CD40

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（CD40L）结合后，抗原呈递细胞会活化，并产生一系列下游反应^[1]。

CD40缺失会造成第三型高IgM症候群（Hyper-IgM syndrome type 3）^[1]。

结构及表达

CD40属于肿瘤坏死因子受体超家族（TNF receptor superfamily）的一员^[1]。含有AT钩构型的转译因子AKNA可以协同调控CD40及其配体^[2]。

功能

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^[1]^[3]。 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的桥接可以活化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、CD23、CD25（IL-12R）、CD69、CD44等分子的表达，也会使淋巴球功能性抗原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^[1]。有研究也发现，要活化β淀粉样蛋白的微胶细胞也需要CD40和CD40L的链接，因此可能也与阿兹海默症的病生理学相关^[4]。

CD40-CD40L反应在免疫上的角色^[1]
	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球比例
体液免疫	胸腺依赖性抗原（Thymus dependent antigen）的初级抗体反应胸腺依赖性抗原（Thymus dependent antigen）的次级抗体反应及免疫球蛋白类型转换记忆B细胞及生发中心的发育	李斯特菌的廓清对抗多糖体的抗体反应
自体免疫	胶原蛋白引起的关节炎狼疮性肾炎实验性自体免疫脑炎（Experimental allergic encephalomyelitis）
胞杀作用及移植	急性或慢性移植物对抗宿主疾病（GVHD）异体移植的胞杀作用	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

CD40可以与TRAF2^[5]^[6]^[7]、TRAF3^[6]^[8]^[9]^[10]、TRAF6^[6]^[10]、TRAF5^[6]^[11]、TTRAP^[12]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^[13]。

临床应用

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，以活化树突细胞刺激抗癌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^[14]。

参考文献

↑ ^1.0 ^1.1 ^1.2 ^1.3 ^1.4 ^1.5 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. ISSN 1040-8401. doi:10.1615/CritRevImmunol.v37.i2-6.100 （英语）.
↑ 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. ISSN 0028-0836. PMID 11268217. doi:10.1038/35066602.
↑ 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.
↑ 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）.
↑ 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. 1999-07, 96 (15): 8408–13. Bibcode:1999PNAS...96.8408M. PMC 17529 . PMID 10411888. doi:10.1073/pnas.96.15.8408.
↑ ^6.0 ^6.1 ^6.2 ^6.3 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. 1999-02, 96 (4): 1234–9. Bibcode:1999PNAS...96.1234T. PMC 15446 . PMID 9990007. doi:10.1073/pnas.96.4.1234.
↑ Malinin NL, Boldin MP, Kovalenko AV, Wallach D. MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature. 1997-02, 385 (6616): 540–4. PMID 9020361. S2CID 4366355. doi:10.1038/385540a0.
↑ 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. 1994-12, 269 (48): 30069–72. PMID 7527023.
↑ 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. 2000-09, 97 (19): 10395–9. Bibcode:2000PNAS...9710395N. PMC 27035 . PMID 10984535. doi:10.1073/pnas.97.19.10395.
↑ ^10.0 ^10.1 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. 1997-12, 16 (23): 6914–25. PMC 1170295 . PMID 9384571. doi:10.1093/emboj/16.23.6914.
↑ 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. 1996-09, 93 (18): 9437–42. Bibcode:1996PNAS...93.9437I. PMC 38446 . PMID 8790348. doi:10.1073/pnas.93.18.9437.
↑ 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. 2000-06, 275 (24): 18586–93. PMID 10764746. doi:10.1074/jbc.M000531200 .
↑ 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. 2020-12. PMID 33171493. doi:10.1182/blood.2020005627 .
↑ Vonderheide RH. The Immune Revolution: A Case for Priming, Not Checkpoint. Cancer Cell. 2018-04, 33 (4): 563–569. PMC 5898647 . PMID 29634944. doi:10.1016/j.ccell.2018.03.008.

外部链接

Human CD40 genome location and CD40 gene details page in the UCSC Genome Browser.
PDBe-KB provides an overview of all the structure information available in the PDB for Human Tumor necrosis factor receptor superfamily member 5 (CD40)

