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ABSTRACT: Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome is a life-threatening condition with various etiopathogeneses. Without therapy approximately 90% of all patients die from the disease.
We report the case of a 17-year-old Caucasian woman with widespread hematomas and headache. Due to hemolytic anemia, thrombocytopenia, and schistocytosis, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome was suspected and plasma exchange therapy was initiated immediately. Since her thrombocyte level did not increase during the first week of therapy, plasma treatment had to be intensified to a twice-daily schedule. Further diagnostics showed markedly reduced activities of both ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 - also known as von Willebrand factor-cleaving protease) and factor H. Test results for antibodies against both proteins were positive. While plasma exchange therapy was continued, rituximab was given once weekly for four consecutive weeks. After the last dose, thrombocytes and activities of ADAMTS-13 and factor H increased into the normal range. Our patient improved and was discharged from the hospital.
Since no clinical symptoms/laboratory findings indicated a malignant or specific autoimmune-mediated disorder, the diagnosis made was thrombotic thrombocytopenic purpura-hemolytic uremic syndrome due to idiopathic combined, autoantibody-mediated ADAMTS-13/factor H deficiency.
Journal of Medical Case Reports 12/2011; 5:598.
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Therapeutic apheresis and dialysis: official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 10/2011; 15(5):507-9. · 1.39 Impact Factor
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[hide abstract]
ABSTRACT: Endemic nephropathy (EN) is defined as a slow progressive renal tubulointestitial disease that mainly occurs in the restricted areas of the Balkan Peninsula. The complexity of the pathogenesis of EN makes its earlier diagnosis very difficult. Urine samples from healthy volunteers from EN regions, EN patients with proteinuria less than 150 mg/L and EN patients with proteinuria more than 150 mg/L, patients with acute kidney injury, patients with diabetic nephropathy and healthy volunteers from Germany were collected. The urinary proteome analyses were performed using 2-D DIGE and mass spectrometry. The validation of biomarkers was investigated by two approaches (Western blot (WB) and dot blot) in successively increasing size - and partially overlapping - sample sets. Comparative and statistical analyses of the proteomics data from the different patient groups allowed the identification of six proteins (alpha-1-microglobulin, alpha-2-glycoprotein-1, beta-2-microglobulin, mannose-binding-lectin-2, protection-of-telomeres-protein-1, and superoxide-dismutase [Cu-Zn]), which were able to discriminate EN with low and high proteinuria from the other groups with high significance (p<0.05). The reliability of the identified proteins as EN marker was underlined with high statistical significance using WB analyses (sensitivity 66.7-98% and specificity 70-100%), whereas the dot blot analyses revealed a decrease in the sensitivity and specificity of these biomarkers.
Journal of proteomics 05/2011; 74(10):1994-2007. · 5.07 Impact Factor
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ABSTRACT: Sepsis is characterized by systemic microvascular dysfunction. Endothelial progenitor cells (EPCs) are critically involved in maintaining vascular homeostasis under both physiological and pathological conditions. The aim of the present study was to analyze the endothelial progenitor cell system in patients suffering from sepsis with acute renal dysfunction.
Patients with newly diagnosed sepsis were recruited from the ICU in a nonrandomized prospective manner. Blood samples were obtained within the first 12 hours after the diagnosis of sepsis. For quantifying endothelial progenitor cells (EPCs), CD133+/Flk-1+ cells were enumerated by cytometric analysis. Analysis of EPC proliferation was performed by a colony-forming units (CFU) assay. Blood concentrations of proangiogenic mediators were measured by ELISA. Acute renal dysfunction was diagnosed according to the Acute Kidney Injury Network (AKIN) criteria. Depending on the overall mean creatinine concentration during the stay at the ICU, patients were either assigned to a 'normal creatinine group' or to a 'high creatinine group'. Survival rates, frequency of dialysis, the simplified acute physiology score (SAPS) II scores, and different laboratory parameters were collected/used for further clinical characterization
Circulating EPCs were significantly higher in all sepsis patients included in the study as opposed to healthy controls. Patients within the 'high creatinine group' showed an even more pronounced EPC increase. In contrast, EPC proliferation was severely affected in sepsis. Neither total circulating EPCs nor EPC proliferation differed between patients requiring dialysis and patients without renal replacement therapy. Cell numbers and cell proliferation also did not differ between surviving patients and patients with sepsis-related death. Serum levels of vascular endothelial growth factor (VEGF), stromal derived factor-1 (SDF-1), and Angiopoietin-2 were higher in sepsis than in healthy controls. Sepsis patients within the 'high creatinine group' showed significantly higher mean serum levels of uric acid.
