Sex-Biased Aging Effects on Ig Somatic Hypermutation Targeting.
Sex-Biased Aging Effects on Ig Somatic Hypermutation Targeting.
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DOI：
10.4049/jimmunol.2000576
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发表时间：
2021-01-01
期刊：
影响因子：
--
通讯作者：
Kleinstein SH
中科院分区：
文献类型：
--
作者：
Cui A;Chawla DG;Kleinstein SH
老年人，特别是男性，显示出受损的抗体反应水平相比，他们年轻的同行，但负责的差异的分子机制还没有很好地理解。我们假设，这种差异可能与B细胞体细胞超突变（SHM）靶向，包括易错DNA修复活动，是至关重要的抗体多样化。为了研究衰老对SHM靶向的影响，我们分析了来自27名年龄在20至89岁的健康男性和女性人类受试者的B细胞免疫球蛋白库序列。通过研究基于从123，415个序列获得的985，069个突变的突变模式，我们发现微序列基序上的SHM突变等级（即，SHM热/冷点）在不同年龄和性别组之间大多一致。然而，我们观察到老年男性中涉及II期SHM DNA修复活动的突变频率较低，但在女性中并非如此。我们还从一项单独的研究中观察到，与年轻个体相比，老年个体中参与SHM的DNA错配修复基因的表达水平降低，男性的倍数变化大于女性。最后，我们表明I相与II相SHM活性之间的平衡影响所得免疫球蛋白表型。我们的研究结果表明，SHM过程在一些老年人中发生了改变，为观察到不同年龄和性别群体之间免疫反应的临床差异提供了见解。- SHM热点和冷点偏差在不同年龄和性别组之间基本一致-在年轻和老年男性受试者之间观察到SHM靶向的变化-SHM靶向的这种变化影响IG氨基酸组成
Aged individuals, particularly males, display an impaired level of antibody response compared with their younger counterparts, yet the molecular mechanisms responsible for the discrepancy are not well understood. We hypothesize that some of this difference may be linked to B cell somatic hypermutation (SHM) targeting including error-prone DNA repair activities that are crucial to antibody diversification. To examine the effects of aging on SHM targeting, we analyzed B cell immunoglobulin repertoire sequences from 27 healthy male and female human subjects aged 20 to 89. By studying mutation patterns based on 985,069 mutations obtained from 123,415 sequences, we found that the SHM mutability hierarchies on micro-sequence motifs (i.e., SHM hot/cold spots) are mostly consistent between different age and sex groups. However, we observed a lower frequency in mutations involving Phase II SHM DNA repair activities in older males, but not in females. We also observed from a separate study a decreased expression level of DNA mismatch repair genes involved in SHM in older individuals compared with younger individuals, with larger fold changes in males than in females. Finally, we showed that the balance between Phase I vs. Phase II SHM activities impacts the resulting immunoglobulin phenotypes. Our results showed that the SHM process is altered in some older individuals, providing insights into observed clinical differences in immunologic responses between different age and sex groups. - SHM hot- and cold-spot biases are largely consistent between different age and sex groups - A shift in SHM targeting is observed between young and older male subjects - This shift in SHM targeting influences the Ig amino acid composition
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DOI：
10.4049/jimmunol.1900922
发表时间：
2020-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Avey S;Mohanty S;Chawla DG;Meng H;Bandaranayake T;Ueda I;Zapata HJ;Park K;Blevins TP;Tsang S;Belshe RB;Kaech SM;Shaw AC;Kleinstein SH
通讯作者：
Kleinstein SH
DOI：
10.1038/nri2394
发表时间：
2008-09
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Fish EN
通讯作者：
Fish EN
影响因子：
17.1
作者：
Jiang N;He J;Weinstein JA;Penland L;Sasaki S;He XS;Dekker CL;Zheng NY;Huang M;Sullivan M;Wilson PC;Greenberg HB;Davis MM;Fisher DS;Quake SR
通讯作者：
Quake SR
DOI：
10.1016/0167-4781(92)90134-l
发表时间：
1992-11-15
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
ROGOZIN, IB;KOLCHANOV, NA
通讯作者：
KOLCHANOV, NA
影响因子：
5.8
作者：
Vander Heiden, Jason A.;Yaari, Gur;Kleinstein, Steven H.
通讯作者：
Kleinstein, Steven H.