|Title||Treatment response in kawasaki disease is associated with sialylation levels of endogenous but not therapeutic intravenous immunoglobulin G. |
|Publication Type||Journal Article |
|Year of Publication||2013 |
|Authors||Ogata, S, Shimizu, C, Franco, A, Touma, R, Kanegaye, JT, Choudhury, BP, Naidu, NN, Kanda, Y, Hoang, LT, Hibberd, ML, Tremoulet, AH, Varki, A, Burns, JC |
|Journal||PLoS One |
|Date Published||2013 |
|iDASH Category||Kawasaki Disease (DBP1 & DBP4) |
|Abstract||OBJECTIVES: 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. |
|Alternate Journal||PLoS ONE |
|PubMed ID||24324693 |