scholarly journals Serum Interferon (IFN)-Neutralizing Antibodies and Bioactivities of IFNs in Patients with Severe Type II Essential Mixed Cryoglobulinemia

2003 ◽  
Vol 10 (1) ◽  
pp. 70-77 ◽  
Author(s):  
Carolina Scagnolari ◽  
Milvia Casato ◽  
Francesca Bellomi ◽  
Francesca De Pisa ◽  
Ombretta Turriziani ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Clinical Response ◽  
Neutralizing Antibodies ◽  
Mononuclear Cells ◽  
Mixed Cryoglobulinemia ◽  
Mrna Levels ◽  
Type Ii ◽  
Essential Mixed Cryoglobulinemia ◽  
Peripheral Blood Mononuclear ◽  
Severe Type

ABSTRACT The efficacy of alpha interferon (IFN-α) in the treatment of severe type II essential mixed cryoglobulinemia (EMC) has been reported previously. In some patients, the development of neutralizing antibodies to recombinant IFN-α (rIFN-α) can affect the clinical response achieved with rIFN-α; a second treatment with natural IFN-α preparations may reinduce the clinical response. In the present study the ability of leukocyte IFN (LeIFN) to restore the response was investigated from a pharmacodynamic viewpoint. Specifically, the pharmacodynamic profiles of different IFN-α preparations were studied by measuring the serum neopterin levels and the levels of expression of protein MxA mRNA in in vivo peripheral blood mononuclear cells in two patients with EMC whose resistance to rIFN-α2a treatment increased concomitantly with the development of neutralizing antibodies. These markers were measured before injection and at 24 and 48 h after a single injection of rIFN-α2a, consensus IFN [(C)IFN], or LeIFN. No increase or only a slight increase in MxA mRNA levels was detectable after administration of rIFN-α2a or (C)IFN, whereas a significant increase (≥10-fold) in MxA mRNA expression was recorded following administration of LeIFN. The neutralizing antibodies to rIFN-α2a cross-react with (C)IFN. Sera from these patients neutralized most but not all of the subtypes present in the natural IFN-α (LeIFN) mixture, and no significant increase in neopterin levels was observed after these patients were switched to LeIFN treatment. In summary, the data demonstrate that the problem of neutralizing antibodies still exists and that LeIFN may induce an increase in the level of MxA mRNA expression but not an increase in neopterin levels in patients who are resistant to treatment with rIFN-α2a or (C)IFN.

scholarly journals Gene Expression of Adhesion Molecules in Endothelial Cells from Patients with Peripheral Arterial Disease Is Reduced after Surgical Revascularization and Pharmacological Treatment

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Franca Marino ◽  
Luigina Guasti ◽  
Matteo Tozzi ◽  
Laura Schembri ◽  
Luana Castiglioni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Mrna Expression ◽  
Adhesion Molecules ◽  
Mononuclear Cells ◽  
Venous Blood ◽  
Statin Treatment ◽  
Early Event ◽  
Mrna Levels ◽  
Peripheral Blood Mononuclear

Atherosclerosis is an inflammatory disease characterized by immunological activity, in which endothelial dysfunction represents an early event leading to subsequent inflammatory vascular damage. We investigated gene expression of the adhesion molecules (AMs) ICAM-1, VCAM-1, andβ1-integrin in endothelial cells (ECs) isolated from venous blood (circulating EC, cEC) and purified from femoral plaques (pEC) obtained from 9 patients with peripheral artery disease (PAD) submitted to femoral artery thrombendarterectomy (FEA). In addition, in peripheral blood mononuclear cells (PBMCs) of the same subjects, we investigated gene expression of IFN-γ, IL-4, TGF-β, and IL-10. Patients were longitudinally evaluated 1 month before surgery, when statin treatment was established, at the time of surgery, and after 2 and 5 months. All AM mRNA levels, measured by means of real-time PCR, in cEC diminished during the study, up to 41–50% of initial levels at followup. AM mRNA expression was significantly higher in pEC than in cEC. During the study, in PBMCs, TGF-βand IL-10 mRNA levels remained unchanged while IFN-γand IL-4 levels increased; however, the ratio IFN-γ/IL-4 showed no significant modification. In PAD patients, FEA and statin treatment induce a profound reduction of AM expression in cEC and affect cytokine mRNA expression in PBMCs.

