Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0329, Japan.
BMC Immunol. 2013 Sep 24;14:44. doi: 10.1186/1471-2172-14-44.
Candida albicans water-soluble fraction (CAWS), a mannoprotein-β-glucan complex obtained from the culture supernatant of C. albicans NBRC1385, causes CAWS-mediated vasculitis (CAWS-vasculitis) in B6 and DBA/2 mice with mild and lethal symptoms, respectively. Why CAWS is lethal only in DBA/2 mice remains unknown.
We performed DNA microarray analyses using mRNA obtained from peripheral blood mononuclear cells (PBMCs) of B6 and DBA/2 mice and compared their respective transcriptomes. We found that the mRNA levels of interferon-γ (Ifng) and several genes that regulate the complement system, such as C3, C4, Cfb, Cfh, and Fcna, were increased dramatically only in DBA/2 mice at 4 and 8 weeks after CAWS administration. The dramatic increase was confirmed by quantitative real-time polymerase chain reactions (qRT-PCR). Moreover, mRNA levels of immune-related genes, such as Irf1, Irf7, Irf9, Cebpb, Ccl4, Itgam, Icam1, and IL-12rb1, whose expression levels are known to be increased by Ifng, were also increased, but only in DBA/2 mice. By contrast, the mRNA level of Dectin-2, the critical receptor for the α-mannans of CAWS, was increased slightly and similarly in both B6 and DBA/2 mice after CAWS administration.
Taken together, our results suggest that CAWS administration induces Dectin-2 mediated CAWS-vasculitis in both B6 and DBA/2 mice and the expression of Ifng, but only in DBA/2 mice, which led to increased expression of C3, C4, Cfb, Cfh, and Fcna and an associated increase in lethality in these mice. This model may contribute to our understanding of the pathogenesis of severe human vasculitis.
白色念珠菌水溶性部分（CAWS）是一种从白色念珠菌 NBRC1385 的培养上清液中获得的甘露糖蛋白-β-葡聚糖复合物，在 B6 和 DBA/2 小鼠中引起 CAWS 介导的血管炎（CAWS-vasculitis），分别表现为轻度和致死症状。为什么 CAWS 仅在 DBA/2 小鼠中是致命的，目前尚不清楚。
我们使用 B6 和 DBA/2 小鼠外周血单核细胞（PBMC）获得的 mRNA 进行 DNA 微阵列分析，并比较了它们各自的转录组。我们发现，IFN-γ（Ifng）和几个调节补体系统的基因（如 C3、C4、Cfb、Cfh 和 Fcna）的 mRNA 水平在 CAWS 给药后 4 周和 8 周仅在 DBA/2 小鼠中显著增加。通过定量实时聚合酶链反应（qRT-PCR）证实了这一急剧增加。此外，免疫相关基因（如 Irf1、Irf7、Irf9、Cebpb、Ccl4、Itgam、Icam1 和 IL-12rb1）的 mRNA 水平也增加，但仅在 DBA/2 小鼠中增加，这些基因的表达水平已知是由 Ifng 增加的。相比之下，CAWS 给药后，B6 和 DBA/2 小鼠中 Dectin-2 的 mRNA 水平均略有增加，Dectin-2 是 CAWS 的α-甘露聚糖的关键受体。
综上所述，我们的结果表明，CAWS 给药在 B6 和 DBA/2 小鼠中诱导 Dectin-2 介导的 CAWS 血管炎，并且表达 Ifng，但仅在 DBA/2 小鼠中表达，导致 C3、C4、Cfb、Cfh 和 Fcna 的表达增加，并导致这些小鼠的死亡率增加。该模型可能有助于我们理解严重人类血管炎的发病机制。
