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1.  TACI Expression and Signaling in Chronic Lymphocytic Leukemia 
Journal of Immunology Research  2015;2015:478753.
TACI is a membrane receptor of BAFF and APRIL, contributing to the differentiation and survival of normal B cells. Although malignant B cells are also subjected on TACI signaling, there is a remarkable intradisease and interindividual variability of TACI expression in B-cell malignancies. The aim of our study was to explore the possible role of TACI signaling in the biology of chronic lymphocytic leukemia (CLL), including its phenotypic and clinical characteristics and prognosis. Ninety-four patients and 19 healthy controls were studied. CLL patients exhibited variable TACI expression, with the majority of cases displaying low to undetectable TACI, along with low to undetectable BAFF and increased APRIL serum levels compared to healthy controls. CLL cells with high TACI expression displayed a better survival capacity in vitro, when cultured with BAFF and/or APRIL. Moreover, TACI expression was positively correlated with the presence of monoclonal gammopathy and inversely with CD11c expression. Therefore, our study provides further evidence for the contribution of BAFF/APRIL signaling to CLL biology, suggesting also that TACI detection might be useful in the selection of patients for novel targeting therapeutic approaches.
doi:10.1155/2015/478753
PMCID: PMC4408744  PMID: 25950010
2.  MBL2 Genotypes and Their Associations with MBL Levels and NICU Morbidity in a Cohort of Greek Neonates 
Journal of Immunology Research  2015;2015:478412.
The objective of this study was to assess the frequency of MBL2 genotypes and their associations with MBL levels and various morbidities of a neonatal intensive care unit (NICU). One hundred and thirty-four (134) NICU (83 term and 51 preterm) and 150 healthy neonates were enrolled in the study. MBL2 genotype and MBL serum levels at birth were determined prospectively by PCR-RFLP-sequencing and enzyme-linked immunosorbent assay, respectively. NICU neonates displayed significantly lower MBL serum levels compared to healthy ones. MBL deficiency, defined as the low MBL2 expression group (XA/O and O/O), was significantly associated with an increased risk of respiratory morbidity, especially transient tachypnea of the newborn and respiratory distress syndrome (RDS). Moreover, an increase of 100 ng/mL of serum MBL levels decreases by 5% the risk of total respiratory morbidity and by 7% the risk of RDS, after correction for prematurity and sex and regardless of the presence of infections. Our study further supports the notion that neonates with MBL deficiency and low MBL serum levels at birth may be at higher risk of developing severe respiratory complications.
doi:10.1155/2015/478412
PMCID: PMC4387979  PMID: 25879044
3.  Deficiency of the B Cell-Activating Factor Receptor Results in Limited CD169+ Macrophage Function during Viral Infection 
Journal of Virology  2015;89(9):4748-4759.
ABSTRACT
The B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signaling in the generation and maintenance of the CD169+ macrophage compartment. Consequently, Baffr−/− mice exhibited limited induction of innate type I interferon production after viral infection. Lack of BAFFR signaling reduced virus amplification and presentation following viral infection, resulting in highly reduced antiviral adaptive immune responses. As a consequence, BAFFR-deficient mice showed exacerbated and fatal disease after viral infection. Mechanistically, transient lack of B cells in Baffr−/− animals resulted in limited lymphotoxin expression, which is critical for maintenance of CD169+ cells. In conclusion, BAFFR signaling affects both innate and adaptive immune activation during viral infections.
IMPORTANCE Viruses cause acute and chronic infections in humans resulting in millions of deaths every year. Innate immunity is critical for the outcome of a viral infection. Innate type I interferon production can limit viral replication, while adaptive immune priming by innate immune cells induces pathogen-specific immunity with long-term protection. Here, we show that BAFFR deficiency not only perturbed B cells, but also resulted in limited CD169+ macrophages. These macrophages are critical in amplifying viral particles to trigger type I interferon production and initiate adaptive immune priming. Consequently, BAFFR deficiency resulted in reduced enforced viral replication, limited type I interferon production, and reduced adaptive immunity compared to BAFFR-competent controls. As a result, BAFFR-deficient mice were predisposed to fatal viral infections. Thus, BAFFR expression is critical for innate immune activation and antiviral immunity.
doi:10.1128/JVI.02976-14
PMCID: PMC4403498  PMID: 25673724
4.  Identification of a STAT5 Target Gene, Dpf3, Provides Novel Insights in Chronic Lymphocytic Leukemia 
PLoS ONE  2013;8(10):e76155.
