Search

Environmental triggers, including those from pathogens, are thought to play an important role in triggering autoimmune diseases, such as vasculitis, in genetically susceptible individuals. The mechanism by which activation of the innate immune system contributes to vessel-specific autoimmunity in vasculitis is not known. Systemic administration of Candida albicans water-soluble extract (CAWS) induces vasculitis in the aortic root and coronary arteries of mice that mimics human Kawasaki disease. We found that Dectin-2 signaling in macrophages resident in the aortic root of the heart induced early CCL2 production and the initial recruitment of [CCR2.sup.+] inflammatory monocytes (iMos) into the aortic root and coronary arteries. iMos differentiated into monocyte-derived dendritic cells (Mo-DCs) in the vessel wall and were induced to release IL-1[beta] in a Dectin-2/Syk/NLRP3 inflammasome-dependent pathway. IL-1[beta] then activated cardiac endothelial cells to express CXCL1 and CCL2 and adhesion molecules that induced neutrophil and further iMo recruitment and accumulation in the aortic root and coronary arteries. Our findings demonstrate that Dectin-2-mediated induction of CCL2 production by macrophages resident in the aortic root and coronary arteries initiates vascular inflammation in a model of Kawasaki disease, suggesting an important role for the innate immune system in initiating vasculitis., Introduction Kawasaki disease (KD), first described as an acute, febrile, mucocutaneous lymph node syndrome in 1967 (1), is the most common systemic vasculitis of children and infants. KD is recognized [...]

Introduction and Objective: Kawasaki disease (KD) is associated with diffuse and systemic vasculitis of unknown aetiology and primarily affects infants and children. Intravenous immunoglobulin (IVIG) treatment reduces the risk of developing coronary aneurysms, but some children have IVIG-resistant KD, which increases their risk of developing coronary artery injury. Here, we investigated the effect of recombinant human soluble thrombomodulin (rTM), which has anticoagulant, anti-inflammatory, and cytoprotective properties on the development of coronary arteritis in a mouse model of vasculitis. Methods: An animal model of KD-like vasculitis was created by injecting mice with Candida albicans water-soluble fraction (CAWS). This model was used to investigate the mRNA expression of interleukin (IL)-10, tumour necrosis factor alpha (TNF-α), and tissue factor (TF), in addition to histopathology of heart tissues. Results: rTM treatment significantly reduces cardiac vascular endothelium hypertrophy by 34 days after CAWS treatment. In addition, mRNA expression analysis revealed that rTM administration increased cardiac IL-10 expression until day 27, whereas expression of TNF-α was unaffected. Moreover, in the spleen, rTM treatment restores IL-10 and TF expression to normal levels. Conclusion: These findings suggest that rTM suppresses CAWS-induced vasculitis by upregulating IL-10. Therefore, rTM may be an effective treatment for KD. [ABSTRACT FROM AUTHOR]

Abstract Background Chemokines and their receptors play a role in the innate immune response as well as in the disruption of the balance between pro-inflammatory Th17 cells and regulatory T cells (Treg), underlying the pathogenesis of coronary vasculitis in Kawasaki disease (KD). Results Here we show that genetic inactivation of chemokine receptor (CCR)-2 is protective against the induction of aortic and coronary vasculitis following injection of Candida albicans water-soluble cell wall extracts (CAWS). Mechanistically, both T and B cells were required for the induction of vasculitis, a role that was directly modulated by CCR2. CAWS administration promoted mobilization of CCR2-dependent inflammatory monocytes (iMo) from the bone marrow (BM) to the periphery as well as production of IL-6. IL-6 was likely to contribute to the depletion of Treg and expansion of Th17 cells in CAWS-injected Ccr2+/+ mice, processes that were ameliorated following the genetic inactivation of CCR2. Conclusion Collectively, our findings provide novel insights into the role of CCR2 in the pathogenesis of vasculitis as seen in KD and highlight novel therapeutic targets, specifically for individuals resistant to first-line treatments.

