suppression of malaria-specific cytokines/chemokines that play a crucial role in immunity to malaria.     

The IL-1 system in HIV infection: peripheral concentrations of IL-1β, IL-1 receptor antagonist and soluble IL-1 receptor type II

The proinflammatory cytokine IL-1β is thought to be involved in ongoing HIV disease. Furthermore, its naturally occurring inhibitors soluble IL-1 receptor type II (sIL-1RII) and IL-1 receptor antagonist (IL-1Ra) may play a pivotal role in regulating its biological action. To investigate the involvement of the IL-1 system we determined serum levels of IL-1β, IL-1Ra and sIL-1RII in 90 HIV⁺ patients. The obtained values were compared with markers of disease progression such as CD⁺ count, 5′-neopterin, β₂-microglobulin and soluble tumour necrosis factor receptors (sTNF-R) p55 and p75 and then compared with C-reactive protein (CRP), granulocyte count, lL-6 and TNF-α. While IL-1Ra concentrations increased significantly with progressive CDC disease stages, sIL-1RII and IL-1β were not altered in our cohort. IL-1Ra showed statistical relation to decreasing CD4⁺ lymphocytes and increasing 5′-neopterin, β₂-microglobulin, sTNF-R p55, sTNF-R p75. Furthermore, IL-1Ra correlated positively with serum IL-6, TNF-α, CRP and granulocytes. In contrast, sIL-1RII and IL-1β tended to show an inverse correlation or showed no significant relationship to all these parameters. Il-1β was measurable only in a limited number of samples. IL-1Ra showed a clear relationship to acute inflammatory events as well as to the different disease stages. Our data suggest a dissociation between IL-1Ra and sIL-1RII serum levels which may indicate that the two IL-1 binding proteins have different pathophysiological roles in HIV infection.     

Soluble products of inflammatory reactions are not induced in children with asymptomatic Plasmodium falciparum infections

A proportion of children with Plasmodium falciparum infection have a high parasitaemia without accompanying fever, indicative of different clinical thresholds of parasitaemia. Higher levels of IL-10, IL-1Ra and sIL-4R but not sIL-2R were found in children with P. falciparum malaria, compared with levels in children with asymptomatic P. falciparum infections and in healthy children. Concentrations of IL-10 and IL-1Ra were correlated with levels of parasitaemia, but the association of cytokine levels with disease was independent of the association with parasitaemia. Children may tolerate a high parasitaemia by neutralizing the parasite-derived toxins. When studying potential anti-toxic molecules we found that children with symptomatic infections had lower concentrations of a phospholipid-binding molecule, β₂-glycoprotein I (β₂-GPI), compared with children with asymptomatic infections or healthy children. In conclusion, cytokines were found in much higher concentrations in children with symptomatic P. falciparum malaria than in children with asymptomatic infections, whilst the former had lower concentrations of β₂-GPI.     

Serum interleukin-2-receptor in coeliac disease: response to treatment and gluten challenge.

Concentrations of the soluble interleukin-2 receptor (sIL-2R) in the serum of 33 patients with coeliac disease were measured by ELISA. The levels of sIL-2R were significantly raised in 15 patients with untreated coeliac disease compared with treated patients and age- and sex-matched symptomatic and non-symptomatic control groups. Longitudinal studies in individual coeliac patients showed that serum sIL-2R fell following commencement of a gluten-free diet. Gluten challenge of 16 treated coeliac patients for 1 week resulted in a significant increase in serum sIL-2R, which returned to prechallenge levels within 4 weeks of recommencement of a gluten-free diet. We suggest that serum sIL-2R levels in patients with coeliac disease reflect specific immunological activation in response to gluten ingestion. Measurement of serum sIL-2R may therefore be useful in the assessment of response to treatment in patients with coeliac disease.     

Soluble tumour necrosis factor receptors (sTNF-R) and HIV infection: correlation to CD8+ lymphocytes.

