Ishii Takayuki, Fujita Tomoyuki, Matsushita Takashi, Yanaba Koichi, Hasegawa Minoru, Nakashima Hiroko, Ogawa Fumihide, Shimizu Kazuhiro, Takehara Kazuhiko, Tedder Thomas F, Sato Shinichi, Fujimoto Manabu
Department of Dermatology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.
Am J Pathol. 2009 Jun;174(6):2225-33. doi: 10.2353/ajpath.2009.080223. Epub 2009 Apr 23.
Prominent eosinophil infiltration is a characteristic of some forms of vasculitis, such as Churg-Strauss syndrome, also known as allergic granulomatous vasculitis. In the current study, we established a mouse model of cutaneous eosinophilic vasculitis by the cutaneous reverse passive Arthus reaction using IgE injection instead of IgG. Wild-type C57BL/6 mice were injected with IgE anti-trinitrophenyl antibodies, followed immediately by intravenous administration of trinitrophenyl bovine serum albumin. IgE-mediated immune complex challenge induced substantial hemorrhage with marked infiltration of eosinophils in which neutrophils, mast cells, and macrophages were also mixed. This finding contrasted remarkably with the neutrophil-dominant infiltration pattern in IgG-mediated immune complex challenge. In the lesion, the expression level of monocyte chemotactic protein-3 was increased, and anti-monocyte chemotactic protein-3 treatment resulted in a significant but incomplete blockade of eosinophil recruitment. Furthermore, mice lacking E-selectin, P-selectin, L-selectin, or intercellular adhesion molecule-1, as well as wild-type mice that received anti-vascular cell adhesion molecule-1-blocking antibodies were assessed for the IgE-mediated Arthus reaction. After 24 hours, the loss of P-selectin resulted in a significant reduction in eosinophil accumulation compared with both wild-type mice and other mouse mutants. Collectively, the Fc class of immunoglobulins, which forms these immune complexes, critically determines the disease manifestation of vasculitis. The IgE-mediated cutaneous reverse passive Arthus reaction may serve as an experimental model for cutaneous eosinophilic infiltration in vasculitis as well as in other diseases.
显著的嗜酸性粒细胞浸润是某些形式血管炎的特征,如变应性肉芽肿性血管炎(又称Churg-Strauss综合征)。在本研究中,我们通过使用IgE注射而非IgG的皮肤反向被动Arthus反应建立了皮肤嗜酸性粒细胞血管炎小鼠模型。向野生型C57BL/6小鼠注射抗三硝基苯IgE抗体,随后立即静脉注射三硝基苯牛血清白蛋白。IgE介导的免疫复合物激发导致大量出血,并伴有明显的嗜酸性粒细胞浸润,其中还混合有中性粒细胞、肥大细胞和巨噬细胞。这一发现与IgG介导的免疫复合物激发中以中性粒细胞为主的浸润模式形成显著对比。在病变部位,单核细胞趋化蛋白-3的表达水平升高,抗单核细胞趋化蛋白-3治疗导致嗜酸性粒细胞募集显著但不完全受阻。此外,对缺乏E-选择素、P-选择素、L-选择素或细胞间黏附分子-1的小鼠,以及接受抗血管细胞黏附分子-1阻断抗体的野生型小鼠进行了IgE介导的Arthus反应评估。24小时后,与野生型小鼠和其他小鼠突变体相比,P-选择素的缺失导致嗜酸性粒细胞积聚显著减少。总的来说,形成这些免疫复合物的免疫球蛋白Fc类别决定性地决定了血管炎的疾病表现。IgE介导的皮肤反向被动Arthus反应可作为血管炎以及其他疾病中皮肤嗜酸性粒细胞浸润的实验模型。