Publications by authors named "Vladimira Durmanova"

13 Publications

  • Page 1 of 1

Impact of rs243865 and rs3025058 Polymorphisms on Clinical Findings in Alzheimer's Disease Patients.

Mediators Inflamm 2021 19;2021:5573642. Epub 2021 Apr 19.

Institute of Immunology, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia.

Alzheimer's disease (AD) is a chronic neurodegenerative disease of the central nervous system with higher prevalence in elderly people. Despite numerous research studies, the etiopathogenesis of AD remains unclear. Matrix metalloproteinases (MMPs) are endopeptidases involved in the cleavage of extracellular matrix proteins and basement membrane compounds. In the brain, the pathological role of MMPs includes the disruption of the blood-brain barrier leading to the induction of neuroinflammation. Among various MMPs, MMP-2 and MMP-3 belong to candidate molecules related to AD pathology. In our study, we aimed to evaluate the association of rs243865 and rs3025058 polymorphisms with AD susceptibility and their influence on age at onset and MoCA score in patients from Slovakia. Both MMP gene promoter polymorphisms were genotyped in 171 AD patients and 308 controls by the PCR-RFLP method. No statistically significant differences in the distribution of rs243865 (-1306 C>T) and rs3025058 (-1171 5A>6A) alleles/genotypes were found between AD patients and the control group. However, correlation with clinical findings revealed later age at disease onset in rs243865 CC carriers in the dominant model as compared to T allele carriers (CC vs. CT+TT: 78.44 ± 6.28 vs. 76.36 ± 6.39, = 0.036). The results of rs3025058 analysis revealed that 5A/6A carriers in the overdominant model tended to have earlier age at disease onset as compared to other genotype carriers (5A/6A vs. 5A/5A+6A/6A: 76.61 ± 5.88 vs. 78.57 ± 6.79, = 0.045). In conclusion, our results suggest that rs243865 and rs3025058 promoter polymorphisms may have influence on age at onset in AD patients.
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http://dx.doi.org/10.1155/2021/5573642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079184PMC
April 2021

5'URR regulatory polymorphisms are associated with the risk of developing gliomas.

Int J Neurosci 2021 Sep 28:1-10. Epub 2021 Sep 28.

Institute of Immunology, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia.

Background: Human leukocyte antigen G (HLA-G) belongs to non-classical MHC class I molecules that is involved in the suppression of immune response. As HLA-G plays important role in the maintenance of fetal tolerance, its overexpression has been associated with tumor progression. For the regulation of HLA-G levels, genetic variants within the 5' upstream regulatory region (5'URR) are of crucial importance. Our study aimed to analyze the association between 16 5'URR variants, sHLA-G level and clinical variables in glioma patients.

Methods: We investigated 59 patients with gliomas (mean age 54.70 ± 15.10 years) and 131 healthy controls (mean age 41.45 ± 9.75 years). Patient's blood was obtained on the day of surgical treatment. The 5'URR polymorphisms were typed by direct sequencing and the plasma level of sHLA-G assessed by ELISA.

Results: Haploblock within 5'URR consisting of -762T, -716G, -689G, -666T, -633A, followed by -486C and -201A alleles were significantly more frequent in patients with gliomas than in the controls ( < 0.05). No correlation of 5'URR variants with sHLA-G plasma level was found. Analysis of 5'URR variants with main clinical variables in patients with grade IV gliomas revealed that haploblock carriers of -762CT, -716TG, -689AG, -666GT, -633GA, -486AC, -477GC, -201GA followed by -369AC carriers tend to have lower age at onset as compared to other genotype carriers ( = 0.04).

Conclusion: Our results suggest genetic association of 5'URR variants with risk of developing gliomas and possible contribution of HLA-G to disease pathology.
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http://dx.doi.org/10.1080/00207454.2021.1922401DOI Listing
September 2021

Association of CD33 rs3865444:C˃A polymorphism with a reduced risk of late-onset Alzheimer's disease in Slovaks is limited to subjects carrying the APOE ε4 allele.

