澳大利亚加文医学研究所Christopher C. Goodnow等研究人员合作发现，体细胞突变的三联现象在自反应性B细胞中汇聚，导致病毒诱导的自身免疫性疾病。该项研究成果于2025年1月15日出在线发表在《免疫》杂志上。

研究人员表示，感染与自身免疫性疾病之间未解的关联在乙型丙型肝炎病毒诱导的冷球蛋白血症性血管炎（HCV-cryovas）中最为显著。

为了分析其起源，研究人员通过深度单细胞多组学分析，追踪了四名HCV-cryovas患者中致病性类风湿因子（RF）自身抗体的演变，揭示了三种B细胞体细胞突变的来源汇聚在一起，推动了大量致病克隆的积累。

通过定量低亲和力结合的方法，研究人员揭示了V(D)J重组产生的反复出现的抗体可变区组合，这些抗体结合了自体免疫球蛋白G（IgG），但不与病毒E2抗原结合。

全基因组测序揭示了数千个体细胞突变，数量与慢性淋巴细胞白血病和正常记忆B细胞相当，但其中有1至2个突变对应于，在B细胞白血病和淋巴瘤中反复出现的驱动突变。

V(D)J超突变产生的自体抗体与自体IgG结合时溶解性受损。在这种病毒诱导的自身免疫性疾病中，感染促进了单一B细胞后代中体细胞突变的灾难性汇聚。

附：英文原文

Title: A triad of somatic mutagenesis converges in self-reactive B cells to cause a virus-induced autoimmune disease

Author: Clara Young, Mandeep Singh, Katherine J.L. Jackson, Matt A. Field, Timothy J. Peters, Stefano Angioletti-Uberti, Daan Frenkel, Shyamsundar Ravishankar, Money Gupta, Jing J. Wang, David Agapiou, Megan L. Faulks, Ghamdan Al-Eryani, Fabio Luciani, Tom P. Gordon, Joanne H. Reed, Mark Danta, Andrew Carr, Anthony D. Kelleher, Gregory J. Dore, Gail Matthews, Robert Brink, Rowena A. Bull, Dan Suan, Christopher C. Goodnow

Issue&Volume: 2025-01-15

Abstract: The unexplained association between infection and autoimmune disease is strongest for hepatitis C virus-induced cryoglobulinemic vasculitis (HCV-cryovas). To analyze its origins, we traced the evolution of pathogenic rheumatoid factor (RF) autoantibodies in four HCV-cryovas patients by deep single-cell multi-omic analysis, revealing three sources of B cell somatic mutation converged to drive the accumulation of a large disease-causing clone. A method for quantifying low-affinity binding revealed recurring antibody variable domain combinations created by V(D)J recombination that bound self-immunoglobulin G (IgG) but not viral E2 antigen. Whole-genome sequencing revealed thousands of somatic mutations, numerically comparable to chronic lymphocytic leukemia and normal memory B cells, but with 1–2 corresponding to driver mutations found recurrently in B cell leukemia and lymphoma. V(D)J hypermutation created autoantibodies with compromised solubility in complex with self-IgG. In this virus-induced autoimmune disease, infection promotes a catastrophic confluence of somatic mutagenesis in the descendants of a single B cell.

DOI: 10.1016/j.immuni.2024.12.011

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00575-2