Data Sheet 1_High throughput profiling of the B cell repertoire identifies systematic changes in the repertoire of individuals with Crohn’s disease.pdf

The B cell repertoire contains the recombined sequences that encode the entire antibody repertoire of an individual. The repertoire is made from three antigenic binding chains, namely the immunoglobulin heavy chain (IGH) and two immunoglobulin light chains, κ (IGK) and λ (IGL). Compared to the T cell repertoire, the B cell repertoire is understudied in inflammatory bowel diseases (IBD) even though different antibodies such as ASCA (Anti-Saccharomyces cerevisiae) and ANCA (Anti-Neutrophil Cytoplasmic Antibodies) have been shown to be elevated in individuals with IBD. To address this limitation, we profiled the B cell repertoire of peripheral blood from 27 treatment-naive individuals with CD and 21 age-matched symptomatic controls using bulk B cell receptor sequencing. The repertoire of individuals with CD showed a reduction in diversity and an increase in clonality. Furthermore, we observed a significant reduction in the expansion of IgM and IgD and an expansion of IgA2, and IgG2 clonotypes in individuals with CD relative to controls, suggesting an antigen-driven expansion. This was also supported by higher levels of somatic hypermutations, particularly in the complementary determining region 2 (CDR2) of immunoglobulin heavy chain, in individuals with CD relative to the control group. Thus, despite the small sample size, we identified multiple alterations in the B cell repertoire of individuals with CD, highlighting the potential of the B cell repertoire in identifying antigenic exposures implicated in the disease, demanding now larger international studies, ideally including also treatment-naive and pre-clinical cases.

B细胞库（B cell repertoire）包含编码个体完整抗体库的重排序列。该库由三条抗原结合链构成，即免疫球蛋白重链（immunoglobulin heavy chain, IGH）以及两条免疫球蛋白轻链——κ型（IGK）与λ型（IGL）。相较于T细胞库（T cell repertoire），尽管炎症性肠病（inflammatory bowel diseases, IBD）患者体内的多种抗体（如抗酿酒酵母抗体ASCA与抗中性粒细胞胞浆抗体ANCA）已被证实水平升高，但学界针对IBD患者B细胞库的研究仍较为匮乏。为弥补这一研究局限，本研究采用批量B细胞受体测序（bulk B cell receptor sequencing）技术，对27名初治（treatment-naive）克罗恩病（Crohn's disease, CD）患者及21名年龄匹配的有症状对照个体的外周血B细胞库进行了测序分析。克罗恩病患者的B细胞库表现出多样性降低与克隆性升高的特征。此外，相较于对照组，克罗恩病患者体内IgM与IgD克隆型的扩增显著减少，而IgA2及IgG2克隆型的扩增则有所增加，这提示存在抗原驱动的克隆扩增现象。这一结果同样得到了体细胞高频突变（somatic hypermutations）水平数据的支持——相较于对照组，克罗恩病患者的体细胞高频突变水平更高，尤其是在免疫球蛋白重链的互补决定区2（complementary determining region 2, CDR2）中。综上，尽管本研究样本量较小，但我们仍鉴定出克罗恩病患者B细胞库存在多处异常改变，这凸显了B细胞库在识别与疾病相关的抗原暴露方面的应用潜力，同时也呼吁未来开展更大规模的国际研究，理想情况下应纳入初治患者及临床前病例。