The objective of this study was to determine sTNF-R, type I (p55) and type II (p75) in sera of HIV-infected male homosexuals and correlate them to T lymphocyte subpopulations and course of HIV infection. Serum samples were obtained from 39 HIV-1+ asymptomatic male homosexuals, 10 symptomatic (ARC and AIDS) male homosexuals and 44 HIV- non-homosexual healthy controls. sTNF-R levels were determined by ELISA with specific MoAbs and polyclonal antibodies to the sTNF-R proteins. sTNF-RI and II levels were significantly elevated in 72% and 74% respectively of HIV+ asymptomatic male homosexuals and in all of the symptomatic male homosexuals. In sequential studies a highly significant positive correlation was found between sTNF-RI and sTNF-RII (r = 0.8, P < 0.001) and between both sTNF-R and CD8+ lymphocyte counts (r = 0.6 and 0.92, respectively, P < 0.01-0.001) during the asymptomatic stage of the infection. All these correlations were lost, however, during the symptomatic phase of the disease. These results suggest that: (i) HIV infection is associated with elevation of sTNF-R serum levels; (ii) sTNF-R levels are strongly correlated to CD8+ lymphocytes during the asymptomatic stage of HIV infection.     

IL-2 regulation of soluble IL-2 receptor levels following thermal injury.

In the immunosuppressed burn patient serum levels of both IL-2 and a soluble form of IL-2 receptor alpha (sIL-2R alpha) are significantly elevated. Strikingly, the production of these markers by the in vitro activated patients' cells is decreased. This study examines the role of IL-2 in the decreased production of the sIL-2R alpha in vitro in patients with major burns (n = 18, 30 to greater than 70% total body surface area). Peripheral blood mononuclear cell (PBMC) cultures from patients with highly elevated serum sIL-2R alpha, and from healthy controls (n = 12) were activated with concanavalin A (Con A) at initiation. In patients' cultures mitogen-induced increments of sIL-2R alpha levels were significantly lower. There was a significant negative correlation (r = 0.64, P less than 0.001) between a high serum sIL-2R alpha level and a decreased lectin-induced sIL-2R alpha release in vitro. Low levels of sIL-2R alpha in patients' samples were not normalized by increasing the number of T lymphocytes. Also exogenous rIL-1 was without effect, whereas rIL-3 increased sIL-2R alpha release in some cultures. However, sIL-2R alpha levels were significantly increased in patients' cultures by (i) addition of exogenous IL-2; (ii) removal of adherent cells; (iii) addition of cyclooxygenase inhibitor, indomethacin; (iv) bypassing cell surface activation by the combination of the calcium ionophore A23187 and the phorbol ester 12-o-tetradecanoyl acetate. The cyclic AMP-elevating drug, forskolin, abrogated the ability of exogenous IL-2 to increase sIL-2R alpha production. Thus, in the burn patient, the reduced in vitro sIL-2R alpha release appears to relate to abnormalities in IL-2 production and action mediated through its functional surface receptor. Elevated levels of sIL-2R alpha in vivo may, therefore, reflect systemic activation of T lymphocytes in response to biologically active IL-2.     

Serum markers of T cell activation in relapses of Wegener's granulomatosis.

Levels of soluble IL-2 receptor (sIL-2R), soluble CD4 (sCD4) and CD8 (sCD8) were measured by sandwich ELISA as markers for T cell activation in serial serum samples from 16 patients showing 18 histologically proven relapses of Wegener's granulomatosis (WG). Levels of sIL-2R increased from 1065 U/ml (median, range 373-2345 U/ml) 6 months before the relapse to 1684 U/ml (median, range 486-3404 U/ml) at the moment of relapse for the whole group (P = 0.10). The eight major relapses showed a profound rise in sIL-2R levels, from 1008 U/ml (median, range 686-1553 U/ml) 6 months before the relapse, to 1994 U/ml (median, range 1469-3404 U/ml) at the moment of relapse (P < 0.01). The levels of sIL-2R at the moment of relapse were significantly higher at the eight major relapses than at the time of the 10 minor relapses (P < 0.05). Minor relapses were not accompanied by a significant rise in sIL-2R levels. Titres of antineutrophil cytoplasmic antibodies (ANCA) rose by two or more titresteps or from negative to positive in 15/18 patients during the 6 months period before the relapse. In all seven cases with both a rise of the ANCA titre and an at least 25% increase in sIL-2R levels, the rise in ANCA preceded the rise in sIL-2R by at least 1 month. The level of sIL-2R at the moment of relapse correlated with the level of C-reactive protein (r = 0.488, P < 0.05) and with the disease activity score (r = 0.824, P < 0.002). There were no significant changes in levels of sCD4 or sCD8, although the levels of sCD4 tended to be higher at the time of major relapses. We conclude that major relapses of Wegener's granulomatosis are accompanied by systemic T cell activation. T cell activation, however, does not appear to precede the rise in ANCA titre.     

