分化簇40(Cluster of differentiation 40,简称CD40),是一种分布于抗原呈递细胞(APC)的协同刺激因子暨蛋白受体。CD40与辅助型T细胞上的CD154英语CD154CD40L英语CD40L)结合后,抗原呈递细胞会激活,并产生一系列下游反应[6]

CD40
已知的结构
PDB直系同源搜索: PDBe RCSB
识别号
别名CD40;, Bp50, CDW40, TNFRSF5, p50, CD40 (protein), CD40 molecule
外部IDOMIM109535 MGI88336 HomoloGene954 GeneCardsCD40
相关疾病
类风湿性关节炎、​第三型高IgM综合症[1]
基因位置(人类
20号染色体
染色体20号染色体[2]
20号染色体
CD40的基因位置
CD40的基因位置
基因座20q13.12起始46,118,271 bp[2]
终止46,129,863 bp[2]
RNA表达模式




查阅更多表达数据
直系同源
物种人类小鼠
Entrez
Ensembl
UniProt
mRNA​序列

NM_011611
​NM_170702
​NM_170703
​NM_170704

蛋白序列

NP_035741
​NP_733803
​NP_733804
​NP_733805

基因位置​(UCSC)Chr 20: 46.12 – 46.13 MbChr 2: 164.9 – 164.91 Mb
PubMed​查找[4][5]
维基数据
查看/编辑人类查看/编辑小鼠

CD40缺失会造成第三型高IgM综合症英语Hyper-IgM syndrome type 3(Hyper-IgM syndrome type 3)[6]

结构及表达

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CD40属于肿瘤坏死因子受体英语TNF-receptor超家族英语TNF receptor superfamily(TNF receptor superfamily)的一员[6]。含有AT钩英语AT-hook构型的翻译因子AKNA英语AKNA可以协同调控CD40及其配体[7]

功能

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CD40在T细胞相关的免疫和发炎反应具有重要功能,诸如免疫球蛋白类型转换、记忆B细胞发育,以及生发中心形成[6][8]。 B细胞上也有CD40存在,并会与辅助T细胞上的CD40L结合。CD40和CD40L的桥接可以激活B细胞,降低B细胞接触到抗原的反应阈值,使其更容易释放抗体。另外也可以促进B细胞的增殖、同型粘连(homotypic adhesion)、抗体类型转换。在表面蛋白的表达方面,可以刺激MHC class II英语MHC class IICD23英语CD23CD25英语CD25(IL-12R)、CD69英语CD69CD44等分子的表达,也会使淋巴细胞功能性抗原1(LFA-1)的转为高亲合态。在细胞周期方面,则会从间期进入S期,开始进行DNA和RNA的复制及合成CD40L[6]。 有研究也发现,要激活β淀粉样物质的微胶细胞也需要CD40和CD40L的连结,因此可能也与阿茲海默症的病生理学相关[9]

CD40-CD40L反应在免疫上的角色[6]
相关 不相关
一般免疫
  • T细胞启动(priming)
  • 决定周边免疫球蛋白的浓度
  • 周边淋巴器官及次级淋巴器官的淋巴细胞比例
体液免疫
自身免疫
胞杀作用及移植
  • 抗病毒的胞杀反应
  • 抗癌细胞的胞杀反应
T细胞选汰 T细胞的胸腺选汰

交互作用

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CD40可以与TRAF2英语TRAF2[10][11][12]TRAF3英语TRAF3[11][13][14][15]TRAF6英语TRAF6[11][15]TRAF5英语TRAF5[11][16]TTRAP英语TTRAP[17]产生交互作用。TRAF4家族的蛋白质虽不会直接与CD40作用,但可以间接增加CD40的作用[18]

临床应用

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CD40为癌症免疫疗法的潜在标的,目前已经开发出针对该蛋白的刺激性单克隆抗体,以激活树突状细胞刺激抗癌T细胞的途径,且已有相关论文发表。现有多项临床研究正在进行[19]

