The importance of cell-mediated immunity in the course and severity of autoimmune anti-glomerular basement membrane disease in mice
The importance of cell-mediated immunity in the course and severity of autoimmune anti-glomerular basement membrane disease in mice
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DOI：
10.1096/fj.02-0746com
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发表时间：
2003-05-01
期刊：
影响因子：
4.8
通讯作者：
Kalluri, R
中科院分区：
文献类型：
--
作者：
Hopfer, H;Maron, R;Kalluri, R
抗肾小球基底膜(GBM)病是一种快速进行性的肾小球肾炎(GN)，由抗Good及ure抗原Alpha3(IV)Nc1的自身免疫引起。除了抗体的特性外，T辅助细胞1(Th1)反应被怀疑是肾小球损伤的罪魁祸首。我们用重组人α3(IV)NC1诱导DBA/1、C57BL/6、AKR和NOD小鼠产生抗GBM病，以探讨体液和细胞自身免疫的作用。DBA/1小鼠在α3(IV)NC1免疫后11wk出现新月体GN。C57BL/6和AKR小鼠在6个月内出现慢性病程，导致与DBA/1小鼠相似的肾脏损伤。NOD仅显示肾小球轻微改变。我们在DBA/1小鼠血清和脾细胞中的免疫学发现可以解释疾病的快速病程和严重程度：1)高滴度的针对可能与临床相关的Th1型同型α3(IV)NC1表位的抗体滴度；2)强烈的增殖反应和高水平的炎性细胞因子干扰素-γ，由Alpha3(IV)NC1体外刺激的脾细胞分泌，只有少量的抗炎细胞因子IL-10。我们的体内和体外结果提供了直接证据，表明Th1/Th2反应之间的平衡与小鼠抗GBM疾病的结局有关。
Anti-glomerular basement membrane (GBM) disease is a rapidly progressive glomerulonephritis (GN) resulting from autoimmunity against the Goodpasture antigen alpha3(IV)NC1. In addition to the well-characterized antibody contribution, a T helper 1 (Th1) response has been suspected as the culprit for glomerular injury. We induced anti-GBM disease in DBA/1, C57BL/6, AKR, and NOD mice with recombinant human alpha3(IV) NC1 to investigate the involvement of humoral and cellular autoimmunity. DBA/1 mice had crescentic GN 11 wk postimmunization with alpha3(IV)NC1. C57BL/6 and AKR mice developed a chronic disease course resulting in comparable kidney injury to DBA/1 mice within 6 months. NOD revealed only minor glomerular changes. The rapid course and the severity of the disease in DBA/1 mice can be explained by our immunological findings in their sera and splenocytes: 1) high antibody titers specific for the putative clinically relevant epitope of alpha3(IV)NC1 with Th1-type isotypes, and 2) a strong proliferative response and high amounts of the inflammatory cytokine IFN-gamma, secreted by splenocytes stimulated in vitro with alpha3(IV)NC1, with only low amounts of the anti-inflammatory cytokine IL-10. Our in vivo and in vitro results provide direct evidence that the balance between Th1 and Th2 responses associates with the outcome of anti-GBM disease in mice.