Diverse patterns of antibody variable gene repertoire disruption in patients with AL amyloidosis

Immunoglobulin light chain amyloidosis is the most common form of systemic amyloidosis. AL amyloidosis is caused by a misfolded light chain produced by a clonal population of plasma cells. Disease status currently is defined by measuring the absolute quantity of serum free light chain protein, but this measurement often fails to identify the subclinical presence of clonal cells that may merit additional therapy. Next generation sequencing has the sensitivity to measure the relative amount of dominating light chains within the repertoire of a patient, and this technique is in clinical use to identify clonal populations of plasma cells for multiple myeloma, a related disorder. In this proof-of-concept study, we used reverse transcription of the antibody transcriptome followed by next generation sequencing to identify antibody variable-diversity-joining gene sequences for patients with immunoglobulin light chain amyloidosis, and demonstrate that this technology can be used to identify the dominant clone. The data also reveal differing patterns of overall antibody repertoire disruption in different patients. This method merits further study in larger prospective studies to establish its utility in detecting residual disease for patients with immunoglobulin light chain amyloidosis.

免疫球蛋白轻链淀粉样变性（immunoglobulin light chain amyloidosis）是最常见的系统性淀粉样变性类型。AL型淀粉样变性（AL amyloidosis）由克隆性浆细胞群产生的错误折叠轻链所诱发。当前临床主要通过检测血清游离轻链蛋白（serum free light chain protein）的绝对含量来判定疾病状态，但该检测手段往往无法识别可能需要额外治疗的克隆细胞亚临床存在状态。下一代测序（next generation sequencing）具备检测患者抗体库内优势轻链相对占比的灵敏度，且该技术已应用于临床，用于识别多发性骨髓瘤（multiple myeloma，一种相关疾病）中的克隆性浆细胞群。在本概念验证研究（proof-of-concept study）中，我们通过对抗体转录组（antibody transcriptome）进行逆转录后开展下一代测序，对免疫球蛋白轻链淀粉样变性患者的抗体可变-多变-连接基因序列（variable-diversity-joining gene sequences）进行鉴定，并证实该技术可用于识别优势克隆。本研究数据还揭示了不同患者之间整体抗体库紊乱模式的差异。该方法值得在更大规模的前瞻性研究中进一步探索，以确立其在免疫球蛋白轻链淀粉样变性患者残留病检测中的应用价值。