参考文献

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  1. ^ 與CD40相關的疾病;在維基數據上查看/編輯參考. 
  2. ^ 2.0 2.1 2.2 GRCh38: Ensembl release 89: ENSG00000101017 - Ensembl, May 2017
  3. ^ 3.0 3.1 3.2 GRCm38: Ensembl release 89: ENSMUSG00000017652 - Ensembl, May 2017
  4. ^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine. 
  5. ^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine. 
  6. ^ 6.0 6.1 6.2 6.3 6.4 6.5 Laman, Jon D.; Claassen, Eric; Noelle, Randolph J. Functions of CD40 and Its Ligand, gp39 (CD40L). Critical Reviews in Immunology. 2017, 37 (2-6): 371–420 [2021-05-26]. ISSN 1040-8401. doi:10.1615/CritRevImmunol.v37.i2-6.100. (原始内容存档于2021-05-26) (英语). 
  7. ^ Siddiqa, A.; Sims-Mourtada, J. C.; Guzman-Rojas, L.; Rangel, R.; Guret, C.; Madrid-Marina, V.; Sun, Y.; Martinez-Valdez, H. Regulation of CD40 and CD40 ligand by the AT-hook transcription factor AKNA. Nature. 2001-03-15, 410 (6826): 383–387 [2021-05-26]. ISSN 0028-0836. PMID 11268217. doi:10.1038/35066602. (原始内容存档于2021-05-26). 
  8. ^ Grewal IS, Flavell RA. CD40 and CD154 in cell-mediated immunity. Annual Review of Immunology. 1998, 16: 111–35. PMID 9597126. doi:10.1146/annurev.immunol.16.1.111. 
  9. ^ Giunta, Brian; Rezai-Zadeh, Kavon; Tan, Jun. Impact of the CD40-CD40L Dyad in Alzheimers Disease. CNS & Neurological Disorders - Drug Targets. 2010-04-01, 9 (2): 149–155. doi:10.2174/187152710791012099 (英语). 
  10. ^ McWhirter SM, Pullen SS, Holton JM, Crute JJ, Kehry MR, Alber T. Crystallographic analysis of CD40 recognition and signaling by human TRAF2. Proceedings of the National Academy of Sciences of the United States of America. July 1999, 96 (15): 8408–13. Bibcode:1999PNAS...96.8408M. PMC 17529 . PMID 10411888. doi:10.1073/pnas.96.15.8408. 
  11. ^ 11.0 11.1 11.2 11.3 Tsukamoto N, Kobayashi N, Azuma S, Yamamoto T, Inoue J. Two differently regulated nuclear factor kappaB activation pathways triggered by the cytoplasmic tail of CD40. Proceedings of the National Academy of Sciences of the United States of America. February 1999, 96 (4): 1234–9. Bibcode:1999PNAS...96.1234T. PMC 15446 . PMID 9990007. doi:10.1073/pnas.96.4.1234. 
  12. ^ Malinin NL, Boldin MP, Kovalenko AV, Wallach D. MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature. February 1997, 385 (6616): 540–4. PMID 9020361. S2CID 4366355. doi:10.1038/385540a0. 
  13. ^ Hu HM, O'Rourke K, Boguski MS, Dixit VM. A novel RING finger protein interacts with the cytoplasmic domain of CD40. The Journal of Biological Chemistry. December 1994, 269 (48): 30069–72. PMID 7527023. 
  14. ^ Ni CZ, Welsh K, Leo E, Chiou CK, Wu H, Reed JC, Ely KR. Molecular basis for CD40 signaling mediated by TRAF3. Proceedings of the National Academy of Sciences of the United States of America. September 2000, 97 (19): 10395–9. Bibcode:2000PNAS...9710395N. PMC 27035 . PMID 10984535. doi:10.1073/pnas.97.19.10395. 
  15. ^ 15.0 15.1 Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC. The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. The EMBO Journal. December 1997, 16 (23): 6914–25. PMC 1170295 . PMID 9384571. doi:10.1093/emboj/16.23.6914. 
  16. ^ Ishida TK, Tojo T, Aoki T, Kobayashi N, Ohishi T, Watanabe T, Yamamoto T, Inoue J. TRAF5, a novel tumor necrosis factor receptor-associated factor family protein, mediates CD40 signaling. Proceedings of the National Academy of Sciences of the United States of America. September 1996, 93 (18): 9437–42. Bibcode:1996PNAS...93.9437I. PMC 38446 . PMID 8790348. doi:10.1073/pnas.93.18.9437. 
  17. ^ Pype S, Declercq W, Ibrahimi A, Michiels C, Van Rietschoten JG, Dewulf N, de Boer M, Vandenabeele P, Huylebroeck D, Remacle JE. TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor-associated factors (TRAFs), and that inhibits nuclear factor-kappa B activation. The Journal of Biological Chemistry. June 2000, 275 (24): 18586–93. PMID 10764746. doi:10.1074/jbc.M000531200 . 
  18. ^ Sharma S, Pavlasova GM, Seda V, Cerna KA, Vojackova E, Filip D, Ondrisova L, Sandova V, Kostalova L, Zeni PF, Borsky M, Oppelt J, Liskova K, Kren L, Janikova A, Pospisilova S, Fernandes SM, Shehata M, Rassenti LZ, Jaeger U, Doubek M, Davids MS, Brown JR, Mayer J, Kipps TJ, Mraz M. miR-29 Modulates CD40 Signaling in Chronic Lymphocytic Leukemia by Targeting TRAF4: an Axis Affected by BCR inhibitors. Blood. December 2020. PMID 33171493. doi:10.1182/blood.2020005627 . 
  19. ^ Vonderheide RH. The Immune Revolution: A Case for Priming, Not Checkpoint. Cancer Cell. April 2018, 33 (4): 563–569. PMC 5898647 . PMID 29634944. doi:10.1016/j.ccell.2018.03.008. 

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