Aterido Adrià, López-Lasanta María, Blanco Francisco, Juan-Mas Antonio, García-Vivar María Luz, Erra Alba, Pérez-García Carolina, Sánchez-Fernández Simón Ángel, Sanmartí Raimon, Fernández-Nebro Antonio, Alperi-López Mercedes, Tornero Jesús, Ortiz Ana María, Fernández-Cid Carlos Marras, Palau Núria, Pan Wenjing, Byrne-Steele Miranda, Starenki Dmytro, Weber Daniel, Rodriguez-Nunez Ivan, Han Jian, Myers Richard M, Marsal Sara, Julià Antonio
Rheumatology Research Group, Vall Hebron Research Institute, 08035, Barcelona, Spain.
Rheumatology Department, Hospital Juan Canalejo, A Coruña, Spain.
Genome Biol. 2024 Mar 11;25(1):68. doi: 10.1186/s13059-024-03210-0.
In rheumatoid arthritis (RA), the activation of T and B cell clones specific for self-antigens leads to the chronic inflammation of the synovium. Here, we perform an in-depth quantitative analysis of the seven chains that comprise the adaptive immune receptor repertoire (AIRR) in RA.
In comparison to controls, we show that RA patients have multiple and strong differences in the B cell receptor repertoire including reduced diversity as well as altered isotype, chain, and segment frequencies. We demonstrate that therapeutic tumor necrosis factor inhibition partially restores this alteration but find a profound difference in the underlying biochemical reactivities between responders and non-responders. Combining the AIRR with HLA typing, we identify the specific T cell receptor repertoire associated with disease risk variants. Integrating these features, we further develop a molecular classifier that shows the utility of the AIRR as a diagnostic tool.
Simultaneous sequencing of the seven chains of the human AIRR reveals novel features associated with the disease and clinically relevant phenotypes, including response to therapy. These findings show the unique potential of AIRR to address precision medicine in immune-related diseases.
在类风湿性关节炎（RA）中，针对自身抗原的T和B细胞克隆的激活会导致滑膜的慢性炎症。在此，我们对构成类风湿性关节炎适应性免疫受体库（AIRR）的七条链进行了深入的定量分析。
与对照组相比，我们发现类风湿性关节炎患者的B细胞受体库存在多重且显著的差异，包括多样性降低以及同种型、链和区段频率的改变。我们证明，治疗性肿瘤坏死因子抑制可部分恢复这种改变，但发现应答者和无应答者之间潜在的生化反应性存在深刻差异。将适应性免疫受体库（AIRR）与人类白细胞抗原（HLA）分型相结合，我们确定了与疾病风险变异相关的特定T细胞受体库。整合这些特征后，我们进一步开发了一种分子分类器，显示了适应性免疫受体库（AIRR）作为诊断工具的效用。
对人类适应性免疫受体库（AIRR）的七条链进行同步测序揭示了与疾病及临床相关表型（包括对治疗的反应）相关的新特征。这些发现显示了适应性免疫受体库（AIRR）在解决免疫相关疾病精准医学方面的独特潜力。