Sepsis significantly affects the endothelial progenitor cell system, as reflected by increased EPC numbers, increased concentrations of proangiogenic mediators, and reduced proliferative capacity of the cells. This occurs independently from the frequency of dialysis and from patient survival. Increased serum levels of uric acid are possibly responsible for stronger EPC mobilization in sepsis patients with higher average creatinine levels.
Critical care (London, England) 03/2011; 15(2):R94. · 4.61 Impact Factor
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ABSTRACT: The effect of clearance of so-called middle- and high-molecular weight proteins on clinical outcome of patients treated by peritoneal dialysis is still a matter of debate. In our present study, we investigated the impact of short-time alteration of the glucose concentration and the osmolarity of the peritoneal dialysis solution (PDS) on protein removal.
Peritoneal dialysis liquids (PDL) were collected from 19 well-characterized continuous ambulatory peritoneal dialysis (CAPD) patients treated with two types of PDS: Baxter (n = 10) and Fresenius (n = 9). The patients were treated with two different glucose concentration of each PDS in 4-h cycles. The depletion of the six interfering high-abundant proteins from the PDL samples was performed with the Multiple Affinity Removal LC Column-Human 6. The resulting protein fractions were analysed by 2D gel electrophoresis, differential in gel electrophoresis, mass spectrometry and 2D western blot.
Proteomics investigation of the PDL fractions after depletion allowed the identification of 198 polypeptides of 424 excised spots. These polypeptides equates to 48 non-redundant proteins. Comparative analyses of 2D gel electrophoresis protein pattern revealed a clear correlation between protein removal and PDS glucose concentration and osmolarity. An increase for 4 h in the PDS osmolarity (with 43-51 mosmol/L) resulted qualitatively in 18-23% more protein removal in PDL. Moreover, 2D western blot analyses of the protein glycation pattern showed that the short-time increase in PDS glucose concentration (45-50 mM) resulted in significant alteration of the advanced glycosylation end products (AGEs) pattern.
The data presented in this study demonstrate a clear correlation between the short-time changes in glucose concentration and osmolarity of the PDS, and the augmentation of the protein removal and the appearance of AGEs during CAPD.
Nephrology Dialysis Transplantation 02/2011; 26(8):2674-83. · 3.40 Impact Factor
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Carsten P Bramlage,
Gerhard A Müller,
Björn Tampe,
Jelena Bevanda,
Imad Maatouk, Michael Koziolek,
Katharina Lange,
Katharina Ahrens,
Holger Schmid,
Clemens D Cohen,
Peter Bramlage,
Matthias Kretzler,
Frank Strutz
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ABSTRACT: Bone morphogenetic protein-5 (BMP-5) has been shown to be essential for nephrogenesis. Its role in adult kidney and in patients with hypertensive nephrosclerosis is still unknown.
BMP-5 expression was evaluated by immunostaining and real-time PCR in tissue samples from normal and nephrosclerotic human kidneys. The impact of transforming growth factor-ß (TGF-ß), tumor necrosis factor-α (TNF-α) and angiotensin-II (AT-II) on expression of BMP-5 and its receptors was quantified in proximal tubular cells (HK-2). Functional characteristics of BMP-5 were evaluated by testing its influence on TGF-ß-induced epithelial-to-mesenchymal transition (EMT), TNF-α-induced apoptosis of HK-2 cells and inflammatory cell infiltration.
