Experimental Pathological Analysis of Intractable Inflammatory Disease:Role of mutant genes and macrophage functions

顽固性炎症性疾病的组织病理学特征是肉芽肿性病变与巨噬细胞作为效应细胞的聚集有关。由于近年来发展起来的免疫学概念，这些疾病的发病机制被认为是在异常的宿主免疫反应下发生的，而不是病原体的种类。也就是说，巨噬细胞和属于单核巨噬细胞系统的其他细胞的功能受到包括某些淋巴因子或免疫复合体在内的特殊免疫产物的调节，这些细胞释放的几种化学介质直接或通过细胞内刺激诱导组织破坏。另一方面，这些细胞对宿主免疫系统发挥反馈作用，并对其进行修改。难治性炎症性疾病可能与这种不寻常的体内平衡状况有关。我们项目的第一个目标是通过使用几个品系的免疫疾病小鼠来验证这一假说的合理性。因此，我们研究了：1)免疫复合体在与巨噬细胞相关的炎性病变发生中的定量作用，2)免疫功能障碍诱导的淋巴增殖性突变基因LPR或GLD对巨噬细胞功能的影响，3)作用于巨噬细胞的细胞因子的分子特征，与淋巴增殖性基因的表达或从人类T细胞系释放的细胞因子有关。第二，阐明这些疾病的遗传因素。我们分析了LPR或GLD基因同源的几个品系小鼠的病理特征和巨噬细胞功能。此外，还发现特定分离的背景基因与淋巴增殖性基因有关，促进了这些疾病的发展。

Intractable inflammatory diseases are histopathologically characterized by granulomatous lesions associated with the accumulation of macrophages as effector cells. Owing to the immunological concepts developed in a last few years, pathogenesis of these diseases is suggested to be under the unusual host-immune response rather than the kind of pathogens. That is, the functions of macrophages and other cells belonging to mononuclear phagocyte system are regulated by unusual immune products including some lymphokines or immune complexes, and several chemical mediators released from these cells induce tissue-destruction directly or via intrinsic cell stimulation. On the other hand, these cells-play feedback actions against host immune system and modify it. Intractable inflammatory diseases may be associated with such unusual homeostatic situation.The first object in our project is to verify the propriety of this hypothesis by using several strains of immune disease mice. Thus, we have studied; 1) quantitative effect of immune complexes on the development of inflammatory lesions associated with macrophages, 2) influence of the lymphoproliferative mutant gene, lpr or gld, inducible of immunological dysfunctions upon macrophage functions, and 3) molecular characteristics of cytokines acting on macrophages, released from spleen cells in association with the lymphoproliferative gene expression or from a human T cell line.The second is to clarify the genetic factors responsible for these diseases. We have analyzed the pathologic features and macrophage functions in several strains of mice congenic of the lpr or gld gene. Moreover, it was found that particular segregated background genes contribute to the development of these diseases in association with the lymphoproliferative gene.