KD is the most common acquired heart disease in children. High-dose IVIG has proven effective for stopping aberrant immune reactions in KD, which led to the research for an association between KD and abnormal B cell development during infection.18-20
Corticosteroid or aspirin could not be a substitute for IVIG for the protection of coronary arteries in KD.17,21,22
Thus, KD is different from other types of adult autoimmune vasculitis. As early as 1996, Lee et al.20
suggested that abnormal immunoglobulin switching might be involved in the pathogenesis of KD based on evidence that aberrantly increased immature B cells (CD5+
B cells) were suppressed by IVIG therapy. In 2000, the IL-21/IL-21R pathway was reported to be a major factor in B cell development.23
Interestingly, until now, IL-21 and IL-21R had not been investigated in KD, although hypotheses regarding defective B cell differentiation had been suspected as the pathogenesis of KD. Therefore, we concentrated on IL-21 as another possible factor in aberrant immune reactions, and found elevated levels of IL-21 in the serum of patients with KD.
Compared with other cytokines, IL-21 has a potent effect on isotype switching and development for plasma cells, resulting in the production of large quantities of immunoglobulin (up to 50-fold increases).24
IL-21 is important for T cell-dependent antigen-specific immunoglobulin production via CD40 ligand stimulation in humans.24
If there is a blockade in producing effective IgG against a specific antigen, IL-21 could be increased. IL-21 affects germinal center formation of lymph nodes, and IL-21-producing CD4+
T cells are prohibited by another T cell marker, the PD-1 molecule.25
If there is a defect in PD-1 expression, IL-21 production would be increased due to absence of inhibitory feedback. Hence, immunoglobulin-like structures such as PD-1 and IgG may regulate the production of IL-21. We have not yet known if any other abnormality exists in other factors related to B cell development such as Blimp-1, SAP, SOCS-1, or Bcl-6 expression in patients with KD.
In the present study, KD patients had elevated IL-21 levels regardless of age. Andersen et al.26
found that IL-21 was increased in adult spondyloarthritis compared with healthy volunteers. Therefore, elevated serum IL-21 may suggest an inflammatory cascade of autoimmunity in adults and children. In febrile controls (i.e., patients with EBV infection), IL-21 levels were low, although ESR levels were not statistically different from those in KD patients. No difference was noted in IL-21 levels between patients with typical and atypical KD. Thus, we may use serum levels of IL-21 for the differential diagnosis of KD.
We suspected that the high incidence of CAD in patients with atypical KD may be related to elevated IL-21 rather than CRP or IL-6. A low CRP is often found in patients with atypical KD. We predicted that these incompatible results between coronary findings and CRP levels could be explained by the existence of a high IL-21 level. However, our data showed no difference in IL-21 between patients with and without CAD. We interpret these results as follows. First, minimal arterial changes are undetectable, so only severe cases are categorized as having coronary arteritis. If IL-21 is involved in the initial phase of arteritis, IL-21 may be elevated both in patients with CAD and in those with coronary arteritis but without CAD. Second, the role of other factors such as vascular endothelial growth factor (VEGF) or transforming growth factor-β (TGF-β) may be more important than IL-21 in progressing arteritis.
Initially, we thought that the phenomenon of low IL-4 and increased IgE in KD could be explained by the involvement of IL-21 because IL-21 works together with IL-4 competitively. However, our data showed no direct correlation between IgE and IL-21 in patients with KD. The normal range of IgE increases with age.27
Thus, evaluating whether the measured level of IgE is elevated is difficult because the level should be compared with the normal range for each age. We defined an elevated level of IgE as 100 IU/mL, according to previous report.27
We tried to determine whether the high level of IgE may affect inflammatory reactions in patients with KD. However, no difference was observed in inflammatory markers between the group with IgE >100 IU/mL and the group with IgE <100 IU/mL. Thus, we assumed that elevated levels of IgE may not reflect the severity of inflammation. The total eosinophil count was not different between those two groups either.
What is the role of IL-21 in vasculitis? According to the literature, increased IL-21 enhances the production of autoantibodies.28,29
Blocking IL-21 with IL-21R Fc antibodies reduces inflammation in lupus-prone mice.28
IL-21 induces the development of Th17
cells, which are involved in autoimmune vasculitis.8
Interferon regulatory factor 4 (IRF4) is the main transcription factor for IL-17 and IL-21.8
IL-17 has been reported to be increased in KD.14,15
We think that abnormally increased IL-21 may be a sign of the ineffective production of antibodies against a certain infection in patients with KD. To maximize antibody production in individuals whose IL-21R is transiently down regulated due to young age, frequent infections, or frequent vaccinations, IL-21 could be increased. Elevated IL-21 may increase the production of IgE despite the high level of IFN-γ in patients with KD. In another aspect of pathogenesis of KD, if KD patients are producing autoantibodies such as anti-endothelial cell antibodies,30
α-human cardiac myosin autoantibodies,32
and cardiolipin antibodies,33
the autoreactive process could be augmented by an increased IL-21 level.29
Thus, IVIG therapy in KD may effectively suppress the ineffectively activated immune system by providing effective IgG directly and decreasing level of IL-21.
The phenomenon of increased IgE in KD has been explained as increased activity of IL-4,34
IL-5, or eosinophils.35
Our study was performed in line with these studies but showed different results. Although we could not find a direct correlation between IgE and IL-21 in the present study, further studies on IL-21, IRF4, and anti-IL-21 would solve the mysteries that remain concerning allergy, autoimmune vasculitis, and KD.