Increased levels of beta 2-microglobulin, soluble interleukin-2 receptor, and soluble CD8 in patients with subacute sclerosing panencephalitis.

We measured beta 2-microglobulin (beta 2-M), soluble interleukin-2 receptor (sIL-2R), and soluble CD8 (sCD8) antigen levels in paired cerebrospinal fluid (CSF) and sera from patients with subacute sclerosing panencephalitis (SSPE), multiple sclerosis (MS), and other neurological diseases (OND) using enzyme-linked immunosorbent assay. beta 2-M was significantly increased in CSF of the SSPE group compared to the MS or the OND group. Similarly, beta 2-M in the MS versus OND group was significantly increased in CSF. Although serum levels of beta 2-M were similar in the three groups, the CSF/serum ratios were higher in SSPE versus the MS group and in the MS versus the OND group. Levels of sIL-2R and sCD8 were higher in SSPE CSF than OND CSF; however, there were no differences between levels in SSPE and MS CSF. The levels of sIL-2R were increased in SSPE sera compared to those of MS or the OND group, whereas levels of sCD8 in serum from the three groups were similar. The findings of increased CSF/serum ratio of beta 2-M and higher levels of serum sIL-2R and CSF sCD8 in SSPE patients are consistent with those seen in patients with acute and chronic viral infections. When the levels between the initial and follow-up CSF and serum samples from SSPE patients were compared, the data showed that CSF levels of sCD8 elevated during periods of clinical worsening and decreased during clinical improvement. In contrast, serum beta 2-M decreased during periods of worsening and increased during improvement. The measurement of serum beta 2-M and CSF sCD8 may be useful in SSPE patients as markers to monitor disease activity.     

Laboratory markers of systemic inflammation as predictors of bloodstream infection in acutely ill patients admitted to hospital in medical emergency

The aim of the present study was to determine whether the presence of an infectious focus or of fever alone can predict bloodstream infection and whether levels of C-reactive protein, procalcitonin, interleukin (IL)-6, IL-8, and soluble IL-2 receptor (sIL-2R) improve the diagnosis of community-acquired bloodstream infection. Markers of systemic inflammation were studied in 92 patients with community-acquired infection. On admission to hospital, 54 patients had an infectious focus, 25 had fever without an infectious focus, and 13 had neither. The presence of focus or fever predicted bloodstream infection (n=13 patients) with a sensitivity of 100% (95% confidence interval, 75–100), a specificity of 16% (95%CI, 9–26), a negative predictive value of 100% (95%CI, 75–100), and a positive predictive value of 16% (95%CI, 9–26). Positive predictive values of C-reactive protein, procalcitonin, IL-6, IL-8, and sIL-2R, all measured on admission, were also low (33–44%). Eight febrile patients in whom an infectious focus was found during a 3-day follow-up period had higher on-admission IL-6 (P=0.005) and sIL-2R (P=0.046) levels than did 17 febrile patients without an infectious focus. In conclusion, markers of systemic inflammation do not improve the diagnosis of community-acquired bloodstream infection; however, they may aid in identifying patients with fever due to occult infection.     

Soluble TNF receptor production by activated T lymphocytes: differential effects of acute and chronic exposure to TNF.

Soluble tumour necrosis factor receptors (sTNF-R) are up-regulated at sites of chronic inflammation such as rheumatoid synovial joints. The p75 sTNF-R is the more abundant, suggesting an important role for this TNF inhibitor in regulating TNF bioactivity in vivo. As the precise cellular source of these soluble receptors is not known, we investigated the production and regulation of sTNF-R by T lymphocytes, an abundant cell type in inflammatory infiltrates, which upon activation express high levels of p75 surface receptors. Using panels of T-cell lines and clones expressing high levels of p75 TNF-R, we found that p75 sTNF-R production upon stimulation is a feature common to all subsets of T cells, including cells of the CD4-CD8- double negative phenotype expressing either alpha beta or gamma delta T-cell receptors (TCR). In contrast, levels of p55 sTNF-R were only detected when T cells were stimulated at higher densities and by potent mitogens such as phorbol 12-myristate 13-acetate (PMA). Detailed kinetic analyses revealed that the production of p75 sTNF-R was biphasic, the first phase was activation dependent, occurring in the absence of detectable TNF, while the second phase of p75 sTNF-R production was regulated by cytokines such as TNF. Unlike short-term exposure to TNF which enhances sTNF-R production in vitro and in vivo, prolonged exposure of T lymphocytes to TNF suppressed p75 sTNF-R (but not p55 sTNF-R) production in a dose- and time-dependent fashion. These results suggest that in patients with chronic inflammatory disease, which are exposed to augmented levels of bioactive TNF for prolonged periods, the production of p75 sTNF-R may be impaired.     

