Institute for Immunodeficiency, Center for Chronic Immunodeficiencies, Medical Center - University Hospital Freiburg, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany.
Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
Front Immunol. 2022 Aug 16;13:938240. doi: 10.3389/fimmu.2022.938240. eCollection 2022.
Common variable immunodeficiency (CVID) is the most prevalent form of symptomatic primary immunodeficiency in humans. The genetic cause of CVID is still unknown in about 70% of cases. Ten percent of CVID patients carry heterozygous mutations in the tumor necrosis factor receptor superfamily member 13B gene (), encoding TACI. Mutations in alone may not be sufficient for the development of CVID, as 1% of the healthy population carry these mutations. The common hypothesis is that TACI mutations are not fully penetrant and additional factors contribute to the development of CVID. To determine these additional factors, we investigated the perturbations of transcription factor (TF) binding and the transcriptome profiles in unstimulated and CD40L/IL21-stimulated naïve B cells from CVID patients harboring the C104R mutation in and compared them to their healthy relatives with the same mutation. In addition, the proteome of stimulated naïve B cells was investigated. For functional validation, intracellular protein concentrations were measured by flow cytometry. Our analysis revealed 8% less accessible chromatin in unstimulated naïve B cells and 25% less accessible chromatin in class-switched memory B cells from affected and unaffected TACI mutation carriers compared to healthy donors. The most enriched TF binding motifs in TACI mutation carriers involved members from the ETS, IRF, and NF-κB TF families. Validation experiments supported dysregulation of the NF-κB and MAPK pathways. In steady state, naïve B cells had increased cell death pathways and reduced cell metabolism pathways, while after stimulation, enhanced immune responses and decreased cell survival were detected. Using a multi-omics approach, our findings provide valuable insights into the impaired biology of naïve B cells from TACI mutation carriers.
普通变异性免疫缺陷症（CVID）是人类最常见的症状性原发性免疫缺陷症。在大约 70%的病例中，CVID 的遗传原因仍然未知。10%的 CVID 患者携带肿瘤坏死因子受体超家族成员 13B 基因（）的杂合突变，该基因编码 TACI。TACI 突变本身可能不足以导致 CVID 的发生，因为健康人群中有 1%携带这些突变。常见的假设是 TACI 突变不完全穿透，并且其他因素有助于 CVID 的发展。为了确定这些额外的因素，我们研究了携带突变的 CVID 患者和携带相同突变的健康亲属的未刺激和 CD40L/IL21 刺激的幼稚 B 细胞中转录因子（TF）结合和转录组谱的扰动。此外，还研究了刺激的幼稚 B 细胞的蛋白质组。为了进行功能验证，通过流式细胞术测量细胞内蛋白质浓度。我们的分析显示，与健康供体相比，受影响和未受影响的 TACI 突变携带者的未刺激幼稚 B 细胞中的染色质可及性降低 8%，而在类别转换的记忆 B 细胞中降低 25%。TACI 突变携带者中最丰富的 TF 结合基序涉及 ETS、IRF 和 NF-κB TF 家族的成员。验证实验支持 NF-κB 和 MAPK 途径的失调。在静止状态下，幼稚 B 细胞的细胞死亡途径增加，细胞代谢途径减少，而在刺激后，检测到增强的免疫反应和减少的细胞存活。使用多组学方法，我们的研究结果为 TACI 突变携带者的幼稚 B 细胞受损生物学提供了有价值的见解。
