Anti-Hinge Antibodies Recognize IgG Subclass- and Protease-Restricted Neoepitopes
Anti-Hinge Antibodies Recognize IgG Subclass- and Protease-Restricted Neoepitopes
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DOI：
10.4049/jimmunol.1601096
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发表时间：
2017-01-01
影响因子：
4.4
通讯作者：
Rispens, Theo
中科院分区：
文献类型：
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作者：
Falkenburg, Willem J. J.;van Schaardenburg, Dirkjan;Rispens, Theo
抗铰链Ab（AHA）靶向IgG的蛋白水解切割后暴露的新表位。在这项研究中，我们探讨了蛋白酶和IgG亚类限制性AHA的多样性和它们作为健康供体（HD）和类风湿关节炎（RA）或系统性红斑狼疮（SLE）患者的免疫学标记物的潜力。测定了AHA对所有四种人IgG亚类的化脓链球菌IgG降解酶（IdeS）或胃蛋白酶产生的F（ab '）（2）片段的反应性。在68%（68/100）的HD、69%（68/99）的SLE患者和81%（79/97）的RA患者中发现了针对八个F（ab '）（2）靶点中的一个或多个的AHA反应性。铰链表位的特异性识别依赖于IgG亚类和用于产生F（ab '）（2）靶标的蛋白酶，如用F（ab'）（2）片段和铰链肽的抑制实验所证实的。最常发现针对IdeS产生的F（ab '）（2）靶标的反应性，而针对胃蛋白酶产生的F（ab'）（2）靶标的反应性更好地区分RA和HD或SLE，针对IgG 1/3/4的AHA水平显著更高。相比之下，针对胃蛋白酶切割的IgG 2的AHA水平相当。未检测到针对IdeS产生的IgG 2-F（ab '）（2）s的反应性。RA中最具鉴别力的AHA反应性是针对胃蛋白酶切割的IgG 4，患病率为35%，比HD/SLE高≥ 5.8倍，且水平显著更高（p < 0.0001）。仅在具有同源F（ab '）（2）C末端的亚类（IgG 1/3/4）中观察到由不同IgG亚类产生的F（ab'）（2）的交叉反应性。对于IgG 2，确定了两个胃蛋白酶切割位点;抗铰链反应性仅限于其中之一。总之，AHA特异性识别IgG亚类和蛋白酶限制性铰链新表位。它们的蛋白酶限制的特异性表明，不同的AHA反应在不同的炎症或感染条件下发展，可能是这些过程的标志物和参与者。
Anti-hinge Abs (AHAs) target neoepitopes exposed after proteolytic cleavage of IgG. In this study, we explored the diversity of protease-and IgG subclass-restricted AHAs and their potential as immunological markers in healthy donors (HDs) and patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). AHA reactivity against IgG-degrading enzyme of Streptococcus pyogenes (IdeS)-or pepsin-generated F(ab')(2) fragments of all four human IgG subclasses was determined. AHA reactivity against one or more out of eight F(ab')(2) targets was found in 68% (68 of 100) of HDs, 69% (68 of 99) of SLE patients, and 81% (79 of 97) of RA patients. Specific recognition of hinge epitopes was dependent on IgG subclass and protease used to create the F(ab')(2) targets, as confirmed by inhibition experiments with F(ab')(2) fragments and hinge peptides. Reactivity against IdeS-generated F(ab')(2) targets was found most frequently, whereas reactivity against pepsin-generated F(ab')(2) targets better discriminated between RA and HDs or SLE, with significantly higher AHA levels against IgG1/3/4. In contrast, AHA levels against pepsin-cleaved IgG2 were comparable. No reactivity against IdeS-generated IgG2-F(ab')(2)s was detected. The most discriminatory AHA reactivity in RA was against pepsin-cleaved IgG4, with a 35% prevalence, >= 5.8-fold higher than in HDs/SLE, and significantly higher levels (p < 0.0001). Cross-reactivity for F(ab')(2)s generated from different IgG subclasses was only observed for subclasses having homologous F(ab') (2) C termini (IgG1/3/4). For IgG2, two pepsin cleavage sites were identified; anti-hinge reactivity was restricted to only one of these. In conclusion, AHAs specifically recognize IgG subclass-and protease-restricted hinge neoepitopes. Their protease-restricted specificity suggests that different AHA responses developed under distinct inflammatory or infectious conditions and may be markers of, and participants in, such processes.