Cytokines in bipolar disorder: A systematic review and meta-analysis

BackgroundCurrent research and hypothesis regarding the pathophysiology of bipolar disorder suggests the involvement of immune system dysfunction that is possibly related to disease activity. Our objective was to systematically review evidence of cytokine alterations in bipolar disorder according to affective state.MethodsWe conducted a systemtic review of studies measuring endogenous cytokine concentrations in patients with bipolar disorder and a meta-analysis, reporting results according to the PRISMA statement.ResultsThirteen studies were included, comprising 556 bipolar disorder patients and 767 healthy controls, evaluating 15 different cytokines-, cytokine receptors- or cytokine antagonists. The levels of tumor necrosis factor-α (TNF-α), the soluble tumor necrosis factor receptor type 1 (sTNF-R1) and the soluble inlerleukin-2 receptor (sIL-2R) were elevated in manic patients compared with healthy control subjects (p<0.01 for each). Levels of sTNF-R1 and TNF-α were elevated in manic patients compared to euthymic patients (p=0.01 and p=0.04, respectively). sTNF-R1 levels were elevated in euthymic patients compared with healthy control subjects (p<0.01). There were no significant findings for other comparisons, including intra-individual alterations of cytokine levels.LimitationsStratification according to mood state resulted in small study numbers for some cytokines. Findings were limited by heterogeneity, small sample sizes and a lack of control for confounding factors in individual studies.ConclusionsThis meta-analysis found some support for immune dysregulation in bipolar disorder. Future research is warranted to elucidate the role of endogenous cytokine alterations in bipolar disorder. Clinical studies examining longitudinal changes within individuals are recommended.     

Soluble interleukin-2 receptors in plasma cell dyscrasias

Levels of the soluble form of the interleukin-2 receptor (sIL-2R) were evaluated in the peripheral blood of 69 patients with plasma cell dyscrasias. A close relationship was seen between serum sIL-2R levels and clinical features. Among patients with normal BUN and creatinine levels, the mean (+/- 1SD) level of sIL-2R in 44 patients with multiple myeloma (MM) was higher than that of normal controls (457 +/- 227 U/ml vs 288 +/- 124 U/ml, P = 0.01). The mean level of sIL-2R in eight patients with primary macroglobulinemia was 722 +/- 251 U/ml. In MM, those with active or refractory disease showed a significantly higher mean level of sIL-2R than those in the remission phase (577 +/- 240 U/ml vs 335 +/- 103 U/ml, P = 0.01). There was a negative correlation between sIL-2R and hemoglobin levels in MM patients (r = -0.45, P = 0.01). Five patients with complications of renal insufficiency had elevated levels of sIL-2R. In a longitudinal study of a patient with plasmacytoma and an extremely high sIL2-R level, the sIL-2R level showed a strong relationship with tumor burden. Patients with high sIL-2R levels generally had a poor prognosis than those with normal levels. Thus a high sIL-2R level may be an indicator of a poor prognosis in MM.     

HFRS患者血浆中TNF、sIL-2R、IL-6、IL-4和IFN-γ水平的变化及其意义

目的 :探讨肾综合征出血热 (HFRS)患者血浆中的TNF、sIL 2R、IL 6、IL 4和IFN γ水平的变化及其与血清中丙氨酸转氨酶ALT活性水平的相关性。方法 :利用双mAb夹心ELISA法检测HFRS患者血浆中细胞因子的水平 ,应用美国RA 10 0 0全自动生化仪检测患者血清中ALT的水平。结果 :HFRS患者血浆中TNF、IL 6、IL 4、IFN γ和sIL 2R水平分别为 (95 .82± 12 .0 4 )、(36 2 .4 6± 14 1.2 6 )、(17.76± 3.5 2 )、(116 .18± 19.80 )ng/L及 (89882 0± 12 72 0 0 )U/L ,健康对照组依次为 (17.89± 1.6 8)、(4 3.81± 18.0 8)、(4 .86± 1.14 )、(7.5 7± 2 .4 1)ng/L及(6 6 730± 2 96 90 )U/L、(P <0 .0 1) ;患者血清中ALT的水平也显著升高 ,为正常对照的 4 .4倍。通过相关性分析 ,发现TNF、sIL 2R、IL 6和IFN γ水平与患者血清中ALT的水平高度相关 (P <0 .0 1)。结论 :HFRS患者体内TNF、sIL 2R、IL 6和IFN γ水平显著升高 ,且与患者体内ALT水平的升高高度相关 ,提示HTNV感染所致肝脏的损伤可能与上述细胞因子水平的升高有关     