Elevated Expression of the NLRP3 Inflammasome and Its Correlation with Disease Activity in Adult-onset Still Disease

2017 ◽  
Vol 44 (8) ◽  
pp. 1142-1150 ◽  
Author(s):  
Chia-Wei Hsieh ◽  
Yi-Ming Chen ◽  
Chi-Chen Lin ◽  
Kuo-Tung Tang ◽  
Hsin-Hua Chen ◽  
...  
Keyword(s):  
Disease Activity ◽  
Mrna Expression ◽  
Nlrp3 Inflammasome ◽  
Mononuclear Cells ◽  
Mrna Levels ◽  
Adult Onset ◽  
Peripheral Blood Mononuclear ◽  
Protein Expressions ◽  
Still Disease ◽  
Stimulation Of

Objective.The dysregulation of the NLRP3 (NLR containing a pyrin domain) inflammasome is involved in autoinflammatory diseases. Adult-onset Still disease (AOSD) is regarded as an autoinflammatory disease. However, the pathogenic involvement of NLRP3 inflammasome in AOSD remains unclear and NLRP3 activators in AOSD are currently unknown.Methods.The mRNA expression of NLRP3 inflammasome signaling in peripheral blood mononuclear cells (PBMC) from 34 patients with AOSD and 14 healthy subjects was determined using quantitative-PCR (qPCR). The changes in mRNA and protein levels of NLRP3 inflammasome signaling in PBMC treated with the potential activator [imiquimod (IMQ)] or inhibitor of NLRP3 were evaluated using qPCR and immunoblotting, respectively. The supernatant levels of interleukin (IL)-1β and IL-18 were determined by ELISA.Results.Significantly higher mRNA levels of NLRP3 inflammasome signaling were observed in patients with AOSD compared with healthy controls. NLRP3 expressions were positively correlated with disease activity in patients with AOSD. IMQ (an effective Toll-like receptor 7 ligand; 10 µg/ml and 25 µg/ml) stimulation of PBMC from patients with AOSD induced dose-dependent increases of mRNA expression of NLRP3 (mean ± standard error of the mean, 2.06 ± 0.46 and 6.05 ± 1.84, respectively), caspase-1 (1.81 ± 0.23 and 4.25 ± 0.48), IL-1β (5.68 ± 1.51 and 12.13 ± 3.71), and IL-18 (2.32 ± 0.37 and 4.81 ± 0.51) compared with controls (all p < 0.005). IMQ stimulation of PBMC from patients similarly induced greater increases in protein expressions of NLRP3 inflammasome compared with controls. The protein expressions of NLRP3, IL-1β, and IL-18 on PBMC significantly decreased after treatment with NLRP3 inhibitor in patients with AOSD.Conclusion.Increased expression of NLRP3 inflammasome and its positive correlation with disease activity in AOSD suggest its involvement in disease pathogenesis. IMQ upregulated expressions of NLRP3 inflammasome signaling, and IMQ might be an activator of NLRP3 inflammasome in AOSD.

scholarly journals Integrating the lncRNA and mRNA expression profiles of TLR4-primed mesenchymal stem cells in ankylosing spondylitis

2020 ◽  
Author(s):  
Yuxi Li ◽  
Ming Li ◽  
Jiajun Huang ◽  
Yuwei Liang ◽  
Junshen Huang ◽  
...  
Keyword(s):  
Ankylosing Spondylitis ◽  
Mrna Expression ◽  
High Throughput Sequencing ◽  
Mononuclear Cells ◽  
Expression Profiles ◽  
Functional Networks ◽  
Control Group ◽  
Mrna Levels ◽  
Peripheral Blood Mononuclear ◽  
Qrt Pcr

Abstract Background Our previous study found that the toll-like receptor 4 (TLR4) expression of ankylosing spondylitis (AS) patients was significantly different from that of healthy donors. The goals of this study were to explore the expression profiles and functional networks of lncRNAs and mRNAs in TLR4-primed mesenchymal stromal cells from AS patients (AS-MSCs) and to clarify the mechanisms by which TLR4-primed MSCs exert immunoregulatory effects in AS. Methods Firstly, the immunoregulatory effects of MSCs were determined after TLR4 activation. Then, the differentially expressed (DE) lncRNAs and mRNAs between the control group (AS-MSCs without stimulation) and experimental group (AS-MSCs stimulated with lipopolysaccharide) were identified through high-throughput sequencing followed by qRT-PCR confirmation. Finally, bioinformatic analyses were performed to identify the critical biological functions, signalling pathways and associated functional networks involved in the TLR4-primed immunoregulatory function of AS-MSCs. Results TLR4-primed AS-MSCs showed a strong ability to inhibit the proliferation of peripheral blood mononuclear cells (PBMCs) with 1 µg/ml LPS stimulation for 4 hours. A total of 147 DE lncRNAs and 698 DE mRNAs were identified between TLR4-primed AS-MSCs and unstimulated AS-MSCs. Significant fold changes in lncRNA and mRNA levels were confirmed by qRT-PCR. GO and KEGG analysis demonstrated that the DE mRNAs and lncRNAs were highly associated with the inflammatory response. Cis-regulation prediction revealed 9 novel lncRNAs while trans-regulation prediction revealed 15 lncRNAs, respectively. Conclusions Our research describes the lncRNA and mRNA expression profiles and functional networks in TLR4-primed AS-MSCs, which is supposed to enhance the understanding of the pathogenesis of AS-MSC immunoregulatory dysfunction.

