Dataset Information

Technical Considerations and Confounders for Urine CXCL10 Chemokine Measurement.

ABSTRACT: Background:The urine C-X-C motif chemokine 10 (CXCL10) is a promising screening biomarker for renal allograft rejection. The aim of the study was to investigate important technical and biological aspects as well as potential confounders when measuring urine CXCL10. Methods:We analyzed 595 urine samples from 117 patients, who participated in a randomized controlled trial investigating the clinical utility of urine CXCL10 monitoring for posttransplant management. Urine CXCL10 was measured by an immunoassay using electrochemiluminescence. Results:Intraassay coefficient of variation was 2.5%, and interassay coefficient of variation was 10%. Urine CXCL10 remained stable (ie, <10% degradation) for 8 hours at 25°C or 37°C and for 3 days at 4°C. CXCL10 concentrations [pg/mL] strongly correlated with urine CXCL10/creatinine ratios [ng/mmol] (r2 = 0.98; P < 0.0001). Leucocyturia and active BK-polyomavirus infection are associated with higher CXCL10 concentrations, while allograft function, serum CRP, patient age, proteinuria, urine pH, hematuria, squamous epithelia cell count, and bacteriuria did not correlate with urine CXCL10 concentrations. In 145 paired samples obtained within 1-2 weeks, 80% showed a CXCL10/creatinine ratio change of < ±2 ng/mmol or ±50%, respectively. Conclusions:Urine CXCL10 measurement on the used platform is accurate and robust. Leucocyturia and active BK-polyomavirus infection are major confounders, which can be easily detected but represent important diagnostic "blind spots" when using urine CXCL10 to screen for allograft rejection. The intraindividual biological variability of urine CXCL10 within 1-2 weeks is mostly below ±50%, which is still much higher than the technical variability due to sample handling/processing (<20%).

SUBMITTER: Handschin J

PROVIDER: S-EPMC6964934 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Technical Considerations and Confounders for Urine CXCL10 Chemokine Measurement.

Handschin Joelle J Hirt-Minkowski Patricia P Hönger Gideon G Mitrovic Sandra S Savic Prince Spasenija S Ho Julie J Nickerson Peter P Schaub Stefan S

Transplantation direct 20191224 1

<h4>Background</h4>The urine C-X-C motif chemokine 10 (CXCL10) is a promising screening biomarker for renal allograft rejection. The aim of the study was to investigate important technical and biological aspects as well as potential confounders when measuring urine CXCL10.<h4>Methods</h4>We analyzed 595 urine samples from 117 patients, who participated in a randomized controlled trial investigating the clinical utility of urine CXCL10 monitoring for posttransplant management. Urine CXCL10 was me ...[more]

PMID: 32047847

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Project description:Clearance of intracellular pathogens, such as Leishmania (L.) major, depends on an immune response with well-regulated cytokine signaling. Here we describe a pathogen-mediated mechanism of evading CXCL10, a chemokine with diverse antimicrobial functions, including T cell recruitment. Infection with L. major in a human monocyte cell line induced robust CXCL10 transcription without increasing extracellular CXCL10 protein concentrations. We found that this transcriptionally independent suppression of CXCL10 is mediated by the virulence factor and protease, glycoprotein-63 (gp63). Specifically, GP63 cleaves CXCL10 after amino acid A81 at the base of a C-terminal alpha-helix. Cytokine cleavage by GP63 demonstrated specificity, as GP63 cleaved CXCL10 and its homologs, which all bind the CXCR3 receptor, but not distantly related chemokines, such as CXCL8 and CCL22. Further characterization demonstrated that CXCL10 cleavage activity by GP63 was produced by both extracellular promastigotes and intracellular amastigotes. Crucially, CXCL10 cleavage impaired T cell chemotaxis in vitro, indicating that cleaved CXCL10 cannot signal through CXCR3. Ultimately, we propose CXCL10 suppression is a convergent mechanism of immune evasion, as Salmonella enterica and Chlamydia trachomatis also suppress CXCL10. This commonality suggests that counteracting CXCL10 suppression may provide a generalizable therapeutic strategy against intracellular pathogens.ImportanceLeishmaniasis, an infectious disease that annually affects over one million people, is caused by intracellular parasites that have evolved to evade the host's attempts to eliminate the parasite. Cutaneous leishmaniasis results in disfiguring skin lesions if the host immune system does not appropriately respond to infection. A family of molecules called chemokines coordinate recruitment of the immune cells required to eliminate infection. Here, we demonstrate a novel mechanism that Leishmania (L.) spp. employ to suppress host chemokines: a Leishmania-encoded protease cleaves chemokines known to recruit T cells that fight off infection. We observe that other common human intracellular pathogens, including Chlamydia trachomatis and Salmonella enterica, reduce levels of the same chemokines, suggesting a strong selective pressure to avoid this component of the immune response. Our study provides new insights into how intracellular pathogens interact with the host immune response to enhance pathogen survival.

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Technical Considerations and Confounders for Urine CXCL10 Chemokine Measurement.

Publications

Technical Considerations and Confounders for Urine CXCL10 Chemokine Measurement.

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