Int J Immunogenet 2020 Oct 24;47(5):397-405. Epub 2020 Apr 24.

Institute of Immunology, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia.

CD33 rs3865444:C>A single nucleotide polymorphism (SNP) has been previously associated with the risk of late-onset Alzheimer's disease (LOAD); however, the results have been inconsistent across different populations. CD33 is a transmembrane receptor that plays an important role in AD pathogenesis by inhibiting amyloid β42 uptake by microglial cells. In this study, we aimed to validate the association between rs3865444 and LOAD risk in the Slovak population and to evaluate whether it was affected by the carrier status of the major LOAD risk allele apolipoprotein (APOE) ε4. CD33 rs3865444 and APOE variants were genotyped in 206 LOAD patients and 487 control subjects using the polymerase chain reaction-restriction fragment length polymorphism method and direct sequencing, respectively. Logistic regression analysis revealed a significant association of rs3865444 A allele with a reduced LOAD risk that was only present in APOE ε4 allele carriers (AA + CA versus CC: p = .0085; OR = 0.45; 95% CI = 0.25-0.82). On the other hand, no such association was found in subjects without the APOE ε4 (p = .75; OR = 0.93; 95% CI = 0.61-1.42). Moreover, regression analysis detected a significant interaction between CD33 rs3865444 A and APOE ε4 alleles (p = .021 for APOE ε4 allele dosage and p = .051 for APOE ε4 carriage status), with synergy factor (SF) value of 0.49 indicating an antagonistic effect between the two alleles in LOAD risk. In conclusion, our results suggest that CD33 rs3865444:C˃A substitution may reduce the risk of LOAD in Slovaks by antagonizing the effect conferred by the major susceptibility allele APOE ε4.
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http://dx.doi.org/10.1111/iji.12489DOI Listing
October 2020

HMGB1 as a potential new marker of disease activity in patients with multiple sclerosis.

Neurol Sci 2020 Mar 14;41(3):599-604. Epub 2019 Nov 14.

Institute of Immunology, Faculty of Medicine, Comenius University, Spitalska 24, 813 72, Bratislava, Slovakia.

Objectives: Neuroinflammation represents one of the two major pathological components of multiple sclerosis (MS). The aim of our study was to find the role of the late pro-inflammatory cytokine HMGB1 (high mobility group box) in MS pathogenesis.

Subjects And Methods: A total of 165 patients from three MS centers in Slovakia were enrolled in the study. Patients underwent a complex clinical investigation and their plasma levels of HMGB1 were analyzed by a sandwich ELISA test.

Results: MS patients had 4.5 times higher plasma level of HMGB1 (median, 13.529 ng/mL; IQR = 2.330-113.45) than healthy controls (median, 2.999 ng/mL; IQR = 1.686-9.844; P < 0.0001). The concentrations of HMGB1 were significantly associated with increased number of affected areas diagnosed by MRI (P < 0.0001) (the median for one affected area, 4.205 ng/mL; median for five affected areas, 17.843 ng/mL; P < 0.05). Patients with at least one active lesion in any of the affected areas in the brain had significantly higher plasma levels of HMGB1 (median, 20.118 ng/mL; IQR, 3.693-100.12) than those without any active lesion (median, 16.695 ng/mL; IQR, 3.255-113.45; P < 0.0235). We found also a very highly significant association of HMGB1 plasma levels with clinical condition expressed as EDSS (expanded disability status scale) (P < 0.0001); patients with higher EDSS had higher levels of HMGB1 (EDSS ≤ 2.5, 11.648 ng/mL vs. EDSS ≥ 3, 17.549 ng/mL; P = 0.0115).

Conclusion: Our results suggest chronic low-grade inflammation in MS patients that correlates with clinical conditions of MS patients, and for HMGB1 as a possible target molecule in future therapy.
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http://dx.doi.org/10.1007/s10072-019-04136-3DOI Listing
March 2020

Association of HLA-G Polymorphisms in the 3'UTR Region and Soluble HLA-G with Kidney Graft Outcome.