Abstract Background Intravenous immunoglobulin (IVIg) treatment results in an effective response from patients with acute-phase Kawasaki disease (KD), but 16.5% of them remain nonresponsive to IVIg. To address this therapeutic challenge, we tried a new therapeutic drug, mizoribine (MZR), in a mouse model of KD, which we have established using injections of Candida albicans water-soluble fractions (CAWS). Methods CAWS (4 mg/mouse) were injected intraperitoneally into C57BL/6N mice for 5 consecutive days. MZR or IgG was administered for 5 days. After 4 weeks, the mice were sacrificed and autopsied, the hearts were fixed in 10% neutral formalin, and plasma was taken to measure cytokines and chemokines using the Bio-Plex system. The incidence of panvasculitis in the coronary arteries and aortic root was 100% in the control group. The incidence of panvasculitis in the MZR group decreased to 50%. Moreover, the scope and severity of the inflammation of those sites were significantly reduced in the MZR group as well as the IgG group. On the other hand, increased cytokines and chemokines, such as IL-1α, TNF-α, KC, MIP-1α, GM-CSF, and IL-13, in the nontreatment group were significantly suppressed by treatment with MZR, but the MCP-1 level increased. In addition, IL-1α, TNF-α, IL-10, IL-13, and MIP-1α were suppressed by treatment in the IgG group. Results The incidence of panvasculitis in the coronary arteries and aortic root was 100% in the control group. The incidence of panvasculitis in the MZR group decreased to 50%. Moreover, the scope and severity of the inflammation of those sites were significantly reduced in the MZR group as well as the IgG group. On the other hand, increased cytokines and chemokines, such as IL-1α TNF-α, KC, MIP-1α, GM-CSF, and IL-13, in the nontreatment group were significantly suppressed by treatment with MZR, but the MCP-1 level increased. In addition, IL-1α, TNF-α, IL-10, IL-13, and MIP-1α were suppressed by treatment in the IgG group. Conclusion MZR treatment suppressed not only the incidence, range, and degree of vasculitis, but also inflammatory cytokines and chemokines in the plasma of the KD vasculitis model mice, suggesting that MZR may be useful for treatment of KD.

Abstract Background Although fungi have been implicated as initiating/deteriorating factors for allergic asthma, their contributing components have not been fully elucidated. We previously isolated soluble β-glucan from Candida albicans (CSBG) (Ohno et al., 2007). In the present study, the effects of CSBG exposure on airway immunopathology in the presence or absence of other immunogenic allergen was investigated in vivo, and their cellular mechanisms were analyzed both in vivo and in vitro. Methods In vivo, ICR mice were divided into 4 experimental groups: vehicle, CSBG (25 μg/animal), ovalbumin (OVA: 2 μg/animal), and CSBG + OVA were repeatedly administered intratracheally. The bronchoalveolar lavage cellular profile, lung histology, levels of cytokines and chemokines in the lung homogenates, the expression pattern of antigen-presenting cell (APC)-related molecules in the lung digests, and serum immunoglobulin values were studied. In vitro, the impacts of CSBG (0–12.5 μg/ml) on the phenotype and function of immune cells such as splenocytes and bone marrow-derived dendritic cells (BMDCs) were evaluated in terms of cell proliferation, the surface expression of APC-related molecules, and OVA-mediated T-cell proliferating activity. Results In vivo, repeated pulmonary exposure to CSBG induced neutrophilic airway inflammation in the absence of OVA, and markedly exacerbated OVA-related eosinophilic airway inflammation with mucus metaplasia in mice, which was concomitant with the amplified lung expression of Th2 cytokines and IL-17A and chemokines related to allergic response. Exposure to CSBG plus OVA increased the number of cells bearing MHC class II with or without CD80 in the lung compared to that of others. In vitro, CSBG significantly augmented splenocyte proliferation in the presence or absence of OVA. Further, CSBG increased the expression of APC-related molecules such as CD80, CD86, and DEC205 on BMDCs and amplified OVA-mediated T-cell proliferation through BMDCs. Conclusion CSBG potentiates allergic airway inflammation with maladaptive Th immunity, and this potentiation was associated with the enhanced activation of APCs including DC.