STAT5 controls essential cellular functions and is encoded by two genes, Stat5a and Stat5b. To provide insight to the mechanisms linking hematologic malignancy to STAT5 activation/regulation of target genes, we identified STAT5 target genes and focused on Dpf3 gene, which encodes for an epigenetic factor. Dpf3 expression was induced upon IL-3 stimulation in Ba/F3 cells, while strong binding of both STAT5a and STAT5b was detected in its promoter. Reduced expression of Dpf3 was detected in Ba/F3 cells with Stat5a and Stat5b knock-down, suggesting that this gene is positively regulated by STAT5, upon IL-3 stimulation. Furthermore, this gene was significantly up-regulated in CLL patients, where DPF3 gene/protein up-regulation and strong STAT5 binding to the DPF3 promoter, correlated with increased STAT5 activation, mainly in non-malignant myeloid cells (granulocytes). Our findings provide insights in the STAT5 dependent transcriptional regulation of Dpf3, and demonstrate for the first time increased STAT5 activation in granulocytes of CLL patients. Novel routes of investigation are opened to facilitate the understanding of the role of STAT5 activation in the communication between non-malignant myeloid and malignant B-cells, and the functions of STAT5 target genes networks in CLL biology.
doi:10.1371/journal.pone.0076155
PMCID: PMC3796511  PMID: 24155890
5.  Heterozygous Alterations of TNFRSF13B/TACI in Tonsillar Hypertrophy and Sarcoidosis 
TNFRSF13B/TACI defects have been associated with CVID pathogenesis and/or phenotype, especially the development of benign lymphoproliferation and autoimmunity. Our purpose was to investigate the role of TNFRSF13B/TACI defects in the pathogenesis of two common lymphoproliferative disorders, namely, sarcoidosis and tonsillar hypertrophy (TH). 105 patients (71 with sarcoidosis and 34 with TH, including 19 without infectious causative and 15 due to Haemophilus influenzae) were analyzed for TNFRSF13B/TACI defects. Two out of 19 TH patients without infectious cause (10.5%) and 2 patients with sarcoidosis (2.8%) displayed rare TNFRSF13B/TACI defects (I87N, L69TfsX12, E36L, and R202H, resp.). Both mutations identified in TH patients have been assessed as deleterious for protein function, while the patient with the R202H mutation and sarcoidosis exhibited also sIgG4D. Our study further supports the notion that TNFRSF13B/TACI defects alone do not result in CVID but may be also found frequently in distinct clinical phenotypes, including benign lymphoproliferation and IgG subclass deficiencies.
doi:10.1155/2013/532437
PMCID: PMC3727192  PMID: 23956760
6.  A Case of Hyperimmunoglobulinemia D Syndrome Successfully Treated with Canakinumab 
Case Reports in Rheumatology  2013;2013:795027.
Hyperimmunoglobulinemia D syndrome is a rare autosomal recessive autoinflammatory disorder caused by mutations in the mevalonate kinase gene (MVK). In a proportion of patients, however, no MVK mutations are detected. Although various standard anti-inflammatory drugs have been tried, until now there is no consensus about how HIDS should be treated. We present a case of HIDS in an 8-year-old girl whose clinical picture had started before the end of the first year of life. The patient had consistently elevated IgD levels but no mutations were found after a full-length analysis of the MVK gene. The method of MVK mutational analysis is presented in details. Treatment with canakinumab in a final single dose of 4 mg/kg every 4 weeks resulted in the disappearance of febrile attacks and a considerable improvement of patients' quality of life during a 12-month follow-up period. The drug has been well tolerated, and no side effects were observed.
