Differences in mutational patterns between rheumatoid factors in health and disease are related to variable heavy chain family and germ-line gene usage
Differences in mutational patterns between rheumatoid factors in health and disease are related to variable heavy chain family and germ-line gene usage
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DOI：
10.1002/eji.1830270323
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发表时间：
1997-03-01
影响因子：
5.4
通讯作者：
Thompson, KM
中科院分区：
文献类型：
--
作者：
Borretzen, M;Chapman, C;Thompson, KM
本文报道了来自5名健康免疫供体（HID）的11个不同种系基因片段的14种IgM类风湿因子（RF）的重链可变区（V-H）序列和解离常数（Kd）。我们扩展了以前的分析，两个克隆从一个捐助者只使用种系段DP-10。在本研究中，这些新的RF和两个早期报道的HID RF克隆的突变模式进行了分析与V-H家族，生殖系起源，和K-d。HID RF组进一步与33个先前描述的来自类风湿性关节炎（RA）患者的IgM RF进行比较。这些是HID RF组中的高突变率（平均10个突变/V-H）起源于RA患者的RF具有相当的突变率（平均11个突变/V-H），这表明IgM RF的超突变与疾病无关。然而，HID RF对IgG的亲和力显著低于RA RE。我们发现HID和RA RF之间差异的结构基础与V-H家族使用有关。V（H）1家族的RF在HID和RA患者中使用非常相似的生殖系基因。然而，V（H）1家族的HID RF在重链互补区（CDR（H））1和2中具有仅为0.41的低比率的互补与沉默（R：S）突变。这在统计学上显著低于V（H）1 RA RE中的相应比率3.14。相反，来自HID和RA患者的V（H）3家族的RF在CDR（H）1和2中分别具有非常相似的R：S比率1.75和1.71。然而，V（H）3RA RF主要由不编码任何HID RE的基因编码。因此，与RA RF相比，在来自HID的RF中可以观察到导致显著更低的R：S比率的库差异和超突变。
The sequences of the heavy chain variable (V-H) Segment and dissociation constants (K-d) Of 14 IgM rheumatoid factors (RF) derived from 11 different germline gene segments from five healthy immunized donors (HID) are described. We extend a previous analysis of two clones from one donor using only the germline segment DP-10. In the present study, the mutation patterns of these new RF and the two earlier reported HID RF clones are analyzed in relation to V-H family, germ-line origin, and K-d. The panel of HID RF is further compared with 33 previously described IgM RF from patients with rheumatoid arthritis (RA). These is a high rate of mutation in the panel of HID RF (mean of ten mutations/V-H) RF originating in RA patients have a comparable mutation rate (mean of 11 mutations/V-H), suggesting that hypermutation of IgM RF is not disease related. The HID RF have, however, a significantly lower affinity for IgG than the RA RE We found that the structural basis of the differences between HID and RA RF is related to V-H family usage. RF of the V(H)1 family use very similar germ-line genes in HID and RA patients. HID RF of the V(H)1 family have, however, a low ratio of replacement-to-silent (R:S) mutations of only 0.41 in the heavy chain complementarity region (CDR(H)) 1 and 2. This is statistically significantly lower than the corresponding ratio of 3.14 in the V(H)1 RA RE In contrast, RF of the V(H)3 family from HID and RA patients have very similar R:S ratios of 1.75 and 1.71 in CDR(H)1 and 2, respectively. The V(H)3 RA RF are, however, predominantly encoded by genes not encoding any HID RE Thus, both repertoire differences and hypermutation resulting in significantly lower R:S ratios can be observed in RF from HID compared with RA RF.