淋巴瘤引起的突变促进致病性自身产生抗体_淋巴瘤

人类自身致病性抗体的进化过程中存在淋巴瘤引起的突变，这一成果由澳大利亚加文医学研究所Joanne H. Reed和Christopher C. Goodnow研究组合作取得。 2020年2月13日，国际学术期刊《细胞》在线发表了这一成果。

利用单细胞多组学分析，研究人员发现淋巴样恶性肿瘤与由常见类风湿因子自身抗体引起的混合型冷球蛋白血症的共享机制。通过将单细胞DNA和RNA测序与血清抗体肽测序和抗体合成相结合，研究人员发现产生积累突变的克隆树是由产生致病性自身抗体的罕见循环B淋巴细胞构成的。调控B细胞增殖和V（D）J突变的基因（CARD11，TNFAIP3，CCND3，ID3，BTG2和KLHL6）中存在淋巴瘤引起的突变，这些突变都存在流氓B细胞产生致病性自身抗体过程中。抗体V（D）J突变通过在低温度下使抗原结合的自身抗体发生相变成为不溶性聚集物而赋予其致病性。这些结果揭示了人类淋巴瘤肿瘤形成的前阶段以及造成致病性自身抗体产生的一系列体细胞突变。

据介绍，许多自身免疫性疾病中存在致病性自身抗体，但尚不了解它们如何逃避细胞免疫检查点的控制。

附：英文原文

Title: Lymphoma Driver Mutations in the Pathogenic Evolution of an Iconic Human Autoantibody

Author: Mandeep Singh, Katherine J.L. Jackson, Jing J. Wang, Peter Schofield, Matt A. Field, David Koppstein, Timothy J. Peters, Deborah L. Burnett, Simone Rizzetto, Damien Nevoltris, Etienne Masle-Farquhar, Megan L. Faulks, Amanda Russell, Divya Gokal, Asami Hanioka, Keisuke Horikawa, Alexander D. Colella, Timothy K. Chataway, James Blackburn, Tim R. Mercer, David B. Langley, D. Margaret Goodall, Roy Jefferis, Muralikrishna Gangadharan Komala, Anthony D. Kelleher, Dan Suan, Maureen Rischmueller, Daniel Christ, Robert Brink, Fabio Luciani, Tom P. Gordon, Christopher C. Goodnow, Joanne H. Reed

Issue&Volume: February 13, 2020

Abstract: Pathogenic autoantibodies arise in many autoimmune diseases, but it is not understoodhow the cells making them evade immune checkpoints. Here, single-cell multi-omicsanalysis demonstrates a shared mechanism with lymphoid malignancy in the formationof public rheumatoid factor autoantibodies responsible for mixed cryoglobulinemicvasculitis. By combining single-cell DNA and RNA sequencing with serum antibody peptidesequencing and antibody synthesis, rare circulating B lymphocytes making pathogenicautoantibodies were found to comprise clonal trees accumulating mutations. Lymphomadriver mutations in genes regulating B cell proliferation and V(D)J mutation (CARD11, TNFAIP3, CCND3, ID3, BTG2, and KLHL6) were present in rogue B cells producing the pathogenic autoantibody. Antibody V(D)Jmutations conferred pathogenicity by causing the antigen-bound autoantibodies to undergophase transition to insoluble aggregates at lower temperatures. These results reveala pre-neoplastic stage in human lymphomagenesis and a cascade of somatic mutationsleading to an iconic pathogenic autoantibody.

DOI: 10.1016/j.cell.2020.01.029

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30110-0