BMP-5 expression was localized in tubular epithelial cells and significantly decreased in nephrosclerotic kidneys. Stimulation of HK-2 cells with TGF-ß, TNF-α and AT-II resulted in a significant decreased expression of BMP-5 and its receptors. BMP-5 attenuated TGF-ß-induced EMT, TNF-α-induced apoptosis and migration of mononuclear cells.
BMP-5 is expressed in the tubuli of adult kidneys. Its decreased expression in nephrosclerosis along with its regenerative capabilities in HK-2 cells may point to a protective role in hypertensive nephrosclerosis.
Journal of nephrology 02/2011; 24(5):647-55. · 1.65 Impact Factor
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Carsten P Bramlage,
Björn Tampe, Michael Koziolek,
Imad Maatouk,
Jelena Bevanda,
Peter Bramlage,
Katharina Ahrens,
Katharina Lange,
Holger Schmid,
Clemens D Cohen,
Matthias Kretzler,
Gerhard A Müller
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ABSTRACT: Bone Morphogenetic Protein (BMP)-7 is protective in different animal models of acute and chronic kidney disease. Its role in human kidneys, and in particular hypertensive nephrosclerosis, has thus far not been described.
BMP-7 mRNA was quantified using real-time PCR and localised by immunostaining in tissue samples from normal and nephrosclerotic human kidneys. The impact of angiotensin (AT)-II and the AT-II receptor antagonist telmisartan on BMP-7 mRNA levels and phosphorylated Smad 1/5/8 (pSmad 1/5/8) expression was quantified in proximal tubular cells (HK-2). Functional characteristics of BMP-7 were evaluated by testing its influence on TGF-β induced epithelial-to-mesenchymal transition (EMT), expression of TGF-β receptor type I (TGF-βRI) and phosphorylated Smad 2 (pSmad 2) as well as on TNF-α induced apoptosis of proximal tubular cells.
BMP-7 was predominantly found in the epithelia of the distal tubule and the collecting duct and was less abundant in proximal tubular cells. In sclerotic kidneys, BMP-7 was significantly decreased as demonstrated by real-time PCR and immunostaining. AT-II stimulation in HK-2 cells led to a significant decrease of BMP-7 and pSmad 1/5/8, which was partially ameliorated upon co-incubation with telmisartan. Only high concentrations of BMP-7 (100 ng/ml) were able to reverse TNF-α-induced apoptosis and TGF-β-induced EMT in human proximal tubule cells possibly due to a decreased expression of TGF-βRI. In addition, BMP-7 was able to reverse TGF-β-induced phosphorylation of Smad 2.
The findings suggest a protective role for BMP-7 by counteracting the TGF-β and TNF-α-induced negative effects. The reduced expression of BMP-7 in patients with hypertensive nephrosclerosis may imply loss of protection and regenerative potential necessary to counter the disease.
BMC Nephrology 11/2010; 11:31. · 2.18 Impact Factor
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ABSTRACT: We report a case of a 27-year-old female with thrombotic microangiopathy as an initial presentation of an unexpected disseminated gastric carcinoma. Based on clinical features and laboratory findings, thrombotic thrombocytopenic purpura (TTP) was diagnosed and plasma exchange started. However, she had responded poorly to plasmapheresis, developed multiorgan failure and died 72 h after admission. Autopsy revealed a disseminated gastric adenocarcinoma with metastatic infiltration of dura mater and disseminated tumor cell emboli in the microcirculation of the liver and lungs. Genetic analysis revealed amplification of KRAS oncogene and aberrations in DCC tumor suppressor gene, which can explain the young age and advanced disease at presentation. The role of plasmapheresis in cancer-associated TTP is uncertain. Plasmapheresis delivers fresh coagulation factors and may theoretically promote microthrombi formation and lead to worsening of the disease. Thrombotic thrombocytopenic purpura seems to be a late and prognostically poor manifestation of an underlying malignancy, with majority of patients dying soon after diagnosis. It is important to be aware of this possibility in thrombotic microangiopathy, especially with atypical features and poor response to standard treatment.
