ANALYSIS FOR THE PATHOGENESIS OF IGA NEPHROPATHY

我们一直从FcR的角度关注IgA肾病的发病机制，特别是IgA/IgA- ic的病理意义。本学期，我们分析了FcR在体内的病理生理作用。1)为了评估FcR的生理作用和探讨IC对肾小球致肾作用的机制，我们检测了先天性缺乏功能性FcR的FcR γ链敲除小鼠（γ(-/-)小鼠）的肾脏。γ(-/-)小鼠组织学检查显示多克隆免疫球蛋白在脉管旁区逐渐大量积累，无肾小球肾炎和肾功能不全。为了进一步研究相关的携带FcR的细胞类型，我们对54周龄的gamma（-/-）小鼠（gamma(-/-)IWT小鼠）进行了骨髓（野生型窝伴）移植。在γ (-/-)/WT小鼠中未发现明显的白细胞浸润和系膜免疫沉积物的减少。随后，我们将兔抗小鼠IgG Ab…More注射到γ(-/-)和γ(-/-)中。/ WT老鼠。在γ (-/-)/WT小鼠中观察到短暂性肾损伤。注射后2周，兔IgG-IC在γ (i -)/WT小鼠中完全消失，而IC在γ (i -)小鼠中仍然存在。这些数据清楚地表明，在生理状态下，FcR有助于全身和局部清除Ab/IC。2)接下来，我们重新评估了抗GBM抗体诱导的GN（抗GBM GN），在两种缺乏FcR γ链（gamma(- i-)）或FcgammaRIIB （RII(-/-)）的小鼠中。在γ(-/-)小鼠中，肾损伤显著减轻，而RH（-/-）小鼠尽管有正常的PMN内流，但肾小球损伤加速。我们的研究结果表明，fcr在抗gbm GN的急性期起关键作用。我们进一步阐明了不依赖于FcR但抗体依赖的导致慢性肾损害的途径的存在。我们假设该通路与肾素-血管紧张素系统（RAS）有关。通过嵌合γ(-/-)和血管紧张素II受体敲除小鼠拮抗剂，我们证明了FcR和RAS是抗gbm GN的关键决定因素。我们目前的数据将有助于了解IgA肾病的发病机制。少

We have been focusing on pathogenesis of IgA nephropathy, especially the pathological meaning of IgA/IgA-IC, from the stand point of FcR.In this term, we analyzed the pathophysiological role of FcR in vivo. 1)To assess the physiological roles of FcR and approach the mechanisms of IC nephritogenic effects on glomeruli, we examined the kidneys of FcR gamma-chain knockout mice (gamma(-/-) mice) which congenitally lack functional FcR.Histological examination of gamma(-/-) mice showed that polyclonal immunoglobulins were gradually and massively accumulated in the paramesangial areas without glomerulonephritis and renal dysfunction. For further investigation of relevant FcR- bearing cell-types, bone marrow (wild type littermates) transplantation was performed in 54 weeks-age gamma(-/-) mice (gamma(-/-)IWT mice). Neither significant infiltration of leukocytes nor decrement of immune-deposits in the mesangium was found in gamma(-/-)/WT mice. Thereafter we next injected rabbit anti-mouse IgG Ab … More into gamma(-/-) and gamma(-/-.)/WT mice. Transient renal injuries were observed in gamma(-/-)/WT mice. The rabbit IgG-IC completely disappeared in gamma(-I-)/WT mice at 2 week after the injection, while the IC remained in gamma(-I-) mice. These data clearly demonstrated that FcR contribute to systemic and local clearance of Ab/IC in the physiological state. 2) Next we reevaluated anti-GBM antibody-induced GN (anti- GBM GN), in mice of two strains which are deficient in FcR gamma chain (gamma(-I-)) or FcgammaRIIB (RII(-/-)). In gamma(-/-) mice, renal injuries were dramatically attenuated, while RH(-/-) mice suffered accelerated glomerular injuries in spite of a normal PMN influx. Our results demonstrated that FcRs play a pivotal role in acute phase of anti-GBM GN.We further clarified the existence of FcR -independent but antibody-dependent pathway which lead to chronic renal damage. We hypothesized this pathway was related to renin-angiotensin system (RAS). By using chimeric mice of gamma(-/-) and angiotensin II receptor knockout mice antagonist, we proved FcR and RAS were critical determinants in anti-GBM GN.Our present data would contribute to the understanding for pathogenesis of IgA nephropathy. Less