Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):5127-32. doi: 10.1073/pnas.1221211110. Epub 2013 Mar 14.
Mutations in the TNF family of proteins have been associated with inherited forms of immune deficiency. Using an array-based sequencing assay, we identified an autosomal-dominant deficiency in TNF-like weak inducer of apoptosis (TWEAK; TNFSF12) in a kindred with recurrent infection and impaired antibody responses to protein and polysaccharide vaccines. This mutation occurs in the sixth exon of TWEAK and results in the amino acid substitution R145C within the conserved TNF-homology domain of the full-length protein. TWEAK mutant protein formed high molecular weight aggregates under nonreducing conditions, suggesting an increased propensity for intermolecular interactions. As a result, mutant TWEAK associated with B-cell-activating factor (BAFF) protein and down-regulated the BAFF-mediated activation of the noncanonical NF-κB pathway through inhibition of p100 processing to p52, resulting in inhibition of BAFF-dependent B-cell survival and proliferation. As BAFF mediates T-cell-independent isotype switching and B-cell survival, our data implicate TWEAK as a disease-susceptibility gene for a humoral immunodeficiency.
TNF 家族蛋白的突变与遗传性免疫缺陷有关。我们使用基于阵列的测序分析，在一个复发性感染和对蛋白质和多糖疫苗的抗体反应受损的家族中，发现 TNF 样凋亡弱诱导物（TWEAK；TNFSF12）的常染色体显性缺陷。该突变发生在 TWEAK 的第六个外显子中，导致全长蛋白的 TNF 同源结构域内的氨基酸取代 R145C。TWEAK 突变蛋白在非还原条件下形成高分子量聚集体，表明其具有更高的分子间相互作用倾向。结果，突变型 TWEAK 与 B 细胞激活因子（BAFF）蛋白结合，并通过抑制 p100 加工为 p52 来下调 BAFF 介导的非典型 NF-κB 通路的激活，从而抑制 BAFF 依赖性 B 细胞存活和增殖。由于 BAFF 介导 T 细胞非依赖性同种型转换和 B 细胞存活，我们的数据表明 TWEAK 是一种体液免疫缺陷的易感基因。