Therapeutic apheresis and dialysis: official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 04/2010; 14(2):222-5. · 1.39 Impact Factor
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Carsten Bramlage,
Björn Tampe, Michael Koziolek,
Imad Maatouk,
Jelena Bevanda,
Peter Bramlage,
Katharina Ahrens,
Katharina Lange,
Holger Schmid,
Clemens Cohen,
Matthias Kretzler,
Gerhard Müller
[show abstract]
[hide abstract]
ABSTRACT: Abstract Background Bone Morphogenetic Protein (BMP)-7 is protective in different animal models of acute and chronic kidney disease. Its role in human kidneys, and in particular hypertensive nephrosclerosis, has thus far not been described. Methods BMP-7 mRNA was quantified using real-time PCR and localised by immunostaining in tissue samples from normal and nephrosclerotic human kidneys. The impact of angiotensin (AT)-II and the AT-II receptor antagonist telmisartan on BMP-7 mRNA levels and phosphorylated Smad 1/5/8 (pSmad 1/5/8) expression was quantified in proximal tubular cells (HK-2). Functional characteristics of BMP-7 were evaluated by testing its influence on TGF-β induced epithelial-to-mesenchymal transition (EMT), expression of TGF-β receptor type I (TGF-βRI) and phosphorylated Smad 2 (pSmad 2) as well as on TNF-α induced apoptosis of proximal tubular cells. Results BMP-7 was predominantly found in the epithelia of the distal tubule and the collecting duct and was less abundant in proximal tubular cells. In sclerotic kidneys, BMP-7 was significantly decreased as demonstrated by real-time PCR and immunostaining. AT-II stimulation in HK-2 cells led to a significant decrease of BMP-7 and pSmad 1/5/8, which was partially ameliorated upon co-incubation with telmisartan. Only high concentrations of BMP-7 (100 ng/ml) were able to reverse TNF-α-induced apoptosis and TGF-β-induced EMT in human proximal tubule cells possibly due to a decreased expression of TGF-βRI. In addition, BMP-7 was able to reverse TGF-β-induced phosphorylation of Smad 2. Conclusions The findings suggest a protective role for BMP-7 by counteracting the TGF-β and TNF-α-induced negative effects. The reduced expression of BMP-7 in patients with hypertensive nephrosclerosis may imply loss of protection and regenerative potential necessary to counter the disease.
BMC Nephrology. 01/2010;
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ABSTRACT: Endothelial progenitor cells (EPCs) have been shown to promote neovascularization under physiologic and pathologic conditions. Statins have been documented to increase the total number of circulating EPCs in long-term treated patients. Lipid apheresis is used to treat patient with refractory hyperlipidemia. The aim of our study was to evaluate whether lipid apheresis is associated with EPC mobilization.
Thirteen patients with refractory hyperlipidemia (analysis at the beginning and at the end of a single lipid apheresis treatment) and 10 healthy controls were included into the study. For quantifying total peripheral EPCs, CD133+/Flk-1+ myelo-monocytic blood cells were enumerated by flow cytometry. The proliferative potential of EPCs was evaluated by a "colony-forming unit" assay. In some patients, EPC eNOS expression was evaluated before and after treatment.
Circulating EPCs and the cells' proliferative activity were lower in hyperlipidemia patients as compared to controls (0.14 +/- 0.07 vs. 0.6 +/- 0.14, P = 0.01, and 13.9 +/- 4.9 vs. 45.6 +/- 8.1, P = 0.0007). Lipid apheresis treatment was not associated with an increase in total EPCs. The cells' proliferative activity was strongly stimulated by lipid apheresis as reflected by an increase in the number of EPC colonies (13.9 +/- 4.9 to 34.1 +/- 7.3, P = 0.035). Analysis of EPC eNOS expression revealed a threefold increase in the cellular expression intensity after lipid apheresis.
Patients with refractory hyperlipidemia exhibit lower peripheral EPC numbers and a lower proliferative activity of circulating EPCs than healthy controls. A single lipid apheresis treatment significantly stimulates EPC proliferation, it furthermore increases cellular eNOS. In summary, these results show that lipid apheresis mediates beneficial effects on the EPC system as an essential element in the process of vascular repair in the human organism.
