Evolution of anti-modified protein antibody responses can be driven by consecutive exposure to different post-translational modifications.
Evolution of anti-modified protein antibody responses can be driven by consecutive exposure to different post-translational modifications.
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DOI：
10.1186/s13075-021-02687-5
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发表时间：
2021-12-08
影响因子：
4.9
通讯作者：
van der Woude D
中科院分区：
文献类型：
--
作者：
Volkov M;Kampstra ASB;van Schie KA;Kawakami A;Tamai M;Kawashiri S;Maeda T;Huizinga TWJ;Toes REM;van der Woude D
除了抗瓜氨酸蛋白抗体(ACPA)外，类风湿关节炎患者(RA)通常对其他翻译后修饰(PTM)蛋白表现出自身抗体反应，更具体地说是氨甲酰化和乙酰化蛋白。用一种特定的PTM免疫小鼠，会产生识别不同PTM抗原的抗修饰蛋白抗体(AMPA)反应。此外，根据对一种PTM的反应性而分离的人AMPA与其他PTM发生交叉反应。然而，目前尚不清楚AMPA反应性曲线是否在时间上是固定的，或者连续暴露于不同的PTM是否可以塑造对特定PTM的不断演变的AMPA反应。对8例RA高危人群和5例早期RA患者的纵向采集的血清标本进行了酶联免疫吸附试验，并进行了滴度分析，以探讨AMPA应答随时间的演变。用乙酰化(或氨基甲酰化)蛋白(卵清蛋白)免疫小鼠(每组13只)两次，或用乙酰化蛋白和氨甲酰化蛋白(或反之亦然)交叉免疫，分析它们的血清AMPA反应。人类数据显示了类风湿性关节炎高危个体和早期类风湿性关节炎患者AMPA反应性的动态变化。单独用乙酰化或氨基甲酰化的卵清蛋白(Acova或CaOVA)免疫的小鼠对乙酰化和氨基甲酰化的抗原都有反应性。无论第一次免疫使用的是PTM抗原，用携带另一种PTM的抗原进行加强免疫会导致第二次/加强免疫PTM的滴度增加。此外，交叉免疫使整个AMPA反应谱向相对较高的反应性倾斜，以对抗“助推器”PTM。AMPA反应中不同反应性之间的关系是动态的。最初接触一种PTM抗原会引起交叉反应，这种交叉反应可以被带有这种或其他PTM的抗原增强，这表明交叉反应免疫记忆的形成。在随后暴露于携带另一种类型的PTM的抗原时，总体反应模式可能偏向于更好地识别后来遇到的PTM。这些数据可能解释了AMPA反应谱的时间差异，并指出负责启动AMPA反应的PTM可能与后来主要识别的PTM不同。网上版载有补充材料，可在10.1186/s13075-021-02687-5查阅。
Besides anti-citrullinated protein antibodies (ACPA), rheumatoid arthritis patients (RA) often display autoantibody reactivities against other post-translationally modified (PTM) proteins, more specifically carbamylated and acetylated proteins. Immunizing mice with one particular PTM results in an anti-modified protein antibody (AMPA) response recognizing different PTM-antigens. Furthermore, human AMPA, isolated based on their reactivity to one PTM, cross-react with other PTMs. However, it is unclear whether the AMPA-reactivity profile is “fixed” in time or whether consecutive exposure to different PTMs can shape the evolving AMPA response towards a particular PTM. Longitudinally collected serum samples of 8 human individuals at risk of RA and 5 with early RA were tested with ELISA, and titers were analyzed to investigate the evolution of the AMPA responses over time. Mice (13 per immunization group in total) were immunized with acetylated (or carbamylated) protein (ovalbumin) twice or cross-immunized with an acetylated and then a carbamylated protein (or vice versa) and their serum was analyzed for AMPA responses. Human data illustrated dynamic changes in AMPA-reactivity profiles in both individuals at risk of RA and in early RA patients. Mice immunized with either solely acetylated or carbamylated ovalbumin (AcOVA or CaOVA) developed reactivity against both acetylated and carbamylated antigens. Irrespective of the PTM-antigen used for the first immunization, a booster immunization with an antigen bearing the other PTM resulted in increased titers to the second/booster PTM. Furthermore, cross-immunization skewed the overall AMPA-response profile towards a relatively higher reactivity against the “booster” PTM. The relationship between different reactivities within the AMPA response is dynamic. The initial exposure to a PTM-antigen induces cross-reactive responses that can be boosted by an antigen bearing this or other PTMs, indicating the formation of cross-reactive immunological memory. Upon subsequent exposure to an antigen bearing another type of PTM, the overall reactivity pattern can be skewed towards better recognition of the later encountered PTM. These data might explain temporal differences in the AMPA-response profile and point to the possibility that the PTM responsible for the initiation of the AMPA response may differ from the PTM predominantly recognized later in time. The online version contains supplementary material available at 10.1186/s13075-021-02687-5.
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影响因子：
4.9
作者：
Brink M;Verheul MK;Rönnelid J;Berglin E;Holmdahl R;Toes RE;Klareskog L;Trouw LA;Rantapää-Dahlqvist S
通讯作者：
Rantapää-Dahlqvist S
影响因子：
4.6
作者：
Pieterse, E.;Hofstra, J.;van der Vlag, J.
通讯作者：
van der Vlag, J.
影响因子：
6.2
作者：
Jansen, Diahann T. S. L.;Emery, Paul;Huizinga, Tom W. J.
通讯作者：
Huizinga, Tom W. J.
影响因子：
4.9
作者：
de Moel EC;Derksen VFAM;Stoeken G;Trouw LA;Bang H;Goekoop RJ;Speyer I;Huizinga TWJ;Allaart CF;Toes REM;van der Woude D
通讯作者：
van der Woude D
影响因子：
27.4
作者：
Kampstra, Arieke Suzanna Berendina;Dekkers, Jacqueline Stephanie;Toes, Rene E. M.
通讯作者：
Toes, Rene E. M.