Chu Y W, Marin E, Fuleihan R, Ramesh N, Rosen F S, Geha R S, Insel R A
Department of Pediatrics, Microbiology, and Immunology, University of Rochester School of Medicine and Dentistry, New York 14642.
J Clin Invest. 1995 Mar;95(3):1389-93. doi: 10.1172/JCI117791.
Somatic mutation of Ig variable regions occurs prominently in germinal centers, but it has been debated whether the mutation process initiates in germinal centers or is activated before germinal center entry of B cells. We have analyzed for the presence of somatic mutation in Ig gene rearrangements of the nonpolymorphic human VH6 gene in the X-linked HyperIgM syndrome, which is associated with defective CD40 ligand expression and absence of germinal centers and generation of memory B lymphocytes. IgM and rare IgG VH6 productive rearrangements were isolated from PBL of patients with X-linked HyperIgM syndrome. Although the majority of both the IgM and IgG VH6 rearrangements had a germline VH6 sequence, 7 of 102 VH6 IgM and 1 of 6 IgG rearrangements had a mutated VH6 gene. The mutation frequency (mutations/bp) was 1.4% with a range of 2-9 mutations per clone, a mutation frequency lower, however, than that observed in IgM (3.2%) and IgG (5.4%) VH6 rearrangements of normal individuals. These results suggest that somatic mutation may be initiated in a CD40 ligand-independent pathway before entry of B cells into germinal centers, but fails to achieve the high mutation frequency observed in the presence of germinal centers.
免疫球蛋白可变区的体细胞突变在生发中心显著发生，但关于突变过程是在生发中心启动还是在B细胞进入生发中心之前就被激活一直存在争议。我们分析了X连锁高IgM综合征中人类非多态性VH6基因的免疫球蛋白基因重排中体细胞突变的存在情况，该综合征与CD40配体表达缺陷、生发中心缺失以及记忆B淋巴细胞生成缺陷有关。从X连锁高IgM综合征患者的外周血淋巴细胞中分离出IgM和罕见的IgG VH6有效重排。虽然大多数IgM和IgG VH6重排都具有种系VH6序列，但102个VH6 IgM重排中有7个和6个IgG重排中有1个具有突变的VH6基因。突变频率（突变数/碱基对）为1.4%，每个克隆的突变数范围为2至9个，然而，该突变频率低于正常个体的IgM（3.2%）和IgG（5.4%）VH6重排中观察到的频率。这些结果表明，体细胞突变可能在B细胞进入生发中心之前通过CD40配体非依赖途径启动，但未能达到在生发中心存在时观察到的高突变频率。