The course of a primary infection of Plasmodium yoelii 17XL in both 129S1 and IFN-γ receptor-deficient mice

In the present study, we found that 129S1 mice are resistant to the infection with Plasmodium yoelii 17XL, which is highly virulent and causes lethal infection in various strains of mice. In contrast, IFN-γ receptor-deficient (IFN-γR(-/-)) mice on the 129S1 background were much more susceptible than 129S1 mice with intraperitoneal infection with 1?×?10(5) parasitized erythrocytes. The mortality in 129S1 and IFN-γR(-/-) mice was 11.6 and 79.4 %, respectively. Following inoculation of the parasites, both 129S1 and IFN-γR(-/-) mice showed a progressive increase in parasitemia. Growth rate of malaria parasites at the early stages of infection in the IFN-γR(-/-) mice was faster than that in 129S1 mice, and this difference in growth rate might cause the earlier death of IFN-γR(-/-) host from day 8 of infection than that of 129S1. In surviving mice of both strains, however, malaria parasites in their bloodstream began to decrease in number right after a peak of parasitemia and were not detectable by a microscopic examination during the observation period. Next, we investigated the cytokine and antibody production in 129S1 and IFN-γR(-/-) mice during infection. An analysis of cytokines showed that serum IFN-γ and IL-4 levels elevated significantly from day 1 and day 4 of infection, respectively, in both 129S1 and IFN-γR(-/-) mice when compared with the levels from the uninfected controls. Following the infection, significantly higher levels of malaria-specific IgG1 and IgG2a antibodies in the infected 129S1 mice were detected from day 15, and these elevations were coincident with the decrease of parasitemia. On the other hand, the levels of malaria-specific antibodies in IFN-γR(-/-) mice had a tendency to elevate on day 21 but did not reach statistical significance. The present data indicate that IFN-γR plays an essential role in mediating the early immune mechanisms induced by the infection of erythrocytic stages of P. yoelii 17XL parasite, leading to host survival.     

Lack of soluble TNF-receptors in women with recurrent spontaneous abortion and possibility for its correction

PROBLEM: Tumor necrosis factor (TNF) and soluble TNF receptors (sTNF-Rs) system related with Th1 and Th2 and activity of NF-kappaB/IkappaB regulatory system. This study was designed to compare sTNF-R1 and sTNF-R2 production (shedding) and levels of late activated CD8+ T-lymphocytes in non-pregnant (n = 30) and pregnant (n = 20) normal women and non-pregnant (n = 20) and pregnant (n = 30) RSA women. Effects of progesterone (natural structure) injections in RSA women were studied. METHODS OF STUDY: Levels of sTNF-R1, sTNF-R2, TNF in peripheral blood serum were detected by enzyme-linked immunosorbent assay. Lymphocyte subsets were estimated by multicolor flow cytometry. NK cell cytotoxic activity of peripheral blood lymphocytes (PBL) in whole blood against K562 targets was determined using Europium-release cytotoxicity assay. Mitogen-induced proliferative response of PBL to PHA-P, Con A and PWM were determined by standard 3H-thymidine incorporation assay. RESULTS: Levels of soluble TNF-R1 and TNF-R2 in normal pregnancy were elevated when compared with non-pregnant normal women and pregnant RSA women. Levels of late activated CD8+ T-lymphocytes in normal pregnancy were decreased but no changes were detected in RSA women. After progesterone therapy (i.m. injections of 2.5% oil solution) in RSA women elevation of sTNF-R1 and sTNF-R2 to normal pregnancy ranges was observed. No changes in levels of late activated CD8+ T-lymphocytes after progesterone treatment were detected. CONCLUSIONS: Elevation of levels of sTNF-R1, sTNF-R2 and decrease of late activated cytotoxic T-lymphocytes are pronounce markers of normal human pregnancy. In RSA women there are no elevation of sTNF-R1 and sTNF-R2 levels during pregnancy. This deficiency may be restored by progesterone treatment.