As seen in patients with KD, our murine model of coronary vasculitis was characterized mechanistically by the involvement of T and B cells  as well as the mobilization of iMo [24, 25] with an increase of IL-6 levels [9, 13]. Moreover, Treg/Th17 cell imbalance was correlated with a reduction of IL-10 and TGF-β together with an increase of IL-17 after CAWS administration as in KD [13, 14]. Interestingly, genetic inactivation of CCR2, but not CCR5, is protective against CAWS induced-aortic and coronary vasculitis. Several lines of evidence support our findings that CCR2 plays a critical role in the pathogenesis of coronary vasculitis as possibly seen in KD. First, CCL2 levels, one of the main ligands for CCR2, are elevated in the serum  and urine  of patients with KD in the acute phase of illness; and this elevation is modulated by treatment . Also, genetic evidence points towards a role for CCR2 in the pathogenesis of KD, as suggested by the association between KD and common genetic variants in the chemokine receptor gene-cluster CCR3-CCR2-CCR5 .
The role of lymphocytes and monocytes/macrophages has been described as a key factor in the pathogenesis of KD . Also, in this study we show that T and B cells played a contributory role in the development of CAWS-induced vasculitis, as suggested by the decreased incidence of illness in Rag1
mice. However, innate immune responses play a critical role as 50% of the Rag1
mice still developed a less severe form of the illness. Indeed, selective absence of B or T cells was not associated with significant protection, indicating that in this experimental model the interaction between these two cell types and the innate immune response provides a high degree of redundancy. In our study, the development of vasculitis was likely related to an imbalance between inflammation and immune regulation, triggered by innate immune factors such as IL-6. This cytokine has a pivotal function for dictating whether T cells differentiate into Treg or Th17 cells [13, 28, 29]. In the presence of TGF-β and IL-6, precursors differentiate into Th17 cells, but when only TGF-β is present will they differentiate into Treg . Thus, IL-6 was likely to inhibit the generation of Treg and induced the production of IL-17, a potent pro-inflammatory cytokine. Additionally, levels of mediators commonly released by Treg, such as IL-10 and TGF-β, were significantly elevated in Ccr2
In CAWS-injected Ccr2
mice, we found a significant depletion of Treg in the periphery that coincided with an increased proportion of Th17 cells in the spleen and elevated circulating levels of IL-6. Notably, Ccr2
mice had lower circulating levels of IL-6 compared to Ccr2
mice and interestingly; Ccr2
mice had a higher proportion of circulating Treg after CAWS. In addition, the important role of Ccr2 to control Treg function and proliferation in this model was uncovered by the fact that: i) Ccr2
Treg had a higher suppressor activity on WT responder T cells and ii) in-vivo blocking of CCR2 increased the proportion of Treg in circulation.
Collectively, these data suggested a mechanistic scenario by which this chemokine receptor was involved in the innate response to CAWS leading to the rise in IL-6 production that favored a Th17 cell response at the expense of Treg.
Three lines of evidence emphasize the importance of IL-6 in KD and give credence to the notion that this mediator may be a determinant of the Treg/Th17 imbalance in the pathogenesis of coronary vasculitis . First, higher levels of IL-6 have been consistently reported in patients with KD during the acute phase of illness and serum levels of IL-6 return to normal control levels following successful treatment and parallels the duration of the fever [9, 31].
Second, comparable to our findings in WT mice injected with CAWS, which showed a sustained loss of Treg, the proportion of Treg is lower during acute KD and tends to normalize after the administration of IVIG . In addition, has been shown that IVIG induces not only the expression of CD4+CD25+FoxP3+ cells, but also the secretion of immunosuppressive TGF-β and IL-10 . Interestingly, the protective phenotype related with Ccr2
mice, was associated with an increase in regulatory T cells, TGF-β and IL-10, and a reduction of IL-6 after CAWS administration.
Finally, supporting the role for Th17 responses in KD, serum IL-17 levels has been shown markedly elevated in patients with acute KD and positively correlated with IL-6 levels . Importantly, IL-17 levels gradually decreased in the subacute phase [13, 34].
What was the cellular source of IL-6 in mice injected with CAWS? In line with our findings in the CAWS-induced vasculitis, a growing consensus exists that one of the main pathogenic factors in KD is the activation of monocytes/macrophages [9, 25]. For instance, during the acute phase, patients with KD have a significant increase in the absolute numbers of CD14+ monocytes , as well as in the percentage of CD14+CD16- monocytes, the human correlate of mouse iMo. This increase is quite specific to KD and severe bacterial infections, but not to other febrile illness such as pneumonia, infectious mononucleosis, or anaphylactoid purpura . CD14+CD16- cells also trigger efficient immune responses . Both, in humans and mice, iMo release high levels of pro-inflammatory cytokines, including IL-6 . iMo are directly influenced by CCR2 i.e., cell activation, and indirectly, i.e., regulation of cell migration . We found that CAWS injection promoted a CCR2-dependent emigration of iMo from the BM to periphery (i.e., blood, spleen). Increased availability of iMo in the periphery creates a readily available cellular source of IL-6. These findings were not unexpected considering the elegant work from Serbina et al., and others , indicating that CCR2 is required for the emigration of iMo from the BM into the periphery.
Some limitations need to be considered. First, no animal model can recapitulate all the features of KD, including age of onset . Second, the assessment of T cell responses in peripheral blood of patients with KD or in the spleen of CAWS-injected mice prove informative; and the ongoing T cells dynamics that may be present in KD at the vascular wall, may not fully parallel our model, where we see a systemic ongoing immune activation. Additional experiments are needed to directly demonstrate the role for IL-6, Treg and Th17 in CAWS-induced vasculitis via antibody neutralization, genetic inactivation or cell expansion/depletion.