title: Evaluation of the role of secretory sphingomyelinase and bioactive sphingolipids as biomarkers in hemophagocytic lymphohistiocytosis.
abstract: Hemophagocytic lymphohistiocytosis (HLH) is a rare systemic inflammatory syndrome that results from unrestrained immune cell activation. Despite significant advances in the understanding of the pathophysiology of HLH, interventions remain limited for this often-fatal condition. Secretory sphingomyelinase (S-SMase) is a pro-inflammatory lipid hydrolase that is upregulated in several inflammatory conditions, including HLH. S-SMase promotes the formation of ceramide, a bioactive lipid implicated in several human disease states. However, the role of the S-SMase/ceramide pathway in HLH remains unexplored. To further evaluate the role of S-SMase upregulation in HLH, we tested the serum of patients with HLH (n = 16; primary = 3, secondary = 13) and healthy control patients (n = 25) for serum S-SMase activity with tandem sphingolipid metabolomic profiling. Patients with HLH exhibited elevated levels of serum S-SMase activity, with concomitant elevations in several ceramide species and sphingosine, while levels of sphingosine-1-phosphate were significantly decreased. Importantly, the ratio of C16 -ceramide:sphingosine was uniquely elevated in HLH patients that died despite appropriate treatment, but remained low in HLH patients that survived, suggesting that this ratio may be of prognostic significance. Together, these results demonstrate upregulation of the S-SMase/ceramide pathway in HLH, and suggest that the balance of ceramide and sphingosine determine clinical outcomes in HLH. .
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Russell W
authors.initials: RW
authors.lastname: Jenkins
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Clarke
authors.forename: John Thomas
authors.initials: JT
authors.lastname: Lucas
authors.forename: Munira
authors.initials: M
authors.lastname: Shabbir
authors.forename: Bill X
authors.initials: BX
authors.lastname: Wu
authors.forename: Fabio
authors.initials: F
authors.lastname: Simbari
authors.forename: Joan
authors.initials: J
authors.lastname: Mueller
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.forename: John
authors.initials: J
authors.lastname: Lazarchick
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shirai
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D002518:Ceramides / Q000097:blood / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007223:Infant; D051359:Lymphohistiocytosis, Hemophagocytic / Q000097:blood* / Q000175:diagnosis / Q000276:immunology / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D013107:Sphingolipids / Q000097:blood* / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000097:blood* / Q000378:metabolism; D013110:Sphingosine / Q000097:blood / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D015415:Biomarkers; D002518:Ceramides; D013107:Sphingolipids; D013108:Sphingomyelin Phosphodiesterase; D013110:Sphingosine