淋巴瘤引起的突變促進(jìn)致病性自身產(chǎn)生抗體
人類自身致病性抗體的進(jìn)化過程中存在淋巴瘤引起的突變，這一成果由澳大利亞加文醫(yī)學(xué)研究所Joanne H. Reed和Christopher C. Goodnow研究組合作取得。 2020年2月13日，國際學(xué)術(shù)期刊《細(xì)胞》在線發(fā)表了這一成果。
利用單細(xì)胞多組學(xué)分析，研究人員發(fā)現(xiàn)淋巴樣惡性腫瘤與由常見類風(fēng)濕因子自身抗體引起的混合型冷球蛋白血癥的共享機(jī)制。通過將單細(xì)胞DNA和RNA測序與血清抗體肽測序和抗體合成相結(jié)合，研究人員發(fā)現(xiàn)產(chǎn)生積累突變的克隆樹是由產(chǎn)生致病性自身抗體的罕見循環(huán)B淋巴細(xì)胞構(gòu)成的。調(diào)控B細(xì)胞增殖和V（D）J突變的基因（CARD11，TNFAIP3，CCND3，ID3，BTG2和KLHL6）中存在淋巴瘤引起的突變，這些突變都存在流氓B細(xì)胞產(chǎn)生致病性自身抗體過程中?？贵wV（D）J突變通過在低溫度下使抗原結(jié)合的自身抗體發(fā)生相變成為不溶性聚集物而賦予其致病性。這些結(jié)果揭示了人類淋巴瘤腫瘤形成的前階段以及造成致病性自身抗體產(chǎn)生的一系列體細(xì)胞突變。
據(jù)介紹，許多自身免疫性疾病中存在致病性自身抗體，但尚不了解它們?nèi)绾翁颖芗?xì)胞免疫檢查點(diǎn)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
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