体细胞突变
生发中心
重症肌无力
生物
乙酰胆碱受体
克隆(Java方法)
亲和力成熟
自身抗体
免疫学
人口
体细胞
神经肌肉接头
B细胞
分子生物学
遗传学
抗体
受体
基因
医学
神经科学
环境卫生
作者
Gary P. Sims,Hiroyuki Shiono,Nick Willcox,David I. Stott
出处
期刊:Journal of Immunology
[The American Association of Immunologists]
日期:2001-08-15
卷期号:167 (4): 1935-1944
被引量:175
标识
DOI:10.4049/jimmunol.167.4.1935
摘要
The muscle weakness in myasthenia gravis (MG) is mediated by autoantibodies against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction. Production of these pathogenic autoantibodies is believed to be associated with germinal centers (GC) and anti-AChR-secreting plasma cells in the hyperplastic thymus of patients with early onset MG (EOMG). Here, we describe the repertoire of rearranged heavy chain V genes and their clonal origins in GC from a typical EOMG patient. Three hundred fifteen rearranged Ig V(H) genes were amplified, cloned, and sequenced from sections of four thymic GC containing AChR-specific B cells. We found that thymic GC contain a remarkably heterogeneous population of B cells. Both naive and circulating memory B cells undergo Ag-driven clonal proliferation, somatic hypermutation, and selection. Numerous B cell clones were present, with no individual clone dominating the response. Comparisons of B cell clonal sequences from different GC and known anti-AChR Abs from other patients showed convergent mutations in the complementarity determining regions. These results are consistent with AChR driving an ongoing GC response in the thymus of EOMG patients. This is the first detailed analysis of B cell clones in human GC responding to a defined protein Ag, and the response we observed may reflect the effects of chronic stimulation by autoantigen.
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