Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis.
Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis.
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DOI：
10.1084/jem.20200513
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发表时间：
2020-12-07
期刊：
影响因子：
--
通讯作者：
O'Connor KC
中科院分区：
文献类型：
--
作者：
Fichtner ML;Vieni C;Redler RL;Kolich L;Jiang R;Takata K;Stathopoulos P;Suarez PA;Nowak RJ;Burden SJ;Ekiert DC;O'Connor KC
自身免疫性重症肌无力中的IgG4自身抗体在功能上是单价的，需要高亲和力阈值以达到致病能力。这种能力依赖于自身抗原驱动的成熟，其包括可能改变与抗原的静电相互作用的不可缺少的体细胞突变的积累。自身免疫性重症肌无力（MG）中的致病性肌肉特异性酪氨酸激酶（MuSK）特异性IgG4自身抗体由于Fab臂交换而在功能上是单价的。这些独特的自身抗体的发展还没有得到很好的理解。我们研究了MG患者来源的单克隆自身抗体（mAb），其相应的种系编码的未突变的共同祖先（UCA），和单价抗原结合片段（Fab），以研究亲和力成熟如何有助于结合和免疫病理学。成熟的mAb、UCA mAb和成熟的单价Fab与MuSK结合并显示出致病能力。然而，单价UCA Fab与MuSK结合，但不具有可测量的致病能力。UCA Fab对MuSK的亲和力比成熟Fab的亚纳摩尔亲和力低100倍。两个Fab的晶体结构揭示了亲和力成熟期间获得的突变如何有助于增加MuSK结合亲和力。这些发现表明，自身抗原通过体细胞突变的积累驱动MuSK MG中的自身免疫，使得单价IgG4 Fab臂交换的自身抗体达到致病能力所需的高亲和力阈值。
IgG4 autoantibodies in autoimmune myasthenia gravis are functionally monovalent, requiring a high-affinity threshold to reach pathogenic capacity. This capacity is dependent on self-antigen driven maturation, which includes the accumulation of indispensable somatic mutations that may alter electrostatic interactions with the antigen. Pathogenic muscle-specific tyrosine kinase (MuSK)–specific IgG4 autoantibodies in autoimmune myasthenia gravis (MG) are functionally monovalent as a result of Fab-arm exchange. The development of these unique autoantibodies is not well understood. We examined MG patient–derived monoclonal autoantibodies (mAbs), their corresponding germline-encoded unmutated common ancestors (UCAs), and monovalent antigen-binding fragments (Fabs) to investigate how affinity maturation contributes to binding and immunopathology. Mature mAbs, UCA mAbs, and mature monovalent Fabs bound to MuSK and demonstrated pathogenic capacity. However, monovalent UCA Fabs bound to MuSK but did not have measurable pathogenic capacity. Affinity of the UCA Fabs for MuSK was 100-fold lower than the subnanomolar affinity of the mature Fabs. Crystal structures of two Fabs revealed how mutations acquired during affinity maturation may contribute to increased MuSK-binding affinity. These findings indicate that the autoantigen drives autoimmunity in MuSK MG through the accumulation of somatic mutations such that monovalent IgG4 Fab-arm–exchanged autoantibodies reach a high-affinity threshold required for pathogenic capacity.
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影响因子：
11.2
作者：
Bennett, Jeffrey L.;Lam, Chiwah;Kalluri, Sudhakar Reddy;Saikali, Philippe;Bautista, Katherine;Dupree, Cecily;Glogowska, Magdalena;Case, David;Antel, Jack P.;Owens, Gregory P.;Gilden, Don;Nessler, Stefan;Stadelmann, Christine;Hemmer, Bernhard
通讯作者：
Hemmer, Bernhard
影响因子：
82.9
作者：
Hoch, W;McConville, J;Vincent, A
通讯作者：
Vincent, A
DOI：
10.1212/nxi.0000000000000547
发表时间：
2019-05-01
影响因子：
8.8
作者：
Huijbers, Maartje G.;Vergoossen, Dana L.;Verschuuren, Jan J.
通讯作者：
Verschuuren, Jan J.
影响因子：
5.3
作者：
Lee JY;Stathopoulos P;Gupta S;Bannock JM;Barohn RJ;Cotzomi E;Dimachkie MM;Jacobson L;Lee CS;Morbach H;Querol L;Shan JL;Vander Heiden JA;Waters P;Vincent A;Nowak RJ;O'Connor KC
通讯作者：
O'Connor KC
DOI：
10.1107/s2059798318006551
发表时间：
2018-06-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Poon BK;Read RJ;Sobolev OV;Terwilliger TC;Urzhumtsev A;Adams PD
通讯作者：
Adams PD