生发中心
体细胞突变
生物
泛素连接酶
否定选择
免疫学
过继性细胞移植
细胞生物学
泛素
B细胞
免疫系统
基因
抗体
遗传学
T细胞
基因组
作者
Lindsay Renshaw,Peter Kim,Macaul Crici,Hossein Fazelinia,Lynn Spruce,Paula M. Oliver,Emily Moser
出处
期刊:Journal of Immunology
[The American Association of Immunologists]
日期:2023-03-17
卷期号:210 (10): 1473-1481
标识
DOI:10.4049/jimmunol.2200824
摘要
Abstract Ig diversification occurs in peripheral lymphoid organs after establishment of central tolerance during B cell development. In germinal centers (GCs), somatic hypermutation of Ig genes occurs in dark zones, followed by selection of mutated clones in light zones (LZs). This generates high-affinity Ig receptors to pathogens but can also produce autoreactive Ig receptors, which are removed by selection mechanisms that are incompletely understood. The ubiquitin ligase Itch prevents the emergence of autoimmune disease and autoantibodies in humans and mice, and patients lacking Itch develop potentially fatal autoimmune diseases; yet, how Itch regulates GC B cells is not well understood. By studying Itch-deficient mice, we have recently shown that Itch directly limits the magnitude of GC responses. Proteomic profiling of GC B cells uncovered that Itch-deficient cells exhibit high mTORC1 and Myc activity, hallmarks of positive selection. Bone marrow chimera and adoptive transfer experiments revealed that B cell Itch restricts noncycling LZ cells. These results support, to our knowledge, a novel role for Itch in skewing selection of GC B cells to restrict LZ accumulation and shape GC-derived humoral immunity. Determining how B cells integrate cues within GCs to navigate through LZs and dark zones will aid in understanding how autoreactive clones emerge from GCs in people with autoimmune disease.
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