scholarly journals Borrelia burgdorferi-Induced Tolerance as a Model of Persistence via Immunosuppression

2003 ◽  
Vol 71 (7) ◽  
pp. 3979-3987 ◽  
Author(s):  
Isabel Diterich ◽  
Carolin Rauter ◽  
Carsten J. Kirschning ◽  
Thomas Hartung
Keyword(s):  
Borrelia Burgdorferi ◽  
Neutralizing Antibodies ◽  
Mononuclear Cells ◽  
Bone Marrow Cells ◽  
Mrna Levels ◽  
Blood Monocytes ◽  
Cross Tolerance ◽  
Tlr2 Expression ◽  
Peripheral Blood Mononuclear ◽  
Tlr4 Mrna

ABSTRACT If left untreated, infection with Borrelia burgdorferi sensu lato may lead to chronic Lyme borreliosis. It is still unknown how this pathogen manages to persist in the host in the presence of competent immune cells. It was recently reported that Borrelia suppresses the host's immune response, thus perhaps preventing the elimination of the pathogen (I. Diterich, L. Härter, D. Hassler, A. Wendel, and T. Hartung, Infect. Immun. 69:687-694, 2001). Here, we further characterize Borrelia-induced immunomodulation in order to develop a model of this anergy. We observed that the different Borrelia preparations that we tested, i.e., live, heat-inactivated, and sonicated Borrelia, could desensitize human blood monocytes, as shown by attenuated cytokine release upon restimulation with any of the different preparations. Next, we investigated whether these Borrelia-specific stimuli render monocytes tolerant, i.e. hyporesponsive, towards another Toll-like receptor 2 (TLR2) agonist, such as lipoteichoic acid from gram-positive bacteria, or towards the TLR4 agonist lipopolysaccharide. Cross-tolerance towards all tested stimuli was induced. Furthermore, using primary bone marrow cells from TLR2-deficient mice and from mice with a nonfunctional TLR4 (strain C3H/HeJ), we demonstrated that the TLR2 was required for tolerance induction by Borrelia, and using neutralizing antibodies, we identified interleukin-10 as the key mediator involved. Although peripheral blood mononuclear cells tolerized by Borrelia exhibited reduced TLR2 and TLR4 mRNA levels, the expression of the respective proteins on monocytes was not decreased, ruling out the possibility that tolerance to Borrelia is attributed to a reduced TLR2 expression. In summary, we characterized tolerance induced by B. burgdorferi, describing a model of desensitization which might mirror the immunosuppression recently attributed to the persistence of Borrelia in immunocompetent hosts.

scholarly journals Long-term results of therapy with interferon-alpha for type II essential mixed cryoglobulinemia

Blood ◽  
1991 ◽  
Vol 78 (12) ◽  
pp. 3142-3147 ◽  
Author(s):  
M Casato ◽  
B Lagana ◽  
G Antonelli ◽  
F Dianzani ◽  
L Bonomo
Keyword(s):  
Mixed Cryoglobulinemia ◽  
Long Term Results ◽  
Type Ii ◽  
Essential Mixed Cryoglobulinemia ◽  
Ifn Alpha ◽  
Significant Toxicity ◽  
First Choice ◽  
A Prospective Study ◽  
Severe Type