doi:10.1155/2013/795027
PMCID: PMC3652103  PMID: 23691418
7.  Liver FOXP3 and PD1/PDL1 Expression is Down-Regulated in Chronic HBV Hepatitis on Maintained Remission Related to the Degree of Inflammation 
Background and Aim: T cell expression of PD1 and inhibition of T effector cells by Foxp3+-T regulatory cells are among the most powerful mechanisms for achieving a balanced immune response. Our aim was to investigate, how liver FOXP3 and PD1/PDL1 expression is regulated in chronic HBV hepatitis (CHB) on maintained long-term remission in comparison with active disease, and whether they are correlated to the expression of pro- and anti-inflammatory cytokines and apoptosis mediators, along with the degree of histological inflammation and markers of T cell effector restoration.
Methods: Fifty-three HBeAg-negative CHB patients with both active (30) and completely remitted disease on long-term antiviral treatment (23) and four controls (submitted to liver biopsy due to a mild increase of aminotransferases but without liver necroinflammatory and architecture changes) were enrolled in the study. Liver mRNA levels of immunoregulatory genes (FOXP3, IL10, TGFB1, and those of PD1/PDL1/PDL2 pathway), major apoptosis mediators (FAS, FASL, TNFA, TRAIL), cytokines of effector T cell restoration (IL2, IFNG), and those of IL1B, CD4, and CD8, were evaluated by quantitative real-time reverse-transcriptase PCR and were correlated with each other, along with the intensity of liver inflammation and fibrosis staging. The expression and localization of FOXP3, PD1, PDL1, CD4, and CD8 were also assessed by immunohistochemistry.
Results: The expression of FOXP3, IL10, TGFB1, PD1, PDL1, FASL, and CD8 was significantly down-regulated in the remission state. In contrast, liver expression of IL2 and IFNG, along with CD4, IL1B, TNFA, and FAS did not change significantly. Moreover, FOXP3, PD1, PDL1, and CD8 transcripts were positively correlated to the intensity of liver inflammation.
Conclusion: Our data indicate that in the CHB disease model, the immunosuppressive liver environment is down-regulated in the maintained on-treatment long-term remission state and correlates with the intensity of liver inflammation, but not liver T cell restoration.
doi:10.3389/fimmu.2013.00207
PMCID: PMC3722555  PMID: 23898331
chronic HBV hepatitis; regulatory T cells; FOXP3; PD1/PDL1; FAS/FASL; inflammation
8.  Transient ischemic attacks as the first presentation of JAK2-V617F positive chronic myeloproliferative neoplasm 
Hematology Reports  2012;4(2):e12.
Several studies have shown that thrombotic events may underlie a latent or subclinical myeloproliferative neoplasm (MPN) and precede its definite diagnosis by 1–2 years. An early diagnosis of patients with MPN, especially those with thrombotic events in the latent MPN phase, would be beneficial for their management, preventing further morbidity and improving their quality of life. For the majority of these cases, the location of thrombosis is mainly in the splanchnic major veins, while ischemic stroke and cerebral venous thrombosis are rarely observed. In this report, we present a female patient with transient ischemic attacks who suffered from a latent MPN, on the basis of a positive testing for the JAK2-V617F mutation.
doi:10.4081/hr.2012.e12
PMCID: PMC3401133  PMID: 22826794
TIAs; latent myeloproliferative neoplasm; JAK2-V617F
9.  Foxp3 Expression in Liver Correlates with the Degree but Not the Cause of Inflammation 
Mediators of Inflammation  2011;2011:827565.
