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.

Kawasaki disease (KD) is an acute, systemic vasculitis that predominantly affects children under 5 years of age. It is the leading cause of acquired heart disease in developed countries.¹ Despite its first description in 1967,² the pathogenesis of KD remains elusive.¹ It is generally believed to represent an immune disorder triggered by infectious or environmental factors in genetically predisposed individuals.^3,4 Evidence suggests that pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) play key roles in activating the innate immune system in the pathogenesis of KD.^4,5

The age-restricted occurrence of KD, rarely seen before 6 months or after 5 years of age, suggests potential involvement of maternal (transplacental) antibodies or self-produced antibodies in protective immunity against KD-associated pathogens.⁶ In addition to antibodies against pathogenic microbes, anti-DAMP antibodies, particularly those targeting oxidized low-density lipoproteins (LDL), have been identified in healthy children, those with febrile illnesses, and KD patients.⁷ The ability of anti-DAMP antibodies to prevent vasculitis in KD murine models⁸ raises the possibility that they may confer protective effects against KD development in humans.

During the acute phase of KD and various infectious diseases, blood levels of DAMPs are elevated.^9–14 In our previous studies,^10,11 we performed serial measurements of serum levels of oxidized LDLs and high mobility group box 1 (HMGB1) before and after therapy in KD patients. In this study, we investigated serum levels of anti-oxidized LDL and anti-HMGB1 antibodies in patients with KD and other febrile illnesses. Based on our primary findings, we further examined their correlations with markers of inflammation (i.e., C-reactive protein [CRP]) and oxidative stress (red blood cell distribution width [RDW]¹⁵). The results provide valuable insights into the distinct roles of anti-oxidized LDL and anti-HMGB1 antibodies in KD and other febrile conditions.

Methods

Subjects

The study included 23 patients diagnosed with KD (median age, 22 months; range 3–91 months; male/female, 13/10) and 15 febrile disease controls (DC) (median age, 13 months; range 0–135 months; male/female, 11/4) (Supplementary Table 1). All of them were Japanese and admitted to Fukuoka Children’s Hospital during 2021–2022. The diagnosis of KD followed the criteria outlined in the 6th revised edition of Japan’s KD diagnostic guidelines.¹⁶ All KD patients were treated with oral aspirin (30 mg/kg/day) and 2 g/kg of intravenous immunoglobulin (IVIG). Coronary artery lesions (CALs) were defined as a maximum Z score ≥2.5 at 1 month after onset. Transient coronary artery dilatation was observed in 5 patients, and no CALs at 1 month. The febrile DC group comprised patients with viral and bacterial respiratory infections (n=5), urinary tract infection (n=3), gastrointestinal infections (n=2), COVID-19 (n=2), bacterial meningitis (n=1) and others (n=2). Demographic, clinical, and laboratory data of the patients were extracted from electronic medical records.

Measurements of Anti-Oxidized LDL and Anti-HMGB1 Antibodies

Serum levels of anti-oxidized LDL and anti-HMGB1 antibodies were quantified using enzyme-linked immunosorbent assay (ELISA) kits (Biomedica, Vienna, Austria, and CLOUD-CLONE CORP., Houston, USA, respectively), following the manufacturers’ protocols.

Statistical Analysis

Statistical analyses were conducted using JMP® Pro (version 17, SAS Institute, Cary, NC, USA). Comparisons between the KD and DC groups were made using the Mann-Whitney U test, and the Wilcoxon signed-rank test or Pearson’s correlation test was used for additional analyses. A P value <0.05 was considered statistically significant. Bonferroni’s correction was used when necessary.

Ethics Statement

This study was approved by the Institutional Review Board of Fukuoka Children’s Hospital (approval number 2023-72). Written informed consent was given by all participants’ guardians and/or patients or substituted through an opt-out process. All procedures were conducted in accordance with the Declaration of Helsinki and institutional guidelines for studies involving human samples.

Results

Distinct Kinetics of Anti-Oxidized LDL and Anti-HMGB1 Antibodies Before and After IVIG in Patients With KD

