Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), Badalona, Barcelona, Spain.
Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
Nat Commun. 2022 Apr 1;13(1):1779. doi: 10.1038/s41467-022-29450-x.
Common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, displays impaired terminal B-cell differentiation and defective antibody responses. Incomplete genetic penetrance and ample phenotypic expressivity in CVID suggest the participation of additional pathogenic mechanisms. Monozygotic (MZ) twins discordant for CVID are uniquely valuable for studying the contribution of epigenetics to the disease. Here, we generate a single-cell epigenomics and transcriptomics census of naïve-to-memory B cell differentiation in a CVID-discordant MZ twin pair. Our analysis identifies DNA methylation, chromatin accessibility and transcriptional defects in memory B-cells mirroring defective cell-cell communication upon activation. These findings are validated in a cohort of CVID patients and healthy donors. Our findings provide a comprehensive multi-omics map of alterations in naïve-to-memory B-cell transition in CVID and indicate links between the epigenome and immune cell cross-talk. Our resource, publicly available at the Human Cell Atlas, gives insight into future diagnosis and treatments of CVID patients.
常见变异性免疫缺陷（CVID）是最常见的有症状原发性免疫缺陷，表现为末端 B 细胞分化受损和抗体反应缺陷。CVID 中的不完全遗传外显率和丰富的表型表达表明存在其他致病机制。CVID 不一致的同卵双胞胎对于研究表观遗传学对疾病的贡献具有独特的价值。在这里，我们对 CVID 不一致的同卵双胞胎对中的幼稚 B 细胞向记忆 B 细胞分化进行了单细胞表观基因组学和转录组学普查。我们的分析确定了记忆 B 细胞中的 DNA 甲基化、染色质可及性和转录缺陷，这些缺陷反映了激活时细胞间通讯的缺陷。这些发现在 CVID 患者和健康供体的队列中得到了验证。我们的研究结果提供了 CVID 中幼稚 B 细胞向记忆 B 细胞过渡中改变的全面多组学图谱，并表明表观基因组与免疫细胞相互作用之间存在联系。我们的资源可在人类细胞图谱上公开获取，为 CVID 患者的未来诊断和治疗提供了见解。