Patients with chronic viral hepatitis display increased expression of Foxp3 in liver, suggesting that Tregs expansion contributes to persistent infection. The purpose of this study was to elucidate whether the expression of Foxp3 relates not to the viral infection but to the resulting liver inflammation. Liver biopsies obtained from 69 individuals (26 chronic HBV hepatitis, 14 chronic HCV hepatitis, 11 nonalcoholic fatty liver disease, 8 autoimmune diseases, 2 methotrexate-related toxicity, and 8 controls) were examined, by qRT-PCR, for the mRNA expression of Foxp3, IL-10, TGF-β1, Fas, FasL, TRAIL, caspase-3, TNF-α, IFN-γ, and IL-1β. Significant increase of Foxp3 was observed in all disease groups compared to controls, which was positively correlated with the intensity of inflammation. The expression of the apoptosis mediators Fas, FasL, and TRAIL, but not of IL-10 and TGF-β1, was also significantly elevated. Our findings indicate that, independently of the initial inducer, liver inflammation is correlated with elevated expression of apoptosis mediators and is followed by local Treg accumulation. Further research towards the elucidation of the underlying casual relationships is required, in order to clarify whether our results signify the existence of a uniform Treg-mediated regulatory mechanism of apoptosis-induced inflammation.
doi:10.1155/2011/827565
PMCID: PMC3136102  PMID: 21772667
10.  Toll-Like Receptor 4 Gene (TLR4), but Not TLR2, Polymorphisms Modify the Risk of Tonsillar Disease Due to Streptococcus pyogenes and Haemophilus influenzae▿ †  
Tonsillar disease (recurrent tonsillitis and/or tonsillar hypertrophy) is one of the most common human disorders, with Streptococcus pyogenes (group A beta-hemolytic streptococcus [GAS]) and Haemophilus influenzae representing the most common pathogens. Until now, no study has investigated why some individuals are more susceptible to tonsillar infections caused by specific bacteria than others. The aim of this study was to uncover possible associations between common Toll-like receptor gene (TLR) polymorphisms and tonsillar disease. The TLR2-R753Q, TLR4-D299G, and TLR4-T399I polymorphisms were determined in a cohort of 327 patients subjected to tonsillectomy due to recurrent tonsillitis (n = 245) and tonsillar hypertrophy (n = 82) and 245 healthy bone marrow donors. Associations of the aforementioned polymorphisms with the isolated bacterial strains after tonsillectomy were also investigated. Interestingly, carriers of the TLR4 polymorphisms displayed an approximately 3-fold increased risk for GAS infections (for TLR4-D299G, odds ratio [OR] = 2.81, 95% confidence interval [CI] = 1.16 to 6.79, P = 0.038; for TLR4-T399I, OR = 3.01, 95% CI = 1.29 to 7.02, P = 0.023), and this association was more profound in patients with recurrent tonsillitis. On the contrary, the presence of the TLR4-T399I polymorphism was associated with a 2-fold decreased risk of Haemophilus influenzae carriage (OR = 0.38, 95% CI = 0.15 to 0.96, P = 0.038). In the end, no significant differences were observed, considering the genotype and allele frequencies of the above-mentioned polymorphisms, between patients and controls. Our findings indicate that, regarding tonsillar infections, TLR4 polymorphisms predispose individuals to GAS infection, while they are protective against Haemophilus influenzae infection. This result further elucidates the role that host immune genetic variations might play in the susceptibility to common infections and tonsillar disease.
doi:10.1128/CVI.00460-10
PMCID: PMC3067360  PMID: 21159925
11.  Association of TLR4-T399I Polymorphism with Chronic Obstructive Pulmonary Disease in Smokers 
Tobacco smoking has been considered the most important risk factor for chronic obstructive pulmonary disease (COPD) development. However, not all smokers develop COPD and other environmental and genetic susceptibility factors underlie disease pathogenesis. Recent studies have indicated that the impairment of TLR signaling might play a crucial role in the development of emphysema. For this purpose we investigated the prevalence and any possible associations of common TLR polymorphisms (TLR2-R753Q, TLR4-D299G, and TLR4-T399I) in a group of 240 heavy smokers (>20 pack years), without overt atherosclerosis disease, of whom 136 had developed COPD and 104 had not. The presence of TLR4-T399I polymorphism was associated with a 2.4-fold increased risk for COPD development (P = .044), but not with disease stage or frequency of exacerbations. Considering that infections contribute to COPD and emphysema pathogenesis, our findings possibly indicate that dysfunctional polymorphisms of innate immune genes can affect the development of COPD in smokers. Although this finding warrants further investigation, it highlights the importance of impaired innate immunity towards COPD development.