Immunol Invest 2019 Aug 16;48(6):644-658. Epub 2019 May 16.

d Cancer Research Institute, Biomedical Research Center , Slovak Academy of Sciences , Bratislava , Slovakia.

: Human leukocyte antigen G (HLA-G) belongs to nonclassical HLA I molecule involving in the suppression of immune response. Besides its profound effect to induce fetal tolerance, HLA-G expression has been associated with allograft acceptance. For the regulation of HLA-G levels, polymorphic sites within the 3' untranslated region (3'UTR) are of crucial importance. The aim of the study was to analyze the association between several 3'UTR variants (+3003T/C, +3010C/G, +3027C/A, +3035C/T, +3142G/C, +3187A/G, and +3196C/G), soluble HLA-G (sHLA-G) level, and kidney graft outcome in the Slovak Caucasian population. : We investigated 69 kidney transplant recipients (45 males, 24 females) of age 27-65 years. Out of this group, 37 recipients developed acute rejection that was biopsy proven. Recipient's plasma was obtained at 1 day before transplantation and analyzed by ELISA. The 3'UTR polymorphisms were typed by direct sequencing. : In the recipients with stable allograft function, significantly higher values of sHLA-G were found in the homozygous +3010GG, +3142CC, +3187GG, and +3196CC carriers in comparison to the acute rejection recipients (P = 0.01-0.05). : The study demonstrated genetic association between 3'UTR variants and sHLA-G level in kidney recipients leading to graft acceptance. We suggest to monitor the pretransplantation sHLA-G level as additional marker to predict kidney graft outcome. AMR: Antibody-mediated rejection; APC: antigen-presenting cell; CD: cluster of designation; del: deletion; HLA: human leukocyte antigen; ILT: immunoglobulin-like transcript; ins: insertion; KIR: killer-cell immunoglobulin-like receptor; NK: natural killer; sHLA-G: soluble HLA-G; SNP: single nucleotide polymorphism; TCMR: T cell-mediated rejection; URR: upstream regulatory region; UTR: untranslated region.
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http://dx.doi.org/10.1080/08820139.2019.1610888DOI Listing
August 2019

TNFRSF1A polymorphisms and their role in multiple sclerosis susceptibility and severity in the Slovak population.

Int J Immunogenet 2018 Jul 16. Epub 2018 Jul 16.

Institute of Immunology, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia.

Tumour necrosis factor (TNF)-mediated signalling plays a key role in inflammatory and neurodegenerative processes leading to the development of multiple sclerosis (MS). Recent studies have highlighted the role of tumour necrosis factor receptor superfamily member 1A (TNFRSF1A) gene encoding the type 1 TNF receptor in the genetic predisposition to MS. This study aimed to validate the association of TNFRSF1A rs1800693 and rs4149584 polymorphisms with susceptibility to MS in the Slovak population and analyse their influence on age at disease onset, severity, and disability progression. Polymerase chain reaction-restriction fragment length polymorphism method was used to genotype both TNFRSF1A polymorphisms in 541 MS patients and 724 healthy controls. Logistic regression analysis revealed a significantly increased risk of developing MS for the carriers of rs1800693 C allele (TC + CC vs. TT: pcorr = 0.005; OR = 1.61; 95% CI = 1.23-2.12), irrespective of sex and carriage of the major MS risk allele HLA-DRB1*15:01. On the other hand, no association could be found between rs4149584 and MS risk (GA + AA vs. GG: pcorr = 1.00; OR = 1.25; 95% CI = 0.71-2.21). Moreover, neither polymorphism was significantly associated with age at disease onset, MS Severity Score (MSSS) or MS Progression Index (PI) in any of the inheritance models. In conclusion, our results provide support for a sex- and HLA-DRB1*15:01-independent association of TNFRSF1A rs1800693 SNP with MS susceptibility, but not with age at disease onset, severity or rate of disability accumulation.
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http://dx.doi.org/10.1111/iji.12388DOI Listing
July 2018

A Novel Association of Polymorphism in the Gene Encoding the VLA-4 4 Subunit with Increased Risk of Alzheimer's Disease.

