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Perspective of Immunopathogenesis and Immunotherapies for Kawasaki Disease
Lung Chang1,2,3,4, Horng-Woei Yang3, Tang-Yu Lin5
1Department of Pediatrics, MacKay Memorial Hospital, Taipei, Taiwan.
Insights
Kawasaki Disease (KD) involves inflammation and coronary artery issues in children. Research explores its genetic links, immune responses, and treatment resistance, aiming for better therapies.
Area of Science:
- Pediatric Rheumatology
- Immunology
- Genetics
Background:
- Kawasaki Disease (KD) is an acute inflammatory condition in children under 5, presenting with fever, rash, and potential coronary artery lesions (CAL).
- KD shares symptoms with MIS-C, a COVID-19-related illness, and its genetic associations vary by ethnicity.
- Immune dysregulation involving Th17/Th1 and Th2/Treg pathways, with specific cytokine profiles (IL-6, IL-10, IL-17A, IFN-γ, IP-10, IL-4, IL-5, FoxP3, TGF-β), underlies KD's hyperinflammation.
Purpose of the Study:
- To review the immunopathogenesis of Kawasaki Disease, including genetic factors and immune cell responses.
- To discuss phenotypic variations like IVIG resistance, macrophage activation syndrome (MAS), and KD with shock syndrome (KDSS).
- To highlight current treatment standards and propose future research directions for refractory KD and KDSS.
Main Methods:
- Literature review of studies on Kawasaki Disease genetics, immunology, and clinical presentations.
- Analysis of immune mediator profiles, including cytokines and cell populations (Th17, Th1, Th2, Treg).
- Examination of phenotypic variations and their underlying mechanisms, such as MAS and KDSS.
Main Results:
- Genetic factors (HLA alleles, TLR expression) and immune imbalances (Th17/Th1 vs. Th2/Treg) are linked to KD pathogenesis.
- Phenotypic variations include IVIG resistance, MAS (hyperferritinemia, thrombocytopenia), and KDSS (NO overproduction, coagulopathy).
- Standard treatment (IVIG, aspirin) is effective but not universally, necessitating research into refractory cases.
Conclusions:
- Understanding KD immunopathogenesis is crucial for managing its diverse clinical manifestations and treatment resistance.
- Further research is needed to identify genetic susceptibility, elucidate IVIG resistance mechanisms, and develop targeted therapies for KD and KDSS.
- Novel treatments targeting cytokine storms, NO overproduction, and Treg function may improve outcomes for severe KD cases.
Abstract:
Kawasaki Disease (KD) is an acute inflammatory illness that mostly occurs in children below 5 years of age, with intractable fever, mucocutaneous lesions, lymphadenopathy, and lesions of the coronary artery (CAL). KD is sharing clinical symptoms with systemic inflammatory syndrome in children (MIS-C) which is related to COVID-19. Certain genes are identified to be associated with KD, but the findings usually differ between countries and races. Human Leukocyte Antigen (HLA) allele types and toll-like receptor (TLR) expression are also correlated to KD. The acute hyperinflammation in KD is mediated by an imbalance between augmented T helper 17 (Th17)/Th1 responses with high levels of interleukin (IL)-6, IL-10, IL-17A, IFN-γ, and IP-10, in contrast to reduced Th2/Treg responses with lower IL-4, IL-5, FoxP3, and TGF-β expression. KD has varying phenotypic variations regarding age, gender, intravenous immunoglobulin (IVIG) resistance, macrophage activation and shock syndrome. The signs of macrophage activation syndrome (MAS) can be interpreted as hyperferritinemia and thrombocytopenia contradictory to thrombocytosis in typical KD; the signs of KD with shock syndrome (KDSS) can be interpreted as overproduction of nitric oxide (NO) and coagulopathy. For over five decades, IVIG and aspirin are the standard treatment for KD. However, some KD patients are refractory to IVIG required additional medications against inflammation. Further studies are proposed to delineate the immunopathogenesis of IVIG-resistance and KDSS, to identify high risk patients with genetic susceptibility, and to develop an ideal treatment regimen, such as by providing idiotypic immunoglobulins to curb cytokine storms, NO overproduction, and the epigenetic induction of Treg function.
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