Journal of Clinical Apheresis 09/2009; 24(5):180-5. · 1.93 Impact Factor
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ABSTRACT: Endothelin is the most potent endogenous vasoconstrictor and is involved in several vascular disorders such as arterial hypertension. Its intense interaction with other vasoactive hormone systems revealed the consideration about the endothelin gene as an interesting candidate for influencing the development of essential hypertension and hypertensive endorgan damage. The purpose of this study was to investigate the role of endothelin-1 Lys198Asn polymorphism in patients with severe arterial hypertension as well as associated endorgan damages.
In 400 hypertensive patients and 150 normotensive controls we examined the endothelin-1 Lys198Asn polymorphism by DNA sequencing and patients were divided according to their genotype (GG, GT, and TT). Moreover, the frequency of endothelin-1 Lys198Asn polymorphism was investigated with respect to the prevalence of several actual or historical endorgan damages (renal disorder, coronary artery disease, vascular events, vascular damage, and congestive heart failure) in hypertensive patients.
Genotype distribution for endothelin-1 Lys198Asn polymorphism was 57.3% (GG), 41.3% (GT), and 1.43% (TT) in normotensive individuals; and in hypertensive individuals was 54.75% (GG), 43% (GT) and 2.25% (TT). Genotype distribution was unaffected in patients with severe hypertension, renal disorder, vascular events, vascular damage, and congestive heart failure. We, however, found a significant difference in hypertensive individuals with coronary artery disease and TT genotype (P=0.004).
Homozygous TT carrier contributes to a higher prevalence of coronary artery disease, especially for three-vessel disease in hypertensive individuals. Thus, the polymorphism at position 198 could serve as a possibility to differentiate high-risk subgroups in the heterogeneous population of hypertensive patients.
Coronary Artery Disease 12/2008; 19(7):429-34. · 1.24 Impact Factor
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ABSTRACT: CASE REPORT: A 69-year-old man was admitted to the authors' hospital with an increase of plasma creatinine from 1.4 up to 4.9 mg/dl within 4 months and the clinical complaints of painful purple toes, recurrent epistaxis and disturbances of equilibrium. His past medical history was remarkable for three transient ischemic attacks and the diagnosis of a metabolic syndrome. Magnetic resonance imaging showed vasculitis-like lesions in the brain. Eosinophilia and tubular proteinuria were detected. Renal insufficiency was caused by cholesterol crystal embolism, as shown both by skin and renal biopsy. Aortic plaques were identified as the putative source of cholesterol embolization. CONCLUSION: In case of rapidly progressive renal failure, cholesterol crystal embolism must be considered even without preceding angiography.
Medizinische Klinik 09/2008; 103(8):598-601. · 0.34 Impact Factor
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ABSTRACT: Fallbeschreibung:
Ein 69-jähriger Patient wurde mit einem Kreatininanstieg von 1,4 auf 4,9 mg/dl innerhalb von 4 Monaten, lividen, schmerzhaften
Effloreszenzen an den Füßen, rezidivierender Epistaxis und Gleichgewichtsstörungen aufgenommen. In der Vorgeschichte waren
drei kürzlich aufgetretene transitorische ischämische Attacken sowie ein metabolisches Syndrom bekannt. Im kranialen Magnetresonanztomogramm
zeigten sich fleckförmige vaskulitisähnliche zerebrale Signalanhebungen. Laborchemisch bestanden eine Eosinophilie sowie eine
geringgradige Proteinurie vom tubulären Typ. Haut- und Nierenbiopsien erbrachten die Diagnose einer Cholesterinembolie als
Ursache der Nierenfunktionsverschlechterung. Als mutmaßliche Quelle der rezidivierenden Cholesterinkristallembolien ließ sich
eine massive Sklerose der Aorta sichern.
Schlussfolgerung:
Auch ohne vorausgehende angiographische Intervention muss bei rasch progredienter Niereninsuffizienz eines Atherosklerosepatienten
insbesondere in höherem Alter die Differentialdiagnose Cholesterinkristallembolie in Betracht gezogen werden.
