Oruc Zeliha, Oblet Christelle, Boumediene Ahmed, Druilhe Anne, Pascal Virginie, Le Rumeur Elisabeth, Cuvillier Armelle, El Hamel Chahrazed, Lecardeur Sandrine, Leanderson Tomas, Morelle Willy, Demengeot Jocelyne, Aldigier Jean-Claude, Cogné Michel
Limoges University Hospital Dupuytren, Centre National de la Recherche Scientifique, Limoges University, Limoges, France;
Genetics and Development Instittute, Rennes University, Centre National de la Recherche Scientifique, Rennes, France;
J Am Soc Nephrol. 2016 Sep;27(9):2748-61. doi: 10.1681/ASN.2015080911. Epub 2016 Jan 29.
IgA1 mesangial deposition is the hallmark of IgA nephropathy and Henoch-Schönlein purpura, the onset of which often follows infections. Deposited IgA has been reported as polymeric, J chain associated, and often, hypogalactosylated but with no information concerning the influence of the IgA repertoire or the link between immune stimuli and IgA structure. We explored these issues in the α1KI mouse model, which produces polyclonal human IgA1 prone to mesangial deposition. Compared with mice challenged by a conventional environment, mice in a specific pathogen-free environment had less IgA deposition. However, serum IgA of specific pathogen-free mice showed more galactosylation and much lower polymerization. Notably, wild-type, α1KI, and even J chain-deficient mice showed increased polymeric serum IgA on exposure to pathogens. Strict germfree conditions delayed but did not completely prevent deposition; mice housed in these conditions had very low serum IgA levels and produced essentially monomeric IgA. Finally, comparing monoclonal IgA1 that had different variable regions and mesangial deposition patterns indicated that, independently of glycosylation and polymerization, deposition might also depend on IgA carrying specific variable domains. Together with IgA quantities and constant region post-translational modifications, repertoire changes during immune responses might, thus, modulate IgA propensity to deposition. These IgA features are not associated with circulating immune complexes and C3 deposition and are more pertinent to an initial IgA deposition step preceding overt clinical symptoms in patients.
IgA1系膜沉积是IgA肾病和过敏性紫癜的标志，其发病常继发于感染后。据报道，沉积的IgA为多聚体，与J链相关，且通常为低半乳糖基化，但关于IgA库的影响或免疫刺激与IgA结构之间的联系尚无相关信息。我们在α1KI小鼠模型中探讨了这些问题，该模型产生易于系膜沉积的多克隆人IgA1。与处于常规环境中的小鼠相比，处于无特定病原体环境中的小鼠IgA沉积较少。然而，无特定病原体小鼠的血清IgA显示出更多的半乳糖基化且聚合程度低得多。值得注意的是，野生型、α1KI甚至J链缺陷型小鼠在接触病原体后血清多聚IgA均增加。严格的无菌条件会延迟但不能完全阻止沉积；饲养在这些条件下的小鼠血清IgA水平非常低，且基本产生单体IgA。最后，比较具有不同可变区和系膜沉积模式的单克隆IgA1表明，独立于糖基化和聚合作用，沉积可能还取决于携带特定可变结构域的IgA。因此，与IgA数量和恒定区翻译后修饰一起，免疫反应期间库的变化可能会调节IgA的沉积倾向。这些IgA特征与循环免疫复合物和C3沉积无关，并且与患者明显临床症状之前的初始IgA沉积步骤更相关。
