Proteolysis breaks tolerance toward intact α345(IV) collagen, eliciting novel anti-glomerular basement membrane autoantibodies specific for α345NC1 hexamers.
Proteolysis breaks tolerance toward intact α345(IV) collagen, eliciting novel anti-glomerular basement membrane autoantibodies specific for α345NC1 hexamers.
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DOI：
10.4049/jimmunol.1202204
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发表时间：
2013-02-15
期刊：
影响因子：
--
通讯作者：
Borza DB
中科院分区：
文献类型：
--
作者：
Olaru F;Wang XP;Luo W;Ge L;Miner JH;Kleinau S;Geiger XJ;Wasiluk A;Heidet L;Kitching AR;Borza DB
Goodpasture病是一种自身免疫性肾脏疾病，由抗α3（IV）胶原NC 1单体的自身抗体介导，该单体与肾小球基底膜（GBM）结合，通常引起快速进行性肾小球肾炎。我们鉴定了一种与轻度非进行性肾小球肾炎相关的新型人IgG 4限制性抗GBM autoAb，其特异性靶向α 345 NC 1六聚体，而非α 3 NC 1单体。在重现该表型的小鼠模型中研究了引发这些抗GBM autoAb的机制。用自体鼠GBM NC 1六聚体免疫的野生型和FcγRIIB−/−小鼠产生了对α 345 NC 1六聚体具有特异性的小鼠IgG 1限制性autoAb，其在体内与GBM结合，但不会引起肾小球肾炎。在这些小鼠中，来自鼠GBM的完整胶原IV没有免疫原性。然而，在Col 4a 3 −/− Alport小鼠中，来自鼠GBM的完整IV型胶原和NC 1六聚体均引发特异性针对α3α4α 5 NC 1六聚体的IgG抗体，其不受亚类限制。作为COL 4A 3人源化小鼠中的异源性抗原，鼠GBM NC 1六聚体引发了对α 345 NC 1六聚体具有特异性的小鼠IgG 1、IgG 2a和IgG 2b autoAb，并诱导了抗GBM Ab肾小球肾炎。这些发现表明，在表达该抗原的宿主中建立了对自体完整α3α4α5（IV）胶原的耐受性，即使对α 345 NC 1六聚体具有特异性的自身反应性B细胞未从其库中清除。蛋白水解通过产生自身免疫原性α3α4α 5 NC 1六聚体选择性地破坏这种耐受性。这提供了一种引发α 345 NC 1六聚体特异性自身抗体的机制，其仅限于非炎性IgG亚类和非致肾炎性。在Alport综合征中，对α3α4α5（IV）胶原缺乏耐受性促进了α 345 NC 1六聚体的同种抗体产生，包括介导移植后抗GBM肾炎的促炎性IgG亚类。
Goodpasture disease is an autoimmune kidney disease mediated by autoAbs against NC1 monomers of α3(IV) collagen that bind to the glomerular basement membrane (GBM), usually causing rapidly progressive glomerulonephritis. We identified a novel type of human IgG4-restricted anti-GBM autoAbs associated with mild non-progressive glomerulonephritis, which specifically targeted α345NC1 hexamers but not α3NC1 monomers. The mechanisms eliciting these anti-GBM autoAbs were investigated in mouse models recapitulating this phenotype. Wild type and FcγRIIB−/− mice immunized with autologous murine GBM NC1 hexamers produced mouse IgG1-restricted autoAbs specific for α345NC1 hexamers, which bound to the GBM in vivo but did not cause glomerulonephritis. In these mice, intact collagen IV from murine GBM was not immunogenic. However, in Col4a3−/− Alport mice, both intact collagen IV and NC1 hexamers from murine GBM elicited IgG antibodies specific for α3α4α5NC1 hexamers, which were not subclass restricted. As heterologous antigen in COL4A3-humanized mice, murine GBM NC1 hexamers elicited mouse IgG1, IgG2a and IgG2b autoAbs specific for α345NC1 hexamers and induced anti-GBM Ab glomerulonephritis. These findings indicate that tolerance toward autologous intact α3α4α5(IV) collagen is established in hosts expressing this antigen, even though autoreactive B cells specific for α345NC1 hexamers are not purged from their repertoire. Proteolysis selectively breaches this tolerance by generating autoimmunogenic α3α4α5NC1 hexamers. This provides a mechanism eliciting autoAbs specific for α345NC1 hexamers, which are restricted to non-inflammatory IgG subclasses and non-nephritogenic. In Alport syndrome, lack of tolerance toward α3α4α5(IV) collagen promotes production of alloantibodies to α345NC1 hexamers, including pro-inflammatory IgG subclasses which mediate post-transplant anti-GBM nephritis.
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影响因子：
19.6
作者：
Brainwood, D;Kashtan, C;Turner, AN
通讯作者：
Turner, AN
影响因子：
4.8
作者：
Hopfer, H;Maron, R;Kalluri, R
通讯作者：
Kalluri, R
影响因子：
7
作者：
Doyle HA;Mamula MJ
通讯作者：
Mamula MJ
DOI：
10.4049/jimmunol.1001152
发表时间：
2010-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Luo W;Wang XP;Kashtan CE;Borza DB
通讯作者：
Borza DB
影响因子：
56.9
作者：
Kolfschoten, Marijn van der Neut;Schuurman, Janine;Parren, Paul W. H. I.
通讯作者：
Parren, Paul W. H. I.