延伸阅读

Parham P. The Immune System 2nd. Garland Science. 2004: 169–173. ISBN 978-0-8153-4093-5. 已忽略未知参数|name-list-style= (帮助)
Wang JH, Zhang YW, Zhang P, Deng BQ, Ding S, Wang ZK, Wu T, Wang J. CD40 ligand as a potential biomarker for atherosclerotic instability. Neurological Research. 2013-09, 35 (7): 693–700. PMC 3770830 . PMID 23561892. doi:10.1179/1743132813Y.0000000190.
Banchereau J, Bazan F, Blanchard D, Brière F, Galizzi JP, van Kooten C, Liu YJ, Rousset F, Saeland S. The CD40 antigen and its ligand. Annual Review of Immunology. 1994, 12: 881–922. PMID 7516669. doi:10.1146/annurev.iy.12.040194.004313.
van Kooten C, Banchereau J. CD40-CD40 ligand. Journal of Leukocyte Biology. 2000-01, 67 (1): 2–17. PMID 10647992. S2CID 35592719. doi:10.1002/jlb.67.1.2.
Schattner EJ. CD40 ligand in CLL pathogenesis and therapy. Leukemia & Lymphoma. 2000-05, 37 (5–6): 461–72. PMID 11042507. S2CID 39398949. doi:10.3109/10428190009058499.
Bhushan A, Covey LR. CD40:CD40L interactions in X-linked and non-X-linked hyper-IgM syndromes. Immunologic Research. 2002, 24 (3): 311–24. PMID 11817328. S2CID 19537892. doi:10.1385/IR:24:3:311.
Cheng G, Schoenberger SP. CD40 signaling and autoimmunity. Signal Transduction Pathways in Autoimmunity. Current Directions in Autoimmunity 5. 2002: 51–61. ISBN 978-3-8055-7308-5. PMID 11826760. doi:10.1159/000060547.
Dallman C, Johnson PW, Packham G. Differential regulation of cell survival by CD40. Apoptosis. 2003-01, 8 (1): 45–53. PMID 12510151. S2CID 22461134. doi:10.1023/A:1021696902187.
O'Sullivan B, Thomas R. Recent advances on the role of CD40 and dendritic cells in immunity and tolerance. Current Opinion in Hematology. 2003-07, 10 (4): 272–8. PMID 12799532. S2CID 43043879. doi:10.1097/00062752-200307000-00004.
Benveniste EN, Nguyen VT, Wesemann DR. Molecular regulation of CD40 gene expression in macrophages and microglia. Brain, Behavior, and Immunity. 2004-01, 18 (1): 7–12. PMID 14651941. S2CID 8081107. doi:10.1016/j.bbi.2003.09.001.
Xu Y, Song G. The role of CD40-CD154 interaction in cell immunoregulation. Journal of Biomedical Science. 2005, 11 (4): 426–38. PMID 15153777. S2CID 202658036. doi:10.1159/000077892.
Contin C, Couzi L, Moreau JF, Déchanet-Merville J, Merville P. [Immune dysfuntion of uremic patients: potential role for the soluble form of CD40]. Nephrologie. 2004, 25 (4): 119–26. PMID 15291139.

[:0-1] 1.0 ^1.1 ^1.2 ^1.3 ^1.4 ^1.5 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. ISSN 1040-8401. doi:10.1615/CritRevImmunol.v37.i2-6.100 （英语）.

[2] 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. ISSN 0028-0836. PMID 11268217. doi:10.1038/35066602.

[3] 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.

[4] 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）.

[pmid10411888-5] 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. 1999-07, 96 (15): 8408–13. Bibcode:1999PNAS...96.8408M. PMC 17529 . PMID 10411888. doi:10.1073/pnas.96.15.8408.

[pmid9990007-6] 6.0 ^6.1 ^6.2 ^6.3 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. 1999-02, 96 (4): 1234–9. Bibcode:1999PNAS...96.1234T. PMC 15446 . PMID 9990007. doi:10.1073/pnas.96.4.1234.

[pmid9020361-7] Malinin NL, Boldin MP, Kovalenko AV, Wallach D. MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature. 1997-02, 385 (6616): 540–4. PMID 9020361. S2CID 4366355. doi:10.1038/385540a0.

[pmid7527023-8] 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. 1994-12, 269 (48): 30069–72. PMID 7527023.

[pmid10984535-9] 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. 2000-09, 97 (19): 10395–9. Bibcode:2000PNAS...9710395N. PMC 27035 . PMID 10984535. doi:10.1073/pnas.97.19.10395.

[pmid9384571-10] 10.0 ^10.1 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. 1997-12, 16 (23): 6914–25. PMC 1170295 . PMID 9384571. doi:10.1093/emboj/16.23.6914.

[pmid8790348-11] 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. 1996-09, 93 (18): 9437–42. Bibcode:1996PNAS...93.9437I. PMC 38446 . PMID 8790348. doi:10.1073/pnas.93.18.9437.

[pmid10764746-12] 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. 2000-06, 275 (24): 18586–93. PMID 10764746. doi:10.1074/jbc.M000531200 .

[pmid33171493-13] 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. 2020-12. PMID 33171493. doi:10.1182/blood.2020005627 .

[14] Vonderheide RH. The Immune Revolution: A Case for Priming, Not Checkpoint. Cancer Cell. 2018-04, 33 (4): 563–569. PMC 5898647 . PMID 29634944. doi:10.1016/j.ccell.2018.03.008.

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