Mediators Inflamm 2018 27;2018:7623823. Epub 2018 Mar 27.

Institute of Immunology, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia.

Alzheimer's disease (AD) is the most prevalent cause of dementia in elderly people worldwide. Many studies support the hypothesis that the inflammation of the CNS contributes to the neurodegeneration and disease progression. The integrin molecule 41, also known as very late antigen 4 (VLA-4), belongs to adhesion molecules that activate the inflammatory process through the migration of immune cells into the CNS. Therefore, the objective of our study was to analyze the association between two polymorphisms located in the gene encoding the 4 subunit of VLA-4 and the risk of AD. 104 late-onset AD patients and 206 control subjects from Slovakia were genotyped for gene SNP polymorphism rs113276800 (-269C/A) and rs1143676 (+3061A/G). The same study cohorts were also genotyped for the -4, which is a known genetic factor associated with increased risk of AD developing. polymorphism analysis revealed significantly higher frequency of the +3061AG carriers in AD group compared to the controls ( ≤ 0.05). Following the -4 stratification of study groups, the association remained significant only in -4 noncarriers. Our study suggests a novel association of +3061A/G polymorphism with AD and its possible contribution to the disease pathology.
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http://dx.doi.org/10.1155/2018/7623823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892238PMC
October 2018

High mobility group box 1 protein in bronchoalveolar lavage fluid and correlation with other inflammatory markers in pulmonary diseases.

Sarcoidosis Vasc Diffuse Lung Dis 2018 28;35(3):268-275. Epub 2018 Apr 28.

Institute of Immunology, Comenius University Faculty of Medicine, Bratislava, Slovakia.

Analysis of new markers in bronchoalveolar lavage fluid (BALF) provides new insights into the immunopathogenesis and may be helpful in differential diagnosis of lung diseases. High mobility group box 1 protein (HMGB1) is a non-histone nuclear protein and its release into the extracellular environment may be associated with the inflammatory response. The aim of the study is the analysis of HMGB1 in BALF, correlations with other markers of inflammation and differences in extracellular HMGB1 levels in various lung diagnoses. The concentration of HMGB1 was tested by an Elisa test. We calculated correlations with other inflammatory markers (leukocytes, total protein, albumin, IgG, IgA, IgM, C3 complement component, alpha-2macroglobuline, CD3, CD4, CD8, TREM-1 and TREM-2) and specified HMGB1 level in various diagnoses. A positive correlation was found between the level of HMGB1 and total protein levels (p=0.0001), albumin (p=0.0058), IgA (p=0.011), IgM (0.0439) and TREM-2 (p=0.0188). Conversely, a negative correlation was revealed between HMGB1 and TREM-1 (p=0.0009). HMGB1 level varied in different diagnoses: the highest level was detected in QuantiFERON TB-positive subjects (median: 30.2) and hypersensitivity pneumonitis (median: 33.2), followed by pulmonary sarcoidosis (median: 16.8) and idiopathic pulmonary fibrosis (median: 8.8). HMGB1 correlates with other inflammatory markers tested in BALF. Its level varies in different lung diagnoses. .
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http://dx.doi.org/10.36141/svdld.v35i3.5726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170153PMC
April 2018

Analysis of ICAM1 gene polymorphism in Slovak multiple sclerosis patients.

Folia Microbiol (Praha) 2017 Jul 27;62(4):287-293. Epub 2017 Jan 27.

Institute of Immunology, Faculty of Medicine, Comenius University, Odborarske nam. 14, 813 72, Bratislava, Slovakia.