Case Report:
A 69-year-old man was admitted to the authors' hospital with an increase of plasma creatinine from 1.4 up to 4.9 mg/dl within
4 months and the clinical complaints of painful purple toes, recurrent epistaxis and disturbances of equilibrium. His past
medical history was remarkable for three transient ischemic attacks and the diagnosis of a metabolic syndrome. Magnetic resonance
imaging showed vasculitis-like lesions in the brain. Eosinophilia and tubular proteinuria were detected. Renal insufficiency
was caused by cholesterol crystal embolism, as shown both by skin and renal biopsy. Aortic plaques were identified as the
putative source of cholesterol embolization.
Conclusion:
In case of rapidly progressive renal failure, cholesterol crystal embolism must be considered even without preceding angiography.
07/2008; 103(8):598-601.
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Journal of Neurology 10/2007; 254(9):1288-9. · 3.47 Impact Factor
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ABSTRACT: Pain of Achilles tendon (AT) is a common symptom in patients with severe familial hypercholesterolemia (FH) and often associated with AT xanthomas. It is unknown if these changes are potentially reversible during lipid lowering treatment. LDL-apheresis (LA) represents the most effective lipid lowering regimen. Aim of this investigation was to determine clinical and ultrasonographic reduction of AT xanthomas in patients with severe FH undergoing regular LA.
At baseline, patient history of 22 patients with FH undergoing LA was obtained and their 44 ATs were evaluated clinically and with ultrasound for the presence of xanthomas. Three years later, both examinations of ATs could be repeated at follow-up visits in 16 patients. AT thickness and changes in echo structure were assessed at both points of time and compared to each other as well as to a healthy control group (n = 21). ROC analysis was performed to identify the optimal cut-off in AT thickness between healthy and affected ATs.
Twelve of 22 FH patients suffered from AT pain at least once during their life-time. At baseline, AT thickness was significantly increased compared to the healthy control group (mean sagittal diameter 10.1 +/- 3.6 mm). At follow-up, AT thickness was significantly reduced to 8.2 +/- 3.3 mm (mean) under LA, whereas changes in echo structure were less distinct between both visits. Conversely, in the control group, mean AT thickness was 5.2 +/- 0.6 mm. The optimal cut-off between healthy and affected ATs was determined to be 6mm.
Ultrasonographic changes of the AT (thickening and changes in echo structure) are frequent in patients with severe FH, even if xanthomas are not clinically evident. LA treatment has the capability to reduce AT xanthomas and thickness. Ultrasound may give information about diagnosis and follow-up of AT affection in patients with FH.
Atherosclerosis 06/2004; 174(1):133-9. · 3.79 Impact Factor
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ABSTRACT: Fractalkine (CX3CL1) represents the sole member of the so-called CX3C chemokines. In rheumatoid arthritis (RA), functional studies suggest a role for this chemokine in monocyte chemotaxis and angiogenesis in the rheumatoid synovium. We analyzed the expression of fractalkine within different T cell subsets of the peripheral blood and expression of its receptor CX3CR1 within the rheumatoid synovium to further characterize its pathogenic role in RA.
Peripheral blood mononuclear cells (PBMC) were isolated from 17 patients with RA and analyzed by flow cytometry in comparison to healthy blood donors. To identify the T helper cell cytokine profile of fractalkine-expressing cells, flow cytometric analysis of PBMC was performed after stimulation with PMA and ionomycin. Expression of fractalkine and its receptor was characterized in RA synovium by immunohistochemistry and laser capture microdissection microscopy.
Flow cytometric analysis of fractalkine-expressing T cell subsets revealed a low proportion of fractalkine-expressing CD4+ and CD8+ T cells in both RA patients and controls. In addition, fractalkine was predominantly expressed in CD4+ T cells with a Th1-type cytokine expression profile. In RA synovium, fractalkine was detected in synovial macrophages, dendritic cells, endothelial cells, and a small proportion of T cells. The fractalkine receptor CX3CR1 was found in synovial macrophages, dendritic cells, and T cells as well as in synovial fibroblasts. Fractalkine stimulation of cultured synovial fibroblasts resulted in a marked upregulation of matrix metalloproteinase-2 (MMP-2) production.