Abstract Severe type II essential mixed cryoglobulinemia (EMC) bears a poor prognosis. Treatment with corticosteroids and/or cytotoxic drugs infrequently results in long-term remissions, and is associated with significant toxicity. We conducted a prospective study with interferon (IFN) in 21 patients with severe type II EMC unresponsive to immunosuppressive regimens. They were treated with recombinant IFN- alpha 2a (18 patients) or with natural IFN-beta (three patients), alone, at a dosage of 3 megaunits (MU)/d for 3 months, followed by 3 MU every other day as maintenance. We observed 11 complete remissions, five partial remissions, and five minor responses. Of 16 patients observed for more than 1 year, 11 remained in remission for 14 to 40 months; five of them remained in complete remission for 18 to 40 months after withdrawal of treatment. Four patients discontinued treatment because of side effects. In four patients who relapsed while on maintenance therapy with recombinant IFN-alpha 2a, remission could be reinduced by treatment with natural IFN-alpha. The response rate of 77% achieved in this study prompts the use of IFN-alpha as a first-choice drug for type II EMC.

mRNA expression profile in peripheral blood mononuclear cells based on ADRB1 Ser49Gly and Arg389Gly polymorphisms in essential hypertension — a case-control pilot investigation in South Indian population

2018 ◽  
Vol 56 (8) ◽  
pp. 1230-1237 ◽  
Author(s):  
Varsha Varakantham ◽  
Ashok Kumar Kurakula Sailoo ◽  
Balakrishna Nagalla ◽  
Dinesh Kumar Bharatraj
Keyword(s):  
Essential Hypertension ◽  
Mrna Expression ◽  
Genetic Variants ◽  
Indian Population ◽  
Mononuclear Cells ◽  
Case Control ◽  
South Indian Population ◽  
Mrna Levels ◽  
Peripheral Blood Mononuclear ◽  
South Indian

AbstractBackground:β1-Adrenoreceptor (ADRB1) genetic polymorphisms are widely studied for susceptibility to many cardiovascular diseases such as essential hypertension. However, the mRNA expression ofADRB1is rarely studied.Methods:A case-control pilot study with 292 hypertensives and 324 controls was designed to evaluate the role of the Ser49Gly and Arg389Gly, which are commonly studied single nucleotide polymorphisms (SNP), in the mRNA levels ofADRB1, in conjunction with its genetic predisposition to essential hypertension.Results:Differential expression ofADRB1mRNA was seen between hypertensives and controls (p<0.01) based on genetic variants of Ser49Gly. Among hypertensive subjects, Ser49Ser and Gly49Gly were highly expressed in comparison to Ser49Gly (p<0.05 and p<0.01, respectively), whereas genetic variants of Arg389Gly did not demonstrate any such variations. We found no association between theADRB1SNPs viz., Ser49Gly and Arg389Gly and essential hypertension.Conclusions:The increased mRNA levels of Gly49Gly may indicate a plausible role in the interindividual variations in drug response. Further,ADRB1polymorphisms did not contribute to the genetic risk of essential hypertension. Studies with larger sample size are warranted to confirm these observations in the South Indian population.

Persistent neutralizing antibodies abolish the interferon β bioavailability in MS patients

Neurology ◽  
2003 ◽  
Vol 60 (4) ◽  
pp. 634-639 ◽  
Author(s):  
A. Bertolotto ◽  
F. Gilli ◽  
A. Sala ◽  
M. Capobianco ◽  
S. Malucchi ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Mononuclear Cells ◽  
Mrna Level ◽  
Positive Sample ◽  
Type I Interferons ◽  
Type I ◽  
Mrna Levels ◽  
Antiviral Protein ◽  
Peripheral Blood Mononuclear ◽  
Treatment Naïve

Background: MxA is an antiviral protein exclusively induced by type I interferons (IFN) and some viruses, and MxA gene expression is one of the most appropriate markers for measuring the biologic activity of exogenous IFNβ.Methods: A new quantitative-competitive PCR method was used to quantify MxA mRNA in peripheral blood mononuclear cells of 99 treatment-naïve and 92 IFNβ-treated patients with MS (22 Avonex, 17 Betaferon, and 53 Rebif-22). Every 3 months, IFNβ-induced neutralizing antibodies (NAb) were evaluated in sera using a cytopathic effect assay. Three categories of patients were identified: NAb negative (NAb−), persistent NAb positive (NAb+, ≥2 consecutive positive samples), and isolated NAb+ (one positive sample).Results: Treatment-naïve patients expressed detectable MxA mRNA levels (mean = 36 ± 32 fg MxA/pg glyceraldehyde-3-phosphate dehydrogenase (GAPDH); range 1 to 160) and an upper normal threshold was established (mean + 3 SD = 132 fg MxA/pg GAPDH). IFNβ-treated patients exhibited more than 11-fold higher levels (mean = 412 ± 282 fg MxA/pg GAPDH; range 16 to 1,172). However, 17 patients did not exhibit an increase in MxA mRNA level; 15 of these 17 patients showed a concurrent Nab+ titer. Moreover, 13 were persistent NAb+. Isolated NAb+ patients did not show a decrease in bioavailability of IFNβ (n = 9; mean = 567 ± 366 fg MxA/pg GAPDH; range 83 to 1,120). In NAb− patients, bioavailability was comparable among the three different IFNβ preparations 12 hours after injection.Conclusion: During IFNβ therapy, the presence of NAb reduced or abolished bioavailability in a relevant percentage of patients. These data could be important for the early detection of patients with MS who are not responsive to IFNβ therapy.

