Recognition of Amino Acid Motifs, Rather Than Specific Proteins, by Human Plasma Cell-Derived Monoclonal Antibodies to Posttranslationally Modified Proteins in Rheumatoid Arthritis.
Recognition of Amino Acid Motifs, Rather Than Specific Proteins, by Human Plasma Cell-Derived Monoclonal Antibodies to Posttranslationally Modified Proteins in Rheumatoid Arthritis.
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DOI：
10.1002/art.40699
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Malmström V
中科院分区：
文献类型：
--
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
针对翻译后修饰蛋白的抗体是类风湿性关节炎 (RA) 的标志，但这些自身抗体的出现和致病性仍不完全清楚。本研究的目的是分析源自 RA 滑膜浆细胞的单克隆抗体 (mAb) 的抗原特异性和突变模式，并解决抗原交叉反应性问题。从 RA 滑液中分离出 IgG 分泌细胞，并对免疫球蛋白的可变区进行测序 (n = 182) 并以全长 mAb (n = 93) 和种系恢复版本表达。研究了 mAb 与 53,019 种瓜氨酸肽和 49,211 种氨甲酰化肽的反应模式以及促进破骨细胞生成的潜力。鉴定出四种不相关的抗瓜氨酸蛋白自身抗体（ACPA），其中一种是克隆扩增的，并发现在 RA 患者的滑液中存在高度体细胞突变。 ACPA 识别出超过 3,000 种经过瓜氨酸化或氨甲酰化修饰的独特肽。这种高度多反应性自身抗体特征在其他 RA 患者外周血 B 细胞衍生的 Ig 序列中得到了复制。浆细胞衍生的单克隆抗体被发现能够靶向不同的氨基酸基序和部分重叠的蛋白质靶点。正如破骨细胞激活测定中所揭示的那样，它们还传达了不同的效应器功能。这些发现表明，RA 自身反应性 B 细胞之间的高水平交叉反应性是不同抗原相遇的结果，可能是在不同部位和不同时间点。这与 RA 在一种情况下（例如在粘膜器官中）启动，然后针对其他部位（例如关节）的概念是一致的。
Antibodies against posttranslationally modified proteins are a hallmark of rheumatoid arthritis (RA), but the emergence and pathogenicity of these autoantibodies are still incompletely understood. The aim of this study was to analyze the antigen specificities and mutation patterns of monoclonal antibodies (mAb) derived from RA synovial plasma cells and address the question of antigen cross‐reactivity. IgG‐secreting cells were isolated from RA synovial fluid, and the variable regions of the immunoglobulins were sequenced (n = 182) and expressed in full‐length mAb (n = 93) and also as germline‐reverted versions. The patterns of reactivity with 53,019 citrullinated peptides and 49,211 carbamylated peptides and the potential of the mAb to promote osteoclastogenesis were investigated. Four unrelated anti–citrullinated protein autoantibodies (ACPAs), of which one was clonally expanded, were identified and found to be highly somatically mutated in the synovial fluid of a patient with RA. The ACPAs recognized >3,000 unique peptides modified by either citrullination or carbamylation. This highly multireactive autoantibody feature was replicated for Ig sequences derived from B cells from the peripheral blood of other RA patients. The plasma cell–derived mAb were found to target distinct amino acid motifs and partially overlapping protein targets. They also conveyed different effector functions as revealed in an osteoclast activation assay. These findings suggest that the high level of cross‐reactivity among RA autoreactive B cells is the result of different antigen encounters, possibly at different sites and at different time points. This is consistent with the notion that RA is initiated in one context, such as in the mucosal organs, and thereafter targets other sites, such as the joints.
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影响因子：
5.3
作者：
Clargo, Alison M.;Hudson, Ashley R.;Lightwood, Daniel J.
通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
Venables, Patrick J
影响因子：
4.9
作者：
Hansson M;Mathsson L;Schlederer T;Israelsson L;Matsson P;Nogueira L;Jakobsson PJ;Lundberg K;Malmström V;Serre G;Holmdahl R;Nystrand M;Klareskog L;Rönnelid J
通讯作者：
Rönnelid J
DOI：
10.1084/jem.20121486
发表时间：
2013-03-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Amara K;Steen J;Murray F;Morbach H;Fernandez-Rodriguez BM;Joshua V;Engström M;Snir O;Israelsson L;Catrina AI;Wardemann H;Corti D;Meffre E;Klareskog L;Malmström V
通讯作者：
Malmström V