An autoimmune "attack" on melanocytes triggers psoriasis and cellular hyperplasia.
An autoimmune "attack" on melanocytes triggers psoriasis and cellular hyperplasia.
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DOI：
10.1084/jem.21213insight3
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发表时间：
2015-12-14
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影响因子：
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通讯作者：
Krueger JG
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作者：
Krueger JG
在各种类型的炎症和自身免疫性疾病中，TLR通路通过与TLR结合的配体被过度激活。在30%的ABC型DLBCL和其他几种B细胞淋巴瘤中，MyD88（将tlr与IRAK1和IRAK4激酶连接起来）受到激活L265P突变的影响。IRAKs的活性导致典型NF-κB通路的激活。IRAK4是通过MyD88发送TLR信号的关键。新开发的IRAK4抑制剂ND-2158和ND-2110可阻断TLR受体或突变MyD88介导的信号传导。在ABC型DLBCL中，NF-κB也通过慢性活性B细胞受体信号通路被激活，其中包括布鲁顿酪氨酸激酶（BTK）。伊鲁替尼对BTK的抑制在初步临床研究中显示出临床效果。值得注意的是，在体外和异种移植模型中，伊布鲁替尼和ND-2158共同应用对ABC DLBCL细胞系具有协同毒性活性。对于信号通路，并不是所有的成分都被显示出来。
The TLR pathway is overactivated in various types of inflammatory and autoimmune diseases by ligands binding to the TLR. In 30% of ABC DLBCL and in several other B cell lymphomas, MyD88, which links TLRs to the IRAK1 and IRAK4 kinases, is affected by activating L265P mutations. Activity of IRAKs leads to activation of the canonical NF-κB pathway. IRAK4 is essential for TLR signaling through MyD88. The newly developed IRAK4 inhibitors ND-2158 and ND-2110 abrogate signaling mediated by TLR receptors or mutated MyD88. In ABC DLBCL, NF-κB is also activated though chronic active B cell receptor signaling, which involves the Bruton’s tyrosine kinase (BTK). Inhibition of BTK by ibrutinib has shown clinical efficiency in first clinical studies. Notably, coapplication of ibrutininb and ND-2158 has synergistic toxic activity for ABC DLBCL cell lines in vitro and in a xenograft model. For the signaling pathways, not all components are shown.