Hygiene Hypothesis as the Etiology of Kawasaki Disease: Dysregulation of Early B Cell Development
Abstract
:1. Clinical Characteristics
2. Etiology of KD
2.1. KD Cannot Be Explained by the Infection Model
2.2. KD Cannot Be Explained by the Autoimmunity Model
2.3. KD Can Be Explained by the Hygiene Hypothesis
3. Epidemiological Evidence for the Hygiene Hypothesis as the Pathogenesis of KD
3.1. The Incidence of KD in East Asia Has Been Increasing Since the First Case in 1961
3.2. Improved Socioeconomic Environments Increase the Incidence of KD
3.3. Vaccination Protects against KD
Factor | Effect on KD | References |
---|---|---|
| Risk | [44] |
| Risk | [42,44,45,46] |
| Risk | [32] |
| Protective | [49] |
| Protective | [52,53,54] |
3.4. Breastfeeding Protects against KD
4. Insufficient B Cell Immunity Is Crucial for the Development of KD
4.1. The Peak Incidence of KD Overlaps with the Lowest Level of B Cell Immunity
4.2. KD Occurs in Children and Adults with Primary and Secondary Immunodeficiencies
4.3. Patients with KD Have a High Risk for Allergic Diseases and Vice Versa
5. Immunological Evidence from Patients with KD Demonstrates that B Cell Immunity Is Crucial for the Etiopathogenesis of KD
5.1. Severe Inflammatory Responses in Patients with KD
5.2. Low IgG Levels in Patients with KD
5.3. High IgE and Eosinophil Levels in Patients with KD
6. Efficacy of IVIG Treatment Demonstrates That B Cell Development and Activation Are Crucial for the Pathogenesis of KD
6.1. Lower IgG Levels in Patients with KD Correlate with Worse Clinical Outcomes, and IVIG Is the Standard Therapy for KD
6.2. The Therapeutic Effect of IVIG Is Not Likely Due to Passive Protection or Anti-Inflammatory Effects
6.3. The Therapeutic Effect of IVIG Is Likely Due to the Activation of Endogenous B Cell Development and Function
7. Genetic Evidence Indicates That Defects in Early B Cell Development May Be Critical for the Etiopathogenesis of KD
7.1. Genetic Susceptibility Affects the Incidence of KD
7.2. KD Susceptibility Genes Are Involved in Early B Cell Development and Function
7.3. Reduced Expression of Risk Alleles of BLK and BCL2L11 Genes in KD Suggests That the Development of KD Is Due to Defects or Dysregulation of Early B Cell Development
7.4. Male-Dominant Incidence of KD May Be Due to Male-Specific Susceptibility through the FCGR2A Gene
8. Conclusions and Proposed Mechanism Underlying the Etiopathogenesis of KD
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Infection Hypothesis | Autoimmunity Hypothesis | Hygiene Hypothesis | |
---|---|---|---|
Pros |
|
|
|
Cons |
|
|
Cell Type | No. of Samples (Acute KD: Convalescent KD: Healthy Controls) | -Fold Change (Compared with Healthy Controls) | p-Value | References | |
---|---|---|---|---|---|
Acute KD | Convalescent KD | ||||
WBC (#) | 33:33:25 | 1.75 ** | 1.05 | <0.01 | [69] |
106:68:22 | 1.85 ** | 1.02 | <0.01 | [68] | |
PBMC (#) | 106:68:22 | 0.94 | 1.08 | ns | [68] |
Neutrophils (#) | 33:33:25 | 2.54 ** | 0.92 | <0.01 | [69] |
Immature neutrophils (#) | 33:33:25 | 37 ** | 2.55 | <0.01 | [69] |
Monocytes (#) | 33:33:25 | 1.58 | 1.06 | ns | [69] |
106:68:22 | 2.89 ** | 1.39 | <0.01 | [68] | |
Lymphocytes (#): | 106:68:22 | 0.87 | 1.04 | ns | [68] |
