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Gene Review

CD40  -  CD40 molecule, TNF receptor superfamily...

Homo sapiens

Synonyms: B-cell surface antigen CD40, Bp50, CD40L receptor, CDW40, CDw40, ...

Disease relevance of CD40


Psychiatry related information on CD40

  • The aberrant expression of CD40 is involved in the initiation and maintenance of various human diseases including multiple sclerosis, arthritis, atherosclerosis, and Alzheimer's disease [6].
  • Overexpression of p50/dynamitin, which causes the dissociation of the dynactin complex, significantly inhibited the formation of aggresomes, suggesting that the minus-end-directed motor activities of cytoplasmic dynein are required for aggresome formation [7].
  • Role of nigral NFkappaB p50 and p65 subunit expression in haloperidol-induced neurotoxicity and stereotyped behavior in rats [8].

High impact information on CD40


Chemical compound and disease context of CD40


Biological context of CD40


Anatomical context of CD40


Associations of CD40 with chemical compounds

  • CD40 binds to a ligand (CD40-L) which is an approximately 35 kDa glycoprotein of 261 aa, a member of the tumor necrosis factor superfamily [1].
  • CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily [21].
  • The effect of DSCG was not specific for CD40-mediated induction of IgE isotype switching because DSCG inhibited IgE synthesis as well as S mu-->S epsilon deletional switch recombination induced by hydrocortisone and IL-4 in B cells [22].
  • CD40-mediated induction of bcl-x required neither wild-type BTK nor extracellular Ca2+ and was insensitive to CsA [23].
  • Thereafter, they become sensitive, which is associated with the CD40-induced expression of the proapoptotic protein B-cell leukemia 2 homology 3 (BH3) interacting domain death agonist (Bid) [24].
  • Cotransfection of Fra-2 with the Jun AP-1 subunits and p50/c-Rel NF-kappaB led to synergistic activation of the relB promoter [25].

Physical interactions of CD40

  • However, single aa substitution of Glu-235 in cyt-N of human CD40 with Ala abolishes the binding of TRAF6 to cyt-N and NFkappaB activation by cyt-N [26].
  • We demonstrate a negative regulatory role for TRAF3 and that this activity is dependent on the availability of an intact TRAF3-binding site in the cytoplasmic domain of CD40 [27].
  • A novel member of the TRAF family of putative signal transducing proteins binds to the cytosolic domain of CD40 [28].
  • The inhibitory mutant has no TNFR-associated factor 2-binding capabilities and inhibits the recruitment of TNFR-associated factor 2 to the CD40 signaling complex after stimulation [29].
  • Structural models based on the homology of CD154 with TNF and lymphotoxin indicate that binding to CD40 involves three regions surrounding amino acids K143, R203 and Q220, and that strands W140-S149 and S198-A210 are critical for such interactions [30].

Enzymatic interactions of CD40

  • Recombinant MP disintegrin tumor necrosis factor-alpha converting enzyme (TACE) cleaved the purified CD40 ectodomain/Fc chimeric protein in vitro, giving rise to an sCD40 form similar to that shed from B cell cultures [31].
  • CD20 was strongly phosphorylated on resting B cells after CDw40 stimulation, suggesting that CD20 may be functionally regulated by a protein kinase(s) [32].
  • In the absence of DNA chymotrypsin cleaