Izui S, Fulpius T, Reininger L, Pastore Y, Kobayakawa T
Department of Pathology, Centre Médical Universitaire, University of Geneva, Switzerland.
Inflamm Res. 1998 Oct;47 Suppl 3:S145-50. doi: 10.1007/s000110050305.
Murine IgG3 anti-IgG2a rheumatoid factor (RF) monoclonal antibodies (mAb) with cryoglobulin activity, are able to induce, in normal mice, skin leukocytoclastic vasculitis and lupus-like glomerulonephritis resembling 'wire-loop' lesions (subendothelial immune deposits). The development of glomerular, but not skin, lesions in immunoglobulin-deficient mice (lacking the corresponding IgG2a autoantigen) receiving IgG3 RF cryoglobulins indicates that the RF activity of IgG3 monoclonal cryoglobulins and subsequent formation of IgG3-IgG2a immune complexes play a critical role in the development of skin vasculitis. In contrast, nephritogenic activity is solely contributed by IgG3-associated cryoglobulin activity. Polymorphonuclear leukocyte (PMN) infiltration is one of the major pathologic changes observed in both types of lesions. Treatment with mAbs against the adhesion molecules leukocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1) (both known for their involvement in PMN-endothelial cell interaction) inhibits the development of skin vascular lesions. However, it has no effect on the generation of glomerulonephritis. Apparently, adhesion molecule requirements for PMN interaction with glomerular capillary endothelial cells are different from those for PMN infiltration of the skin. However, the PMN depletion experiment has clearly shown that PMNs play an active role in the development of 'wire-loop' glomerular lesions. In the absence of the glomerular PMN infiltration, IgG3 RF cryoglobulins induce a different type of glomerular lesion, characterized by voluminous intracapillary thrombi and mesangial deposits, yet lacking subendothelial deposits. This is consistent with the fact that the latter lesions can be induced by certain IgG3 mAbs, which are unable to provoke glomerular PMN infiltration. Finally, the activation of the complement system does not appear to play a major role in either skin or glomerular lesions induced by IgG3 RF cryoglobulins.
具有冷球蛋白活性的鼠源IgG3抗IgG2a类风湿因子（RF）单克隆抗体（mAb），能在正常小鼠中诱发皮肤白细胞破碎性血管炎和类似“铁丝圈”病变（内皮下免疫沉积物）的狼疮样肾小球肾炎。在接受IgG3 RF冷球蛋白的免疫球蛋白缺陷小鼠（缺乏相应的IgG2a自身抗原）中，肾小球病变而非皮肤病变的发展表明，IgG3单克隆冷球蛋白的RF活性以及随后IgG3-IgG2a免疫复合物的形成在皮肤血管炎的发展中起关键作用。相比之下，致肾炎活性仅由IgG3相关的冷球蛋白活性所致。多形核白细胞（PMN）浸润是在这两种病变中观察到的主要病理变化之一。用针对黏附分子白细胞功能相关抗原1（LFA-1）和细胞间黏附分子1（ICAM-1）（两者均因参与PMN-内皮细胞相互作用而闻名）的单克隆抗体进行治疗，可抑制皮肤血管病变的发展。然而，它对肾小球肾炎的发生没有影响。显然，PMN与肾小球毛细血管内皮细胞相互作用所需的黏附分子与PMN浸润皮肤所需的黏附分子不同。然而，PMN清除实验清楚地表明，PMN在“铁丝圈”样肾小球病变的发展中起积极作用。在没有肾小球PMN浸润的情况下，IgG3 RF冷球蛋白会诱发一种不同类型的肾小球病变，其特征为大量的毛细血管内血栓和系膜沉积物，但缺乏内皮下沉积物。这与以下事实一致，即后一种病变可由某些无法引发肾小球PMN浸润的IgG3单克隆抗体诱发。最后，补体系统的激活似乎在由IgG3 RF冷球蛋白诱发的皮肤或肾小球病变中均不起主要作用。
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