doi:10.1155/2009/260286
PMCID: PMC2822240  PMID: 20169003
12.  FIP1L1-PDGFRA molecular analysis in the differential diagnosis of eosinophilia 
Background
Primary eosinophlia associated with the FIP1L1-PDGFRA rearrangement represents a subset of chronic eosinophilic leukaemia (CEL) and affected patients are very sensitive to imatinib treatment. This study was undertaken in order to examine the prevalence and the associated clinicopathologic and genetic features of FIP1L1-PDGFRA rearrangement in a cohort of 15 adult patients presenting with profound eosinophilia (> 1.5 × 109/L).
Methods
Reverse transcriptase-polymerase chain reaction (RT-PCR) was used for the detection of FIP1L1-PDGFRA rearrangement and the results confirmed by direct sequencing. C-KIT-D816V mutation was analysed retrospectively by PCR and restriction-fragment-length-polymorphism (PCR-RFLP), in all cases with primary eosinophilia.
Results
Two male patients with splenomegaly carried the FIP1L1-PDGFRA rearrangement, whilst 2 others were ultimately classified as suffering from idiopathic hypereosinophlic syndrome (HES) and one from systemic mastocytosis. These patients were negative for the C-KIT-D816V mutation and received imatinib (100–400 mg daily). Patients with CEL and HES responded to imatinib and remained in complete haematological, clinical and molecular (for carriers of FIP1L1-PDGFRA rearrangement) remission for a median of 28.2 months (range: 11–54), whilst the patient with systemic mastocytosis did not respond. Interestingly, in both patients with FIP1L1-PDGFRA rearrangement, the breakpoints into PDGFRA were located within exon 12 and fused with exons 8 and 8a of FIP1L1, respectively.
Conclusion
An early diagnosis of FIPIL1-PDGFRA-positive CEL and imatinib treatment offer to the affected patients an excellent clinical therapeutic result, avoiding undesirable morbidity. Moreover, although the molecular mechanisms underlying disease pathogenesis remain to be determined, imatinib can be effective in patients with idiopathic HES.
doi:10.1186/1471-2326-9-1
PMCID: PMC2640376  PMID: 19187542
13.  Foxp3 expression in human cancer cells 
Objective
Transcription factor forkhead box protein 3 (Foxp3) specifically characterizes the thymically derived naturally occurring regulatory T cells (Tregs). Limited evidence indicates that it is also expressed, albeit to a lesser extent, in tissues other than thymus and spleen, while, very recently, it was shown that Foxp3 is expressed by pancreatic carcinoma. This study was scheduled to investigate whether expression of Foxp3 transcripts and mature protein occurs constitutively in various tumor types.
Materials and methods
Twenty five tumor cell lines of different tissue origins (lung cancer, colon cancer, breast cancer, melanoma, erythroid leukemia, acute T-cell leukemia) were studied. Detection of Foxp3 mRNA was performed using both conventional RT-PCR and quantitative real-time PCR while protein expression was assessed by immunocytochemistry and flow cytometry, using different antibody clones.
Results
Foxp3 mRNA as well as Foxp3 protein was detected in all tumor cell lines, albeit in variable levels, not related to the tissue of origin. This expression correlated with the expression levels of IL-10 and TGFb1.
Conclusion
We offer evidence that Foxp3 expression, characterizes tumor cells of various tissue origins. The biological significance of these findings warrants further investigation in the context of tumor immune escape, and especially under the light of current anti-cancer efforts interfering with Foxp3 expression.
doi:10.1186/1479-5876-6-19
PMCID: PMC2386447  PMID: 18430198

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