Cross-reactivity of IgM anti-modified protein antibodies in rheumatoid arthritis despite limited mutational load.
Cross-reactivity of IgM anti-modified protein antibodies in rheumatoid arthritis despite limited mutational load.
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尽管突变负荷有限，但IgM抗修饰蛋白抗体的交叉反应性。
DOI：
10.1186/s13075-021-02609-5
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发表时间：
2021-09-03
影响因子：
4.9
通讯作者：
Toes REM
中科院分区：
文献类型：
--
作者：
Reijm S;Kissel T;Stoeken-Rijsbergen G;Slot LM;Wortel CM;van Dooren HJ;Levarht NEW;Kampstra ASB;Derksen VFAM;Heer PO;Bang H;Drijfhout JW;Trouw LA;Huizinga TWJ;Rispens T;Scherer HU;Toes REM
针对瓜氨酸化、乙酰化和/或氨甲酰化自身抗原的抗修饰蛋白抗体（AMPA）是类风湿性关节炎（RA）的标志。虽然AMPA-IgG对多种翻译后修饰（PTM）的交叉反应性是明显的，但尚不清楚表达IgM的第一个应答B细胞是否显示出相似的特征，或者交叉反应性是否关键地依赖于体细胞超突变（SHM）。我们现在研究了（种系）AMPA-IgM的反应性，以进一步了解B细胞耐受性的破坏，并确定交叉反应性是否依赖于广泛的SHM。此外，我们研究了AMPA-IgM是否可以有效地招募免疫效应机制。从RA患者中分离多克隆AMPA-IgM，并评估对PTM抗原的交叉反应性。AMPA-IgM B细胞受体序列通过使用抗原特异性四聚体的单细胞分离获得。随后，产生五聚体单克隆AMPA-IgM、其种系对应物和单体IgG变体。在一组PTM抗原上分析抗体并测试补体激活。五聚体单克隆和多克隆AMPA-IgM显示出对多种抗原和不同PTM的交叉反应性。PTM抗原识别仍然存在，虽然减少后，恢复IgM到种系。AMPA-IgM的效价对于抗原识别至关重要，因为当AMPA-IgM表达为IgG时，PTM反应性显著降低。此外，AMPA-IgM在补体激活方面的效力是AMPA-IgG的15至30倍。我们提供了AMPA-IgM对不同PTM具有交叉反应性的第一个证据，表明PTM（交叉）反应性不限于IgG，也不一定依赖于广泛的体细胞超突变。此外，我们的数据表明，一组不同的PTM抗原可能参与RA的初始耐受破坏，并表明AMPA-IgM可以诱导补体激活，从而炎症。在线版本包含补充材料，可通过10.1186/s13075-021-02609-5获得。
Anti-modified protein antibodies (AMPA) targeting citrullinated, acetylated and/or carbamylated self-antigens are hallmarks of rheumatoid arthritis (RA). Although AMPA-IgG cross-reactivity to multiple post-translational modifications (PTMs) is evident, it is unknown whether the first responding B cells, expressing IgM, display similar characteristics or if cross-reactivity is crucially dependent on somatic hypermutation (SHM). We now studied the reactivity of (germline) AMPA-IgM to further understand the breach of B cell tolerance and to identify if cross-reactivity depends on extensive SHM. Moreover, we investigated whether AMPA-IgM can efficiently recruit immune effector mechanisms. Polyclonal AMPA-IgM were isolated from RA patients and assessed for cross-reactivity towards PTM antigens. AMPA-IgM B cell receptor sequences were obtained by single cell isolation using antigen-specific tetramers. Subsequently, pentameric monoclonal AMPA-IgM, their germline counterparts and monomeric IgG variants were generated. The antibodies were analysed on a panel of PTM antigens and tested for complement activation. Pentameric monoclonal and polyclonal AMPA-IgM displayed cross-reactivity to multiple antigens and different PTMs. PTM antigen recognition was still present, although reduced, after reverting the IgM into germline. Valency of AMPA-IgM was crucial for antigen recognition as PTM-reactivity significantly decreased when AMPA-IgM were expressed as IgG. Furthermore, AMPA-IgM was 15- to 30-fold more potent in complement-activation compared to AMPA-IgG. We provide first evidence that AMPA-IgM are cross-reactive towards different PTMs, indicating that PTM (cross-)reactivity is not confined to IgG and does not necessarily depend on extensive somatic hypermutation. Moreover, our data indicate that a diverse set of PTM antigens could be involved in the initial tolerance breach in RA and suggest that AMPA-IgM can induce complement-activation and thereby inflammation. The online version contains supplementary material available at 10.1186/s13075-021-02609-5.
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影响因子：
64.8
作者：
Gaebler C;Wang Z;Lorenzi JCC;Muecksch F;Finkin S;Tokuyama M;Cho A;Jankovic M;Schaefer-Babajew D;Oliveira TY;Cipolla M;Viant C;Barnes CO;Bram Y;Breton G;Hägglöf T;Mendoza P;Hurley A;Turroja M;Gordon K;Millard KG;Ramos V;Schmidt F;Weisblum Y;Jha D;Tankelevich M;Martinez-Delgado G;Yee J;Patel R;Dizon J;Unson-O'Brien C;Shimeliovich I;Robbiani DF;Zhao Z;Gazumyan A;Schwartz RE;Hatziioannou T;Bjorkman PJ;Mehandru S;Bieniasz PD;Caskey M;Nussenzweig MC
通讯作者：
Nussenzweig MC
影响因子：
27.4
作者：
Figueiredo, Camille P.;Bang, Holger;Schett, Georg
通讯作者：
Schett, Georg
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.
DOI：
10.1002/art.40699
发表时间：
2019-03
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
--
作者：
Steen J;Forsström B;Sahlström P;Odowd V;Israelsson L;Krishnamurthy A;Badreh S;Mathsson Alm L;Compson J;Ramsköld D;Ndlovu W;Rapecki S;Hansson M;Titcombe PJ;Bang H;Mueller DL;Catrina AI;Grönwall C;Skriner K;Nilsson P;Lightwood D;Klareskog L;Malmström V
通讯作者：
Malmström V
影响因子：
16.6
作者：
Piccoli, Luca;Campo, Ilaria;Fregni, Chiara Silacci;Rodriguez, Blanca Maria Fernandez;Minola, Andrea;Sallusto, Federica;Luisetti, Maurizio;Corti, Davide;Lanzavecchia, Antonio
通讯作者：
Lanzavecchia, Antonio