title: The role of vanin-1 and oxidative stress-related pathways in distinguishing acute and chronic pediatric ITP.
abstract: Pediatric immune thrombocytopenia (ITP) is usually self-limited. However, approximately 20% of children develop chronic ITP, which can be associated with significant morbidity because of long-term immunosuppression and splenectomy in refractory cases. To explore the molecular mechanism of chronic ITP compared with acute ITP, we studied 63 pediatric patients with ITP. Gene expression analysis of whole blood revealed distinct signatures for acute and chronic ITP. Oxidative stress-related pathways were among the most significant chronic ITP-associated pathways. Overexpression of VNN1, an oxidative stress sensor in epithelial cells, was most strongly associated with progression to chronic ITP. Studies of normal persons demonstrated VNN1 expression in a variety of blood cells. Exposure of blood mononuclear cells to oxidative stress inducers elicited dramatic up-regulation of VNN1 and down-regulation of PPARγ, indicating a role for VNN1 as a peripheral blood oxidative stress sensor. Assessment of redox state by tandem mass spectrometry demonstrated statistically significant lower glutathione ratios in patients with ITP versus healthy controls; lower glutathione ratios were also seen in untreated patients with ITP compared with recently treated patients. Our work demonstrates distinct patterns of gene expression in acute and chronic ITP and implicates oxidative stress pathways in the pathogenesis of chronic pediatric ITP.
authors.affiliation: Departments of Pathology, School of Medicine, Stanford University, Stanford, CA, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.forename: Clara
authors.initials: C
authors.lastname: Lo
authors.forename: Lei
authors.initials: L
authors.lastname: Shen
authors.forename: Ruchira
authors.initials: R
authors.lastname: Sood
authors.forename: Carol
authors.initials: C
authors.lastname: Jones
authors.forename: Kristina
authors.initials: K
authors.lastname: Cusmano-Ozog
authors.forename: Shaun
authors.initials: S
authors.lastname: Park-Snyder
authors.forename: Wendy
authors.initials: W
authors.lastname: Wong
authors.forename: Michael
authors.initials: M
authors.lastname: Jeng
authors.forename: Tina
authors.initials: T
authors.lastname: Cowan
authors.forename: Edgar G
authors.initials: EG
authors.lastname: Engleman
authors.forename: James L
authors.initials: JL
authors.lastname: Zehnder
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000581:Amidohydrolases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D006098:Granulocytes / Q000502:physiology; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology; D007223:Infant; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000276:immunology*; D047495:PPAR gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000175:diagnosis / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D058851:GPI-Linked Proteins; D047495:PPAR gamma; D000581:Amidohydrolases; C022314:pantetheinase