ANTI-DNA ANTIBODIES FORM IMMUNE DEPOSITS AT DISTINCT GLOMERULAR AND VASCULAR SITES
ANTI-DNA ANTIBODIES FORM IMMUNE DEPOSITS AT DISTINCT GLOMERULAR AND VASCULAR SITES
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DOI：
10.1038/ki.1992.242
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发表时间：
1992-06-01
影响因子：
19.6
通讯作者：
MADAIO, MP
中科院分区：
文献类型：
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作者：
VLAHAKOS, DV;FOSTER, MH;MADAIO, MP
为了研究狼疮自身抗体产生肾小球免疫沉积物 (ID) 和肾炎的能力，对 24 种鼠单克隆 (m) 抗 DNA 抗体 (Ab) 进行腹腔注射，这些抗体源自 MRL-1pr/lpr、SNF1 或 NZB 狼疮倾向小鼠，并根据与肾炎 Ig 共有的特性进行选择。 （如杂交瘤）和静脉注射（作为纯化的 Ig）对正常小鼠；至少评估了四只小鼠/单克隆抗体。 观察到免疫沉积物形成 (IDF) 的三种一般模式：肾小球内的细胞外 ID（+/- 血管，N = 8）；核内 ID (N = 5);或最小 ID 或无 ID (N = 11)。 产生显着细胞外 ID 的四种 MRL m 抗 DNA Ab 表现出不同的疾病特征，包括：（a）具有抗基底膜染色的系膜和内皮下 ID，与增殖性肾小球肾炎、PMN 浸润和蛋白尿相关； (b) 弥漫性细颗粒系膜和肾小球外血管 ID，与增殖性肾小球肾炎和蛋白尿相关； (c)致密膜内ID和腔内ID，与毛细血管壁增厚、系膜介入和扩张、动脉瘤扩张和肾小球毛细血管袢的腔内闭塞以及重度蛋白尿相关； (d) 系膜和肾小球外血管 ID，伴有轻度节段性系膜扩张，无蛋白尿。 这些 MRL mAb 来自四只不同的小鼠，它们具有不同的 pIs 和同种型。 它们都与多种自身抗原 (autoAg) 发生交叉反应，但是它们的 autoAg 结合谱是可区分的。 在 SNF1 衍生的 mAb 中，有四种产生了组织学和临床上无法区分的疾病，其特征是弥漫性系膜和毛细血管壁 ID，与细胞增殖/浸润和蛋白尿相关。 四种单克隆抗体中的三种来自同一只小鼠，并且具有克隆相关性；它们是：具有 SWR 同种异型的 IgG2b、相对阳离子、与相似的 Ag 结合模式高度交叉反应、独特型相关并由相同的 V(H) 和几乎相同的 V(L) 序列编码。 我们得出的结论是，狼疮自身抗体形成 ID 的能力和 IDF 的位置都取决于个体 Ig 的独特特性。 结果还表明，自身抗体的 Ag 结合区域在此过程中具有影响力，并且表明多种 Ab-Ag 相互作用有助于狼疮性肾炎患者的 IDF。 此外，这些观察结果提出了以下可能性：这些相互作用导致的病理和临床异常受到 IDF 位置的影响，并且在给定个体中，主要相互作用可能对肾炎的表型表达具有高度影响。
To investigate the capacity of lupus autoAb to produce glomerular immune deposits (ID) and nephritis, 24 murine monoclonal (m) anti-DNA antibodies (Ab), derived from either MRL-1pr/lpr, SNF1 or NZB lupus-prone mice and selected based on properties shared with nephritogenic Ig, were administered i.p. (as hybridomas) and i.v. (as purified Ig) to normal mice; at least four mice/mAb were evaluated. Three general patterns of immune deposit formation (IDF) were observed: extracellular ID within glomeruli (+/- blood vessels, N = 8); intranuclear ID (N = 5); or minimal or no ID (N = 11). The four MRL m anti-DNA Ab that produced significant extracellular ID demonstrated different disease profiles including: (a) mesangial and subendothelial ID with anti-basement membrane staining, associated with proliferative glomerulonephritis, PMN infiltration, and proteinuria; (b) diffuse fine granular mesangial and extraglomerular vascular ID, associated with proliferative glomerulonephritis and proteinuria; (c) dense intramembranous ID and intraluminal ID, associated with capillary wall thickening, mesangial interposition and expansion, aneurysmal dilatation and intraluminal occlusion of glomerular capillary loops, and heavy proteinuria; and (d) mesangial and extraglomerular vascular ID, associated with mild segmental mesangial expansion, without proteinuria. These MRL mAb were derived from four different mice, and they had variable pIs and isotypes. They all cross reacted with multiple autoantigens (autoAg), however, their autoAg binding profiles were distinguishable. Among the SNF1 derived mAb, four produced histologically and clinically indistinguishable disease characterized by diffuse mesangial and capillary wall ID, associated with cellular proliferation/infiltration and proteinuria. Three of the four mAb were derived from the same mouse and were clonally related; they were: IgG2b with SWR allotype, relatively cationic, highly cross reactive with similar Ag binding patterns, idiotypically related and encoded by identical V(H) and nearly identical V(L) sequences. We conclude that both the capacity of lupus autoAb to form ID and the location of IDF are dependent on properties unique to individual Ig. The results also indicate that the Ag binding region of the autoAb is influential in this process, and they suggest that multiple Ab-Ag interactions contribute to IDF in individuals with lupus nephritis. Furthermore, these observations raise the possibility that the pathologic and clinical abnormalities resulting from these interactions are influenced by the location of IDF, and that the dominant interaction, in a given individual, may be highly influential in the phenotypic expression of nephritis.