分化簇40(Cluster of differentiation 40,簡稱CD40),是一種分布於抗原呈递细胞(APC)的協同刺激因子暨蛋白受體。CD40與輔助型T細胞上的CD154英语CD154CD40L英语CD40L)結合後,抗原呈递细胞會活化,並產生一系列下游反應[6]

CD40
已知的結構
PDB直系同源搜索: PDBe RCSB
識別號
别名CD40;, Bp50, CDW40, TNFRSF5, p50, CD40 (protein), CD40 molecule
外部IDOMIM109535 MGI88336 HomoloGene954 GeneCardsCD40
相關疾病
類風濕性關節炎、​第三型高IgM症候群[1]
基因位置(人类
20號染色體
染色体20號染色體[2]
20號染色體
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
物種人類小鼠
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]
維基數據
檢視/編輯人類檢視/編輯小鼠

CD40缺失會造成第三型高IgM症候群英语Hyper-IgM syndrome type 3(Hyper-IgM syndrome type 3)[6]

結構及表達

CD40屬於腫瘤壞死因子受體英语TNF-receptor超家族英语TNF receptor superfamily(TNF receptor superfamily)的一員[6]。含有AT鉤英语AT-hook構型的轉譯因子AKNA英语AKNA可以協同調控CD40及其配體[7]

功能

CD40在T細胞相關的免疫和發炎反應具有重要功能,諸如免疫球蛋白類型轉換、記憶B細胞發育,以及生發中心形成[6][8]。 B細胞上也有CD40存在,並會與輔助T細胞上的CD40L結合。CD40和CD40L的橋接可以活化B細胞,降低B細胞接觸到抗原的反應閾值,使其更容易釋放抗體。另外也可以促進B細胞的增殖、同型粘連(homotypic adhesion)、抗體類型轉換。在表面蛋白的表達方面,可以刺激MHC class II英语MHC class IICD23英语CD23CD25英语CD25(IL-12R)、CD69英语CD69CD44等分子的表達,也會使淋巴球功能性抗原1(LFA-1)的轉為高親合態。在細胞週期方面,則會從間期進入S期,開始進行DNA和RNA的複製及合成CD40L[6]。 有研究也發現,要活化β澱粉樣蛋白的微膠細胞也需要CD40和CD40L的連結,因此可能也與阿茲海默症的病生理學相關[9]

CD40-CD40L反應在免疫上的角色[6]
相關 不相關
一般免疫
  • T細胞啟動(priming)
  • 決定周邊免疫球蛋白的濃度
  • 周邊淋巴器官及次級淋巴器官的淋巴球比例
體液免疫
自體免疫
胞殺作用及移植
  • 抗病毒的胞殺反應
  • 抗癌細胞的胞殺反應
T細胞選汰 T細胞的胸腺選汰

交互作用

CD40可以與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]產生交互作用。TRAF4家族的蛋白質雖不會直接與CD40作用,但可以間接增加CD40的作用[18]

臨床應用

CD40為癌症免疫疗法的潛在標的,目前已經開發出針對該蛋白的刺激性单克隆抗体,以活化樹突細胞刺激抗癌T細胞的途徑,且已有相關論文發表。現有多項臨床研究正在進行[19]

參考文獻

  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. 

外部連結

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