Anti-Oxidized Low-Density Lipoprotein Antibodies Before and After Intravenous Immunoglobulin Therapy in Kawasaki Disease - Evidence for a Potentially Protective Role

Abstract

Background: The precise pathogenesis of Kawasaki disease (KD) remains unclear, but immune dysregulation involving damage-associated molecular patterns (DAMPs), such as oxidized low-density lipoprotein (LDL) and high mobility group box 1 (HMGB1), has been implicated. We investigated the roles of 2 anti-DAMPs antibodies in KD and their associations with inflammatory and oxidative stress markers.

Methods and results: Serum levels of anti-oxidized LDL and anti-HMGB1 antibodies were measured by enzyme-linked immunosorbent assay in patients with KD and in febrile disease controls (DC). Correlations with inflammatory (C-reactive protein [CRP]) and oxidative stress (red blood cell distribution width [RDW]) markers were evaluated. Serum anti-oxidized LDL antibody levels increased significantly after intravenous immunoglobulin (IVIG) therapy in KD patients, suggesting a protective role of anti-oxidized LDL antibodies against vascular inflammation. Conversely, anti-HMGB1 antibody levels showed a decreasing trend post-IVIG. A significant correlation between antibody levels and CRP was observed in DC but not in KD patients. Furthermore, a weak inverse trend between anti-oxidized LDL antibodies and RDW-coefficient of variation was noted in KD patients.

Conclusions: This study highlighted the distinct roles of anti-oxidized LDL and anti-HMGB1 antibodies during the acute phase of KD. The increase in anti-oxidized LDL antibodies following IVIG treatment suggests a protective effect, while the transient nature of anti-HMGB1 antibodies warrants further exploration.

Keywords: Antibodies; High mobility group box 1 (HMGB1); Kawasaki disease; Oxidized low-density lipoprotein.

Figure 1.

Serum levels of anti-oxidized LDL (A) and anti-HMGB1 (B) antibodies measured at 3 time points: prior to IVIG administration (a), 2 – 3 days post-IVIG (b), and 1 month post-IVIG (c) in KD patients. (A) Anti-oxidized LDL antibody levels significantly increased from “a” to “b” (P<0.0039) and then decreased from “b” to “c” (P<0.0039). (B) Anti-HMGB1 antibody levels showed a decreasing trend from “a” to “b”, followed by a further decrease from “b” to “c” (both changes were not statistically significant). The Wilcoxon signed-rank test was used and the significance level was adjusted using the Bonferroni correction to P<0.0167 (=0.05/3). HMGB1, high mobility group box 1; LDL, low-density lipoprotein.

Figure 2.

Association between serum levels of anti-oxidized LDL and anti-HMGB1 antibodies (A,B), and the correlation between serum levels of anti-oxidized LDL or anti-HMGB1 antibodies and CRP levels (C–F) in KD patients and DC. (A) No significant association was found between serum levels of anti-oxidized LDL and anti-HMGB1 antibodies in KD patients (Pearson’s correlation coefficient [PCC]: −0.07, P=0.76). (B) Significant association between serum levels of anti-oxidized LDL and anti-HMGB1 antibodies in DC patients (PCC: 0.74, P=0.0015). (C) No significant association between serum levels of anti-HMGB1 antibodies and CRP levels in KD patients (PCC: 0.06, P=0.80). (D) Significant association between serum levels of anti-HMGB1 antibodies and CRP levels in DC patients (PCC: 0.58, P=0.022). (E) No significant association between serum levels of anti-oxidized LDL antibodies and CRP levels in KD patients (PCC: −0.08, P=0.72). (F) Significant association between serum levels of anti-oxidized LDL antibodies and CRP levels in DC patients (PCC: 0.67, P=0.006). CRP, C-reactive protein; DC, febrile disease controls; KD, Kawasaki disease; HMGB1, high mobility group box 1; LDL, low-density lipoprotein.

Figure 3.

Relationship between serum levels of anti-oxidized LDL antibodies and red blood cell distribution width (RDW)-coefficient of variation (CV) in Kawasaki disease (KD) patients. A weak inverse trend was observed between RDW-CV, a marker of oxidative stress, and serum anti-oxidized LDL antibody levels in KD patients (Pearson’s correlation coefficient: −0.25 [95% confidence interval: −0.60 to 0.18], P=0.26), suggesting a potential protective role of anti-oxidized LDL antibodies against oxidative stress in KD. LDL, low-density lipoprotein.