INSERM U768, Hôpital Necker Enfants Malades, F-75015 Paris, France.
J Immunol. 2012 Feb 15;188(4):2023-9. doi: 10.4049/jimmunol.1102984. Epub 2012 Jan 16.
Ig class-switch recombination (Ig-CSR) deficiencies are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE) production. Depending on the molecular defect, defective Ig-CSR may also be associated with impaired somatic hypermutation (SHM) of the Ig V regions. Although the mechanisms underlying Ig-CSR and SHM in humans have been revealed (at least in part) by studying natural mutants, the role of mismatch repair in this process has not been fully elucidated. We studied in vivo and in vitro Ab maturation in eight MSH6-deficient patients. The skewed SHM pattern strongly suggests that MSH6 is involved in the human SHM process. Ig-CSR was found to be partially defective in vivo and markedly impaired in vitro. The resolution of γH2AX foci following irradiation of MSH6-deficient B cell lines was also found to be impaired. These data suggest that in human CSR, MSH6 is involved in both the induction and repair of DNA double-strand breaks in switch regions.
免疫球蛋白类别转换重组（Ig-CSR）缺陷是一种罕见的原发性免疫缺陷病，其特征是转换型同种型（IgG/IgA/IgE）产生缺陷。根据分子缺陷的不同，Ig-CSR 缺陷也可能与免疫球蛋白 V 区的体细胞高频突变（SHM）受损有关。尽管通过研究天然突变体已经揭示了（至少部分揭示了）人类 Ig-CSR 和 SHM 的机制，但错配修复在该过程中的作用尚未完全阐明。我们研究了 8 例 MSH6 缺陷患者的体内和体外 Ab 成熟情况。偏倚的 SHM 模式强烈表明 MSH6 参与了人类 SHM 过程。体内 Ig-CSR 被发现部分缺陷，体外明显受损。照射 MSH6 缺陷 B 细胞系后 γH2AX 焦点的分辨率也发现受损。这些数据表明，在人类 CSR 中，MSH6 参与了开关区中 DNA 双链断裂的诱导和修复。