The results suggest that fractalkine may represent a Th1-type chemokine. Upregulation of MMP-2 production in synovial fibroblasts upon fractalkine stimulation in vitro supports the hypothesis of a proinflammatory role of this chemokine in RA.
The Journal of Rheumatology 10/2003; 30(9):1918-27. · 3.69 Impact Factor
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[hide abstract]
ABSTRACT: To evaluate the possible role of activation-induced, T cell-derived, and chemokine-related cytokine (ATAC)/lymphotactin (Lptn) in the pathogenesis of rheumatoid arthritis (RA).
ATAC/Lptn levels in serum and synovial fluid samples were measured by sandwich enzyme-linked immunosorbent assay. Expression of messenger RNA for ATAC/Lptn in synovial tissues was analyzed by reverse transcription-polymerase chain reaction (PCR) and by in situ hybridization, and was quantitated by real-time PCR. The phenotype of peripheral blood mononuclear cells (PBMCs) expressing ATAC/Lptn was analyzed by intracellular cytokine staining and flow cytometry.
Levels of ATAC/Lptn were similar in sera and synovial fluids from RA patients (n = 20) and osteoarthritis controls (n = 15). In phorbol myristate acetate/ionomycin-stimulated PBMCs, ATAC/Lptn expression was detected in CD8+ T cells and in a significantly increased proportion of CD4+,CD28- T cells from RA patients as compared with healthy controls. In synovial tissues, ATAC/Lptn was predominantly localized in CD3+ T cells in the sublining layer. Lymphocytes, synovial macrophages, and, unexpectedly, fibroblast-like synoviocytes (FLS) were identified as major target cells for ATAC/Lptn in RA synovium, as determined by analysis of the ATAC/Lptn receptor XCR1. In vitro, ATAC/Lptn stimulation of FLS resulted in a marked down-regulation of matrix metalloproteinase 2 production.
These data indicate that in RA synovium, ATAC/Lptn is mainly produced by T cells. Considering its function as a lymphocyte-specific chemoattractant, ATAC/Lptn might be a key modulator for T cell trafficking in the pathogenesis of RA. In addition, functional studies suggest that ATAC/Lptn may exert additional immunomodulatory effects in RA.
Arthritis & Rheumatism 08/2003; 48(7):1858-72. · 7.87 Impact Factor
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Nephrology Dialysis Transplantation (2011).
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[show abstract]
[hide abstract]
ABSTRACT: Endemic nephropathy (EN) is defined as a slow progressive renal tubulointestitial disease that mainly occurs in the restricted areas of the Balkan Peninsula. The complexity of the pathogenesis of EN makes its earlier diagnosis very difficult.Urine samples from healthy volunteers from EN regions, EN patients with proteinuria less than 150 mg/L and EN patients with proteinuria more than 150 mg/L, patients with acute kidney injury, patients with diabetic nephropathy and healthy volunteers from Germany were collected. The urinary proteome analyses were performed using 2-D DIGE and mass spectrometry. The validation of biomarkers was investigated by two approaches (Western blot (WB) and dot blot) in successively increasing size – and partially overlapping – sample sets. Comparative and statistical analyses of the proteomics data from the different patient groups allowed the identification of six proteins (alpha-1-microglobulin, alpha-2-glycoprotein-1, beta-2-microglobulin, mannose-binding-lectin-2, protection-of-telomeres-protein-1, and superoxide-dismutase [Cu–Zn]), which were able to discriminate EN with low and high proteinuria from the other groups with high significance (p < 0.05). The reliability of the identified proteins as EN marker was underlined with high statistical significance using WB analyses (sensitivity 66.7-98% and specificity 70-100%), whereas the dot blot analyses revealed a decrease in the sensitivity and specificity of these biomarkers.Graphical abstractView high quality image (75K)Highlights► Endemic nephropathy (EN) is a progressive renal tubulointestitial disease. ► Earlier diagnosis markers for EN are missing. ► The protein profiles of urine from patients with endemic nephropathy were established. ► Six proteins were identified with the potential to be markers for EN prediction.
Journal of Proteomics. 74(10):1994-2007.
