Zhang Ying, Su Susan C, Hecox Douglas B, Brady Graham F, Mackin Katherine M, Clark Amy G, Foster Mary H
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
J Immunol. 2008 Nov 1;181(9):6092-100. doi: 10.4049/jimmunol.181.9.6092.
Patients and rodents with Goodpasture's syndrome (GPS) develop severe autoimmune crescentic glomerulonephritis, kidney failure, and lung hemorrhage due to binding of pathogenic autoantibodies to the NC1 domain of the alpha3 chain of type IV collagen. Target epitopes are cryptic, normally hidden from circulating Abs by protein-protein interactions and the highly tissue-restricted expression of the alpha3(IV) collagen chain. Based on this limited Ag exposure, it has been suggested that target epitopes are not available as B cell tolerogens. To determine how pathogenic anti-GPS autoantibody responses are regulated, we generated an Ig transgenic (Tg) mouse model that expresses an Ig that binds alpha3(IV)NC1 collagen epitopes recognized by serum IgG of patients with GPS. Phenotypic analysis reveals B cell depletion and L chain editing in Tg mice. To determine the default tolerance phenotype in the absence of receptor editing and endogenous lymphocyte populations, we crossed Tg mice two generations with mice deficient in Rag. Resulting Tg Rag-deficient mice have central B cell deletion. Thus, development of Tg anti-alpha3(IV)NC1 collagen B cells is halted in the bone marrow, at which point the cells are deleted unless rescued by a Rag enzyme-dependent process, such as editing. The central tolerance phenotype implies that tolerizing self-Ag is expressed in bone marrow.
患有古德帕斯彻综合征（GPS）的患者和啮齿动物会发展为严重的自身免疫性新月体性肾小球肾炎、肾衰竭和肺出血，这是由于致病性自身抗体与IV型胶原α3链的NC1结构域结合所致。靶抗原表位是隐蔽的，通常通过蛋白质-蛋白质相互作用以及α3（IV）胶原链高度组织限制性表达而对循环抗体隐藏。基于这种有限的抗原暴露，有人提出靶抗原表位不能作为B细胞耐受原。为了确定致病性抗GPS自身抗体反应是如何被调节的，我们构建了一种Ig转基因（Tg）小鼠模型，该模型表达一种能结合GPS患者血清IgG所识别的α3（IV）NC1胶原表位的Ig。表型分析揭示了Tg小鼠中的B细胞耗竭和轻链编辑。为了确定在没有受体编辑和内源性淋巴细胞群体的情况下的默认耐受表型，我们将Tg小鼠与Rag缺陷小鼠杂交了两代。产生的Tg Rag缺陷小鼠出现中枢B细胞缺失。因此，Tg抗α3（IV）NC1胶原B细胞的发育在骨髓中停止，此时细胞会被删除，除非通过Rag酶依赖性过程（如编辑）得以挽救。中枢耐受表型意味着骨髓中表达了耐受自身抗原。