scholarly journals Long-term results of therapy with interferon-alpha for type II essential mixed cryoglobulinemia

Blood ◽  
1991 ◽  
Vol 78 (12) ◽  
pp. 3142-3147
Author(s):  
M Casato ◽  
B Lagana ◽  
G Antonelli ◽  
F Dianzani ◽  
L Bonomo
Keyword(s):  
Mixed Cryoglobulinemia ◽  
Long Term Results ◽  
Type Ii ◽  
Essential Mixed Cryoglobulinemia ◽  
Ifn Alpha ◽  
Significant Toxicity ◽  
First Choice ◽  
A Prospective Study ◽  
Severe Type

Severe type II essential mixed cryoglobulinemia (EMC) bears a poor prognosis. Treatment with corticosteroids and/or cytotoxic drugs infrequently results in long-term remissions, and is associated with significant toxicity. We conducted a prospective study with interferon (IFN) in 21 patients with severe type II EMC unresponsive to immunosuppressive regimens. They were treated with recombinant IFN- alpha 2a (18 patients) or with natural IFN-beta (three patients), alone, at a dosage of 3 megaunits (MU)/d for 3 months, followed by 3 MU every other day as maintenance. We observed 11 complete remissions, five partial remissions, and five minor responses. Of 16 patients observed for more than 1 year, 11 remained in remission for 14 to 40 months; five of them remained in complete remission for 18 to 40 months after withdrawal of treatment. Four patients discontinued treatment because of side effects. In four patients who relapsed while on maintenance therapy with recombinant IFN-alpha 2a, remission could be reinduced by treatment with natural IFN-alpha. The response rate of 77% achieved in this study prompts the use of IFN-alpha as a first-choice drug for type II EMC.

scholarly journals Association of vitamin D receptor and CYP2R1 mRNA expression with pulmonary tuberculosis

2020 ◽  
Author(s):  
Hong-Miao Li ◽  
Ye Li ◽  
Gen-You Zhang ◽  
Si-Jiu Shi ◽  
Tian-Ping Zhang
Keyword(s):  
Vitamin D ◽  
Pulmonary Tuberculosis ◽  
Mrna Expression ◽  
Vitamin D Receptor ◽  
Clinical Characteristics ◽  
Mononuclear Cells ◽  
Mrna Level ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Peripheral Blood Mononuclear

IntroductionThe vitamin D metabolic pathway has been shown to play a pivotal role in the pathogenesis of pulmonary tuberculosis (PTB), and vitamin D receptor (VDR) and CYP2R1 gene variation are known to affect vitamin D status. Hence, this study aimed to evaluate VDR and CYP2R1 mRNA expression in peripheral blood mononuclear cells (PBMCs) in PTB patients.Material and methodsWe measured VDR and CYP2R1 mRNA levels in 75 PTB patients and 63 healthy controls by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). The associations of VDR and CYP2R1 mRNA levels with clinical characteristics and laboratory indexes of PTB patients were also examined in this study.ResultsCompared to healthy controls, the VDR mRNA level was significantly higher, and the CYP2R1 mRNA level was significantly lower in PBMCs from PTB patients (p = 0.047, p = 0.008, respectively). The CYP2R1 mRNA level in PTB patients with drug-resistant, unilateral tuberculosis foci was significantly higher than that in PTB patients without these clinical characteristics (p = 0.005, p = 0.048, respectively). In addition, our results demonstrated that the VDR mRNA expression level was positively correlated with erythrocyte sedimentation rate (ESR) (p = 0.045), while the CYP2R1 mRNA level was negatively correlated with ESR in PTB patients (p = 0.020).ConclusionsAltered VDR and CYP2R1 mRNA expression levels among PTB patients suggest their involvement in this disease.

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