title: Treatment response in Kawasaki disease is associated with sialylation levels of endogenous but not therapeutic intravenous immunoglobulin G.
abstract: OBJECTIVE
  Although intravenous immunoglobulin (IVIG) is highly effective in Kawasaki disease (KD), mechanisms are not understood and 10-20% of patients are treatment-resistant, manifesting a higher rate of coronary artery aneurysms. Murine models suggest that α2-6-linked sialic acid (α2-6Sia) content of IVIG is critical for suppressing inflammation. However, pro-inflammatory states also up-regulate endogenous levels of β-galactoside:α2-6 sialyltransferase-I (ST6Gal-I), the enzyme that catalyzes addition of α2-6Sias to N-glycans. We asked whether IVIG failures correlated with levels of α2-6Sia on infused IVIG or on the patient's own endogenous IgG.
  
  
  METHODS
  We quantified levels of α2-6Sia in infused IVIG and endogenous IgG from 10 IVIG-responsive and 10 resistant KD subjects using multiple approaches. Transcript levels of ST6GAL1, in patient whole blood and B cell lines were evaluated by RT-PCR. Plasma soluble (s)ST6Gal-I levels were measured by ELISA.
  
  
  RESULTS
  There was no consistent difference in median sialylation levels of infused IVIG between groups. However, α2-6Sia levels in endogenous IgG, ST6GAL1 transcript levels, and ST6Gal-I protein in serum from IVIG-resistant KD subjects were lower than in responsive subjects at both pre-treatment and one-year time points (p <0.001, respectively).
  
  
  CONCLUSIONS
  Our data indicate sialylation levels of therapeutic IVIG are unrelated to treatment response in KD. Rather, lower sialylation of endogenous IgG and lower blood levels of ST6GALI mRNA and ST6Gal-I enzyme predict therapy resistance. These differences were stable over time, suggesting a genetic basis. Because IVIG-resistance increases risk of coronary artery aneurysms, our findings have important implications for the identification and treatment of such individuals.
authors: Department of Pediatrics, University of California San Diego, School of Medicine, La Jolla, California, United States of America.
authors: Shohei
authors: S
authors: Ogata
authors: Chisato
authors: C
authors: Shimizu
authors: Alessandra
authors: A
authors: Franco
authors: Ranim
authors: R
authors: Touma
authors: John T
authors: JT
authors: Kanegaye
authors: Biswa P
authors: BP
authors: Choudhury
authors: Natasha N
authors: NN
authors: Naidu
authors: Yutaka
authors: Y
authors: Kanda
authors: Long T
authors: LT
authors: Hoang
authors: Martin L
authors: ML
authors: Hibberd
authors: Adriana H
authors: AH
authors: Tremoulet
authors: Ajit
authors: A
authors: Varki
authors: Jane C
authors: JC
authors: Burns
mesh_terms: D001402:B-Lymphocytes / Q000201:enzymology; D016022:Case-Control Studies; D002460:Cell Line; D002675:Child, Preschool; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005643:Fucose / Q000378:metabolism; D005690:Galactose / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000737:chemistry / Q000627:therapeutic use*; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome / Q000188:drug therapy* / Q000201:enzymology; D019158:N-Acetylneuraminic Acid / Q000737:chemistry / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics / Q000378:metabolism; D012799:Sialyltransferases / Q000097:blood / Q000235:genetics; D012995:Solubility; D016896:Treatment Outcome; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
chemical_list: D016756:Immunoglobulins, Intravenous; D012333:RNA, Messenger; D005643:Fucose; D012799:Sialyltransferases; D019158:N-Acetylneuraminic Acid; D005690:Galactose; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase