Study on the pathogenesis of Wegener's granulomatosis

本研究探讨了粘附分子在韦格纳肉芽肿病（WG）发病机制中的作用。对于细胞因子，即使在疾病的活动期，肿瘤坏死因子-α（TNF-α）的滴度也不是那么高。活动期可溶性细胞间粘附分子-1（inter-cellular adhesion molecule-1，ICAM-1）水平明显高于非活动期和健康人。对患者血清进行个体化检测，发现随着病情的好转，可溶性ICAM-1水平逐渐下降，且两者之间存在明显的相关性。这一结果意味着在这种疾病中，具有LFA-1的中性粒细胞在其表面上与血管内皮细胞发生粘附。然而，中性粒细胞的配体SLeX或LFA-1在用TNF-α或cANCA（胞质抗中性粒细胞胞质抗体）IgG激活时未显示出变得明显。据推测，整联蛋白如LFA-1具有两种形式，静息形式和活性形式，并且其构象变化改变了对配体的亲和力。该研究还检查了日本受试者中各种人类白细胞抗原（HLA）与cANCA阳性WG之间的关联，以确定HLA抗原是否参与了该疾病的发病机制。该研究涉及在我科治疗的16例cANCA阳性WG受试者。使用淋巴细胞微量细胞毒性试验对淋巴细胞进行HLA分型。cANCA阳性WG组HLA-DR 9阳性率为62. 5%（10/16），健康对照组为26%（10/16）。这种HLA-DR 9升高具有统计学意义（P<0.01，Pc<0.05）;我们还注意到HLA-B55与cANCA阳性WG之间的关联较弱（P<0.05）。结果表明，某些HLA类同种异型与WG之间可能存在关联。

This study examined the role of adhesion molecules in the pathogenesis of Wegener's granulomatosis (WG). For the cytokine, the titers of tumor necrosis factor-alpha (TNF-alpha) are not so high even in the active stage of the disease. The value of soluble ICAM-1 (inter-cellular adhesion molecule-1) in the active stage are significantly high compared with those in the inactive stage of the disease or in healthy volunteers. When we examined the sera of patients individually, the level of soluble ICAM-1 decreases gradually as the disease recover, and the correlation of them was apparently demonstrated. This result means that adhesion of the neutrophils with LFA-1 on its surface take place with the vascular endothelial cells in this disease. However, SLeX or LFA-1, the ligand of the neutrophil, was not revealed to become apparent when activated with TNF-alpha or cANCA (cytoplasmic-antineutrophil cytoplasmic antibody) lgG.It is supposed that integrin such as LFA-1 has two forms, resting form and active form, and its conformational change alter the affinity for the ligand. Further study is needed for this problem.The study also examined the association between various human leukocyte antigens (HLA) and cANCA-positive WG in Japanese subjects to determine whether HLA antigens are involved in the pathogenesis of this disease. The study involved 16 subjects with cANCA-positive WG treated in our department. HLA-typing of the lymphocytes was performed using a lymphocyte microcytotoxicity assay. Of the subjects with cANCA-positive WG,62.5% (10/16) were positive for HLA-DR9, compared with 26% of the healthy control subjects. This HLA-DR9 elevation was statistically significant (P<0.01, Pc<0.05) ; we also noted a weaker association between HLA-B55 and cANCA-positive WG (P<0.05). The results indicated that an association may exist between certain HLA-class allotypes and WG.