Serum levels of anti-oxidized LDL and anti-HMGB1 antibodies were analyzed at 3 time points: prior to IVIG administration, 2–3 days post-IVIG, and 1 month post-IVIG. For this longitudinal analysis, 27 samples were sequentially collected from 9 patients with KD, and underwent measurement of anti-oxidized LDL and anti-HMGB1 antibody levels in serum. As shown in Figure 1A, the serum levels of anti-oxidized LDL antibodies significantly increased from the pre-IVIG baseline (median: 922.2 U/L [range: 340.6–4,255.0 U/L]) to the immediate post-IVIG period (median: 1,707.0 U/L [range: 786.9–6,723.7 U/L]) (P<0.0039, n=9 at each time point, Wilcoxon signed-rank test, the significance level was adjusted using the Bonferroni correction to P<0.0167 (=0.05/3)). These levels subsequently decreased 1 month after IVIG treatment (median: 1,047.0 U/L [range: 385.3–3,592.0 U/L]; P<0.0039 compared with immediately post-IVIG). Conversely, anti-HMGB1 antibody levels showed a decreasing trend from pre-IVIG (median: 16.9 μg/L [range: 5.3–26.2 μg/L]) to post-IVIG (median: 7.0 μg/L [range: 0–15.4 μg/L]), and remained low at 1 month post-IVIG (median: 7.0 μg/L [range: 3.4–17.2 μg/L]). These changes were not statistically significant (n=9 at each time point; Figure 1B). Thus, serum anti-oxidized LDL and anti-HMGB1 antibodies exhibited distinct kinetic patterns following IVIG treatment in KD patients.

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.

Association Between Serum Levels of Anti-Oxidized LDL and Anti-HMGB1 Antibodies in Patients With KD and in DC

We further explored the association between serum levels of anti-oxidized LDL and anti-HMGB1 antibodies in patients with KD and DC on admission. Although no significant association was discerned between the serum levels of anti-oxidized LDL and anti- HMGB1 antibodies in KD patients (Pearson’s correlation coefficient: −0.07 [95% confidence interval, CI: −0.47 to 0.35], P=0.76), a noteworthy positive association was evident in DC (Pearson’s correlation coefficient: 0.74 [95% CI: 0.37–0.91], P=0.0015) (Figure 2A,B).

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.

There were no statistically significant differences in the serum levels of anti-oxidized LDL antibodies between KD patients (median: 1,083 U/L, range: 20.4–5,093 U/L) and DC (median: 1,103 U/L, range: 12.8–7,000 U/L), nor in the levels of anti-HMGB1 antibodies between KD patients (median: 18.4 μg/L, range: 5.3–67.3 μg/L) and DC (median: 14.6 μg/L, range: 7.2–48.9 μg/L) (P=0.859 and P=0.492, respectively).

Association Between Serum Levels of Anti-Oxidized LDL or Anti-HMGB1 Antibodies and CRP Levels

In patients with KD, there was no statistically significant association between serum levels of anti-oxidized LDL or anti-HMGB1 antibodies and CRP levels on admission (Pearson’s correlation coefficient: 0.06 [95% CI: −0.37 to 0.46], P=0.80 and Pearson’s correlation coefficient: −0.08 [95% CI: −0.48 to 0.35], P=0.72, respectively) (Figure 2C,E). Conversely, DC exhibited a significant association between serum levels of anti-oxidized LDL or anti-HMGB1 antibodies and CRP levels (Pearson’s correlation coefficient: 0.58 [95% CI: 0.10–0.84], P=0.022, and Pearson’s correlation coefficient: 0.67 [95% CI: 0.25–0.88], P=0.0059, respectively) (Figure 2D,F). Additionally, serum CRP levels in KD patients (median: 8.57 mg/dL, range: 1.25–25.1 mg/dL) were significantly higher than in DC (median: 2.09 mg/dL, range: 0–11.05 mg/dL) (P=0.00066).

Association Between Serum Levels of Anti-Oxidized LDL or Anti-HMGB1 Antibodies and Coronary Z Scores

In 23 patients with KD, no statistically significant association was observed between serum levels of pre-IVIG anti-oxidized LDL or anti-HMGB1 antibodies and maximal coronary Z scores (Pearson’s correlation coefficient: 0.057 [95% CI: −0.36 to 0.46], P=0.796, and Pearson’s correlation coefficient: 0.36 [95% CI: −0.064 to 0.67], P=0.094, respectively) (Supplementary Figure A,B). Similarly, changes in Z scores across 4 coronary artery sites (proximal right coronary artery, left main coronary artery, proximal left anterior descending artery, and proximal left circumflex artery) before and after IVIG treatment in nine KD patients did not significantly correlate with corresponding changes in anti-oxidized LDL antibody levels or anti-HMGB1 antibody levels (Supplementary Table 2). Additionally, 3 of the 23 KD patients were classified as IVIG non-responders who showed a higher tendency to develop CALs (Supplementary Table 1). Further research is warranted to explore the relationship between IVIG unresponsiveness and serum levels of anti-HMGB1 or anti-oxidized LDL antibodies in a larger cohort of patients with KD.