Infiltration of immune cells into CNS is one of the essential events in multiple sclerosis (MS) development. Adhesion molecules like the intercellular adhesion molecule 1 (ICAM-1) play critical role in this process. Therefore, the ICAM1 gene containing two important single-nucleotide polymorphisms (SNPs) belongs to candidate loci with possible involvement in MS susceptibility and/or severity. The objective of our case-control study was to analyze the association of two functional ICAM1 polymorphisms rs1799969 (or G241R) and rs5498 (or K469E) with susceptibility to MS and evaluate their influence on the age at disease onset, severity, neurological disability and progression rate. Two hundred forty-eight MS subjects (mean 39.2 years) and 208 age-matched controls (mean 35.6 years) were involved in the study. Genotyping of ICAM1 rs1799969 and rs5498 SNPs was performed by PCR-RFLP. Presence of the rs3135388 polymorphism tagging the major MS risk allele HLA-DRB1*15:01 allele was determined as well. Our analysis revealed no statistically significant association of ICAM1 polymorphisms with risk of MS development in the Slovak population. Stratification of study cohorts by gender, age at onset and presence of the HLA-DRB1*15:01 risk allele showed only moderate changes. Correlation of clinical findings as age at onset, Kurtzke Expanded Disability Status Scale, Multiple Sclerosis Severity Score and progression index with ICAM1 genotypes in MS patients revealed no significant association; however, patients with earlier onset of MS showed slightly higher frequencies of the homozygous G allele at rs5498 in comparison to other genotypes (P = 0.04), suggesting that GG carriers tend to induce MS at an earlier age.
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http://dx.doi.org/10.1007/s12223-017-0499-6DOI Listing
July 2017

The +190 G/A (rs1799864) polymorphism in the C-C chemokine receptor 2 (CCR2) gene is associated with susceptibility to multiple sclerosis in HLA-DRB1*15:01-negative individuals.

J Neurol Sci 2015 Feb 9;349(1-2):138-42. Epub 2015 Jan 9.

Department of Immunology, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia.

C-C chemokine receptor 2 (CCR2) is one of the key players involved in the transmigration of mononuclear cells into the central nervous system (CNS) and subsequent development of multiple sclerosis (MS). The aim of the current study was to analyse the association of CCR2 +190 G/A (rs1799864) polymorphism with susceptibility to MS and its influence on the age at onset, severity and neurological disability in MS. CCR2 genotyping was carried out by a polymerase chain reaction with restriction fragment length polymorphism (PCR-RFLP) in 301 MS patients and 342 healthy controls. Logistic regression analysis suggested a marginally significant association between MS and rs1799864 A allele (AA+GA vs. GG, P=0.047, OR=1.50, 95% CI=1.00-2.25), however, after stratification of study groups for the presence of HLA-DRB1*15:01 risk allele, this association could be found in HLA-DRB1*15:01-negative individuals only (AA+GA vs. GG, P=0.014, OR=1.84, 95% CI=1.13-2.98). Furthermore, there was no association between CCR2 polymorphism and clinical features of MS. In conclusion, our results suggest that CCR2 +190 G/A polymorphism may increase the susceptibility to MS, but its action seems to be restricted to individuals who do not possess the major risk allele HLA-DRB1*15:01.
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http://dx.doi.org/10.1016/j.jns.2015.01.002DOI Listing
February 2015

Epstein-Barr virus (HHV-4) inoculation to rabbits by intranasal and oral routes results in subacute and/or persistent infection dissimilar to human disease.

Intervirology 2014 28;57(5):254-69. Epub 2014 Jun 28.

Research Triangle Europe Research Center, Mosonmagyaróvár, Hungary.

Objective: We report the infection of New Zealand white rabbits with Epstein-Barr virus (EBV).

Methods: EBV prepared in B95-8 (producer) cells was inoculated to rabbits by combined intranasal and oral routes. Blood and white blood cell (WBC) samples were taken before infection, then on days 8, 28 and 98 post-infection (p.i.).