CD3+ T cells | 106:68:22 | 0.80 | 1.06 | ns | [68] |
CD4+ T cells | 106:68:22 | 0.78 * | 0.97 | <0.05 | [68] |
CD8+ T cells | 106:68:22 | 0.83 * | 1.21 | <0.05 | [68] |
CD57+ NK cells | 106:68:22 | 0.69 * | 1.66 | <0.05 | [68] |
CD19+ B cells | 106:68:22 | 1.31 * | 1.06 | <0.05 | [68] |
IgG (mg/dL) | 33:33:25 | 0.95 | 1.50 ** | ns | [69] |
CRP (mg/dL) | 33:33:25 | 39 ** | 1 | <0.01 | [69] |
Gene | SNP | Population | Sample Size (Case:Control) | OR | p-Value | References |
---|---|---|---|---|---|---|
BLK | rs2254546 | Japan | 1182:4326 | 1.85 | 8.2 × 10−21 | [119] |
rs2736340 | Taiwan | 883:1657 | 1.54 | 9.0 × 10−10 | [120] | |
rs6993775 | Korea | 915:4553 | 1.52 | 2.5 × 10−11 | [121] | |
BCL2L11 | rs3789065 | Korea | 846:4553 | 1.42 | 4.4 × 10−11 | [122] |
CD40 | rs4813003 | Japan | 1182:4326 | 1.41 | 4.8 × 10−8 | [119] |
rs1569723 | Taiwan | 883:1657 | 1.42 | 5.7 × 10−9 | [120] | |
rs1883834 | Korea | 915:4553 | 1.18 | 0.003912 | unpublished data | |
FCGR2A | rs1801274 | Multi-ethnic | 1433:7764 | 1.32 | 7.4 × 10−11 | [123] |
Japan | 1182:4326 | na | 1.6 × 10−6 | [119] | ||
Korea | 915:4553 | 1.30 | 5.7 × 10−5 | [121] | ||
IGHV | rs4774175 | Japan, Taiwan, Korea | 3428:7837 | 1.20 | 6.0 × 10−9 | [124] |
rs6423677 * | Japan | 3603:5731 | 1.25 | 6.8 × 10−10 | [124] |
Gene | SNP | Risk Allele | Functional Effects of Risk Alleles | References |
---|---|---|---|---|
BLK | rs2254546 (A/G) | G | Decreased BLK mRNA expression | [125] |
BCL2L11 | rs3789065 (C/G) | C | Reduced BCL2L11 mRNA expression | [126] |
CD40 | rs4813003 (C/T) | C | Enhancement of CD40 function | [118] |
FCGR2A | rs1801274 (A/G; H167R *) | A | High-affinity receptor leading to immune activation | [118,123] |
IGHV3-66 | rs6423677 (A/C; p.Cys/Gly) | C | C (risk allele): very high mRNA expression. | [124] |
Risk Allele of the FCGR2A Variant (rs1801274; A/G = H167R *) | Effect of Risk Allele on IgG Binding | Disease or Trait Associated with Same Risk Allele | OR or Beta | p-Value | References |
---|---|---|---|---|---|
A allele encoding His (H) | high affinity | AS | 1.11 | 1 × 10−9 | [148] |
IBD | 1.13 | 9 × 10−36 | [150] | ||
IBD | 1.12 | 2 × 10−38 | [152] | ||
UC | 1.19 | 1 × 10−41 | [150] | ||
UC | 1.21 | 2 × 10−20 | [151] | ||
CD | 1.08 | 9 × 10−11 | [150] | ||
KD | 1.32 | 7 × 10−11 | [123] | ||
G allele encoding Arg (R) | little or no affinity | SLE | 1.16 | 1 × 10−12 | [149] |
Basophil count | 0.017 unit increase | 3 × 10−14 | [141] | ||
Blood FcγRIIa levels | 1.24 unit increase | 1 × 10−2102 | [162] |
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Lee, J.-K. Hygiene Hypothesis as the Etiology of Kawasaki Disease: Dysregulation of Early B Cell Development. Int. J. Mol. Sci. 2021, 22, 12334. https://doi.org/10.3390/ijms222212334
Lee J-K. Hygiene Hypothesis as the Etiology of Kawasaki Disease: Dysregulation of Early B Cell Development. International Journal of Molecular Sciences. 2021; 22(22):12334. https://doi.org/10.3390/ijms222212334
Chicago/Turabian StyleLee, Jong-Keuk. 2021. "Hygiene Hypothesis as the Etiology of Kawasaki Disease: Dysregulation of Early B Cell Development" International Journal of Molecular Sciences 22, no. 22: 12334. https://doi.org/10.3390/ijms222212334