Weak Inverse Trend Between Serum Anti-Oxidized LDL Antibody Levels and RDW in Patients With KD

Given the established role of oxidative stress in modulating RDW, a known marker of oxidative stress in vivo,¹⁵ we explored the relationship between anti-oxidized LDL antibody levels and the RDW-coefficient of variation (CV) in KD patients on admission (Figure 3). Interestingly, a weak inverse trend (Pearson’s correlation coefficient: −0.25 [95% CI: −0.60 to 0.18], P=0.26) was observed between these factors, suggesting a potential protective role of anti-oxidized LDL antibodies against oxidative stress in KD.

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.

Discussion

Oxidized LDL encompasses a broad spectrum of oxidative modifications to the LDL particle, functioning as a signaling molecule and serving as a DAMP that activates the innate immune system.¹⁷ These oxidized LDLs present oxidation-specific epitopes (OSEs) that are recognized by both IgM and IgG antibodies.¹⁸ Although IgM anti-oxidized LDL antibodies generally have protective effects against vascular inflammation,^19–21 the role of IgG antibodies in aged individuals, with or without cardiovascular disease (CVD), remains unclear and may range from protective to neutral or even harmful.^19,20,22

In younger populations, including children and adolescents, IgG anti-oxidized LDL antibodies appear predominantly protective against vascular inflammation. Children and young individuals consistently exhibit higher levels of anti-oxidized LDL antibodies.^23,24 In healthy subjects or the general population, inverse correlations have been observed between anti-oxidized LDL antibody levels and oxidized LDL levels^25,26 or the intima–media thickness of the carotid arteries.²⁷ Additionally, children and adolescents whose parents had familial hypercholesterolemia, and/or early coronary artery disease in first-degree relatives, showed lower titers of anti-oxidized LDL antibodies compared with children from normal families.²⁸

In KD patients, serum CRP levels were significantly elevated compared with DC, yet anti-oxidized LDL antibody levels did not increase proportionally with inflammation, suggesting a suppression of the antibody response during the acute phase of KD.²⁹ Our findings demonstrated that IVIG administration significantly elevated the anti-oxidized LDL antibody levels in KD patients and concurrently improved KD symptoms, suggesting a protective role of anti-oxidized LDL antibodies against vascular inflammation. This is consistent with previous findings showing the presence of anti-oxidized LDL antibodies in IVIG preparations³⁰ and the role of circulating oxidized LDL in the development of KD-associated vascular pathology.^9,10

In infectious diseases, serum anti-oxidized LDL antibody levels correlate with the degree of inflammation, as indicated by CRP levels. In a murine model of sepsis, both IgM and IgG antibodies against OSEs were prominent.³¹ Given the probably persistent nature of anti-oxidized LDL antibodies, reduced exposure to infections, potentially due to improved sanitation, may decrease anti-oxidized LDL antibody levels and subsequently increase the risk of KD. Additionally, vaccinations may induce pathogen-specific antibodies without affecting the production of anti-oxidized LDL antibodies, potentially contributing to KD susceptibility.

In contrast, anti-HMGB1 antibodies are typically absent in healthy individuals.³² In this study, no significant changes in serum anti-HMGB1 antibody levels were observed across the acute, post-IVIG, and convalescent stages of KD, suggesting that these antibodies do not inhibit the development of KD, in contrast to the findings from murine studies.⁸ The observed decline in anti-HMGB1 antibodies following IVIG suggests that these antibodies may exhibit a transient autoimmune response.

Study Limitations

This study was limited by its small sample size and the focus on a single ethnic group (Japanese).

Conclusions

This study has provided valuable insights into the distinct roles of anti-oxidized LDL and anti-HMGB1 antibodies in KD and febrile conditions. The observed increase in anti-oxidized LDL antibodies following IVIG administration may indicate a potentially protective role in mitigating vascular inflammation, while the transient nature of anti-HMGB1 antibodies warrants further investigation. Future studies will provide a rationale for the therapeutic potential of anti-oxidized LDL antibodies in KD.

Acknowledgments

We thank T. Tanaka, PhD, Kyushu University for help with the ELISA assays, and all the staff of Fukuoka Children’s Hospital who cared for the patients in this study. During the preparation of this work, the authors used ChatGPT-4 (Open AI) to check grammar and spelling, and to improve readability. After using these tools/services, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication. This study was supported by the Fukuoka Children’s Hospital Research fund. The funding source had no role in the study design, the collection, analysis, and interpretation of data, the writing of the report, or in the decision to submit the paper for publication.

Disclosures

The authors declare that there are no conflicts of interest.

IRB Information

This study was approved by the Institutional Review Board of Fukuoka Children’s Hospital (approval number 2023-72).

Data-Sharing Statement

Data are available upon reasonable request.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circrep.CR-25-0018

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