Results: Administration of either 3 × 10(8) (group A, 11 rabbits) or 1 × 10(9) (group B, 10 rabbits) EBV DNA copies per animal induced subacute and/or persistent infection. The IgG antibodies in plasma were detected by ELISA as well as by immunoblot (IB). The IB bands showed mainly antibodies to the BZRF1/Zta transactivation polypeptide (69.2%), the p54 early protein (53.4%) and to the p23 capsid protein (35.8%). No anti-EBNA1 antibody was detected throughout. Viral DNA could be detected by PCR in WBCs and/or spleen of 7 out of 21 infected rabbits (30%), while 60-80% of them showed serologic response. The transiently present EBV DNA was accompanied by LMP1 antigen.

Conclusions: Rabbits developed persistent EBV infection in the absence of EBNA1 antibodies and by the lack of typical infectious mononucleosis-like syndrome. The absence of EBNA1 antibody may reflect the lack of EBNA1 in B cells of EBV-inoculated rabbits.
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http://dx.doi.org/10.1159/000360223DOI Listing
April 2015

Donor non-specific MICA antibodies in renal transplant recipients.

Immunobiology 2014 Feb 23;219(2):109-12. Epub 2013 Aug 23.

Department of Immunology, Comenius University Faculty of Medicine, Odborárske nám. 14, 813 72 Bratislava, Slovakia.

Despite recent advances in solid organ transplantations, an antibody mediated rejection caused by donor specific antibodies is still a major problem in kidney graft survival. Besides HLA-induced humoral response, antibodies against MICA antigens have recently attracted attention because of their possible role in graft rejection. The aim of our study was to establish whether renal recipients produce antibodies against MICA molecules due to the transplantation and if they are specific for MICA antigens of the donors. MICA antibody screening was performed in 124 kidney recipient sera. 22 sera, that were found to be MICA antibody positive, were further examined for MICA antibody profiles and compared with donor MICA alleles. The analysis of MICA antibody positive sera showed mostly more complex reactivity patterns. A significant fraction of patient sera (59%) reacted not only with the donor MICA antigens, but also with other MICA patterns. A match between antibody specificities and MICA antigens was observed in 41% of renal recipients only. On the other hand, as much as in 36% of recipient sera were detected antibodies against their own MICA molecules. We did not prove a complete correlation between the recipient MICA antibody specificities and MICA antigens of the donor. We assume that MICA antibody induction occurs not only due to the allogeneic stimulation itself but also due to other factors that need to be elucidated.
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http://dx.doi.org/10.1016/j.imbio.2013.08.006DOI Listing
February 2014

Inflammatory marker sTREM-1 reflects the clinical stage and respiratory tract obstruction in allergic asthma bronchiale patients and correlates with number of neutrophils.

Mediators Inflamm 2012 5;2012:628754. Epub 2012 Jul 5.

Institute of Immunology, Comenius University, Bratislava, Slovakia.

The knowledge that asthma is an inflammatory disorder has prompted us to investigate the plasma levels of a new inflammatory marker sTREM-1 that is released from the surfaces of activated neutrophils and monocytes. The plasma levels of sTREM-1 were analysed by a sandwich ELISA test in the cohort of 76 patients with allergic asthma bronchiale and 39 healthy controls. Our results revealed more than 3.5 times higher levels of sTREM-1 in AB patients (92.3 pg/mL ± 125.6) compared with healthy subjects (25.7 pg/mL ± 9.2; P = 0.0001). Higher levels of sTREM-1 were found also in patients with exacerbated AB (170.5 pg/mL ± 78.2) compared with nonexacerbated AB patients (59.1 ± 78.2; P < 0.0001), patients with respiratory tract obstruction (176.4 pg/mL ± 177.8), than those without obstruction (51.99 pg/mL ± 64.0; P < 0.0001) and patients with anti-IgE therapy (P < 0.0001). Levels of sTREM-1 correlated with number of leucocytes (P = 0.002), and absolute number of neutrophils (P = 0.001). Elevated plasma levels of sTREM-1 reflect the severity, state of exacerbation, presence of respiratory tract obstruction in AB patients and together with increased number of neutrophils point to the role of neutrophils in inflammation accompanying AB.
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http://dx.doi.org/10.1155/2012/628754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3399449PMC
November 2012
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