Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency.
Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency.
复制标题
DOI：
10.1084/jem.20091927
复制
发表时间：
2010-07-05
期刊：
影响因子：
--
通讯作者：
Notarangelo LD
中科院分区：
文献类型：
--
作者：
Walter JE;Rucci F;Patrizi L;Recher M;Regenass S;Paganini T;Keszei M;Pessach I;Lang PA;Poliani PL;Giliani S;Al-Herz W;Cowan MJ;Puck JM;Bleesing J;Niehues T;Schuetz C;Malech H;DeRavin SS;Facchetti F;Gennery AR;Andersson E;Kamani NR;Sekiguchi J;Alenezi HM;Chinen J;Dbaibo G;ElGhazali G;Fontana A;Pasic S;Detre C;Terhorst C;Alt FW;Notarangelo LD
B细胞对Omenn综合征和渗漏性严重联合免疫缺陷（SCID）病理学的贡献以前没有研究过。我们研究了一个mut/mut小鼠模型的漏SCID与纯合子Rag 1 S723 C突变，损害，但不废除，V（D）J重组活性。尽管在前B细胞阶段存在严重阻滞和严重的B细胞淋巴细胞减少症，但在mut/mut小鼠中检测到免疫球蛋白（IG）G、IgM、伊加和IgE的显著血清水平以及高比例的Ig分泌细胞。对三硝基苯基（TNP）-Ficoll的抗体反应和对TNP-钥孔血蓝蛋白的高亲和力抗体的产生严重受损，即使在野生型CD 4 + T细胞过继转移后。Mut/mut小鼠产生大量的低亲和力自身反应性抗体，并在外周组织中显示出显著的淋巴细胞浸润。自身抗体的产生与受体编辑受损和血清B细胞活化因子（BAFF）浓度升高相关。在Omenn综合征和渗漏性SCID患者中也发现了自身抗体和升高的BAFF水平，这是由于亚型RAG突变所致。这些数据表明，随机产生的自身反应性B细胞库，这是与缺陷的中央和外周检查点的B细胞的耐受性，是一个重要的，以前未认识到，免疫缺陷与亚型RAG突变的一个方面。
The contribution of B cells to the pathology of Omenn syndrome and leaky severe combined immunodeficiency (SCID) has not been previously investigated. We have studied a mut/mut mouse model of leaky SCID with a homozygous Rag1 S723C mutation that impairs, but does not abrogate, V(D)J recombination activity. In spite of a severe block at the pro–B cell stage and profound B cell lymphopenia, significant serum levels of immunoglobulin (Ig) G, IgM, IgA, and IgE and a high proportion of Ig-secreting cells were detected in mut/mut mice. Antibody responses to trinitrophenyl (TNP)-Ficoll and production of high-affinity antibodies to TNP–keyhole limpet hemocyanin were severely impaired, even after adoptive transfer of wild-type CD4+ T cells. Mut/mut mice produced high amounts of low-affinity self-reactive antibodies and showed significant lymphocytic infiltrates in peripheral tissues. Autoantibody production was associated with impaired receptor editing and increased serum B cell–activating factor (BAFF) concentrations. Autoantibodies and elevated BAFF levels were also identified in patients with Omenn syndrome and leaky SCID as a result of hypomorphic RAG mutations. These data indicate that the stochastic generation of an autoreactive B cell repertoire, which is associated with defects in central and peripheral checkpoints of B cell tolerance, is an important, previously unrecognized, aspect of immunodeficiencies associated with hypomorphic RAG mutations.
登录
查看更多内容
影响因子：
32.4
作者：
Cariappa, A;Tang, M;Pillai, S
通讯作者：
Pillai, S
影响因子：
4.4
作者：
He, B;Qiao, XG;Cerutti, A
通讯作者：
Cerutti, A
影响因子：
64.8
作者：
DURDIK, J;MOORE, MW;SELSING, E
通讯作者：
SELSING, E
影响因子：
30.5
作者：
Halverson, R;Torres, RM;Pelanda, R
通讯作者：
Pelanda, R
影响因子：
4.4
作者：
Cabatingan, MS;Schmidt, MR;Woodland, RT
通讯作者：
Woodland, RT