Vκ polymorphisms in NOD mice are spread throughout the entire immunoglobulin kappa locus and are shared by other autoimmune strains
Vκ polymorphisms in NOD mice are spread throughout the entire immunoglobulin kappa locus and are shared by other autoimmune strains
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DOI：
10.1007/s00251-010-0457-9
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发表时间：
2010-08-01
期刊：
影响因子：
3.2
通讯作者：
Thomas, James W.
中科院分区：
文献类型：
--
作者：
Henry, Rachel A.;Kendall, Peggy L.;Thomas, James W.
可用于形成淋巴细胞库的免疫球蛋白（IG）和T细胞受体（TCR）基因的多样性具有产生广泛的保护性和有害特异性的能力。在1型糖尿病（T1D）中，胰岛素和其他胰岛抗原抗体的存在预示着小鼠和人类的疾病发展，并证明免疫耐受性在疾病过程的早期丧失。从T1D易感的非肥胖糖尿病（NOD）小鼠分离的抗胰岛素T细胞使用多态性TCR α链，表明在这些自身免疫小鼠中可用的T细胞库被改变。为了探测胰岛素结合B细胞是否也具有多态性V基因，从携带IG重链转基因的NOD小鼠中分离并测序了IG轻链。三个胰岛素结合V κ基因进行了鉴定，所有这些都是多态性的最接近的种系序列匹配存在于GenBank数据库中。对来自多个来源（包括种系DNA）的超过300个轻链序列的额外分析显示，多态性遍布整个NOD IG κ基因座，因为这些多态性序列代表属于14个V κ家族的43个不同的V κ基因。数据库检索显示，在NOD中鉴定的大多数多态性V κ基因与从SLE易感NZBxNZW F1或MRL小鼠品系中分离的V κ基因相同，表明可能存在共享的IG κ单倍型。预测的氨基酸变化优先发生在CDR中，因此可以改变自身免疫与非自身免疫小鼠品系的种系B细胞库的抗原识别。
The diversity of immunoglobulin (Ig) and T cell receptor (TCR) genes available to form the lymphocyte repertoire has the capacity to produce a broad array of both protective and harmful specificities. In type 1 diabetes (T1D), the presence of antibodies to insulin and other islet antigens predicts disease development in both mice and humans, and demonstrate that immune tolerance is lost early in the disease process. Anti-insulin T cells isolated from T1D-prone non-obese diabetic (NOD) mice use polymorphic TCR alpha chains, suggesting that the available T cell repertoire is altered in these autoimmune mice. To probe whether insulin-binding B cells also possess polymorphic V genes, Ig light chains were isolated and sequenced from NOD mice that harbor an Ig heavy chain transgene. Three insulin-binding V kappa genes were identified, all of which were polymorphic to the closest germline sequence matches present in the GenBank database. Additional analysis of over 300 light chain sequences from multiple sources, including germline DNA, shows that polymorphisms are spread throughout the entire NOD Ig kappa locus, as these polymorphic sequences represent 43 distinct V kappa genes which belong to 14 V kappa families. Database searches reveal that a majority of polymorphic V kappa genes identified in NOD are identical to V kappa genes isolated from SLE-prone NZBxNZW F1 or MRL strains of mice, suggesting that a shared Ig kappa haplotype may be present. Predicted amino acid changes preferentially occur in CDR, and thus could alter antigen recognition by the germline B cell repertoire of autoimmune versus non-autoimmune mouse strains.