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

IF 25.5 1区医学 Q1 IMMUNOLOGY

Immunity Pub Date : 2025-01-15 DOI:10.1016/j.immuni.2024.12.011

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, Christopher C. Goodnow

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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.

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三种体细胞突变在自身反应性B细胞中汇合，引起病毒诱导的自身免疫性疾病

在丙型肝炎病毒引起的冷球蛋白血症性血管炎（HCV-cryovas）中，感染与自身免疫性疾病之间无法解释的关联最强。为了分析其起源，我们通过深入的单细胞多组学分析追踪了4例HCV-cryovas患者致病性类风湿因子（RF）自身抗体的进化，揭示了B细胞体细胞突变的三个来源聚集驱动了一个大的致病克隆的积累。一种量化低亲和力结合的方法显示，通过V(D)J重组产生的反复抗体可变结构域组合与自身免疫球蛋白G （IgG）结合，而不与病毒E2抗原结合。全基因组测序揭示了数千个体细胞突变，在数量上与慢性淋巴细胞白血病和正常记忆B细胞相当，但有1-2个对应于B细胞白血病和淋巴瘤中反复发现的驱动突变。V(D)J高突变产生与自身igg复合物溶解度受损的自身抗体。在这种病毒诱导的自身免疫性疾病中，感染促进了单个B细胞后代体细胞突变的灾难性汇合。

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来源期刊

Immunity 医学-免疫学

CiteScore

49.40

自引率

2.20%

发文量

205

审稿时长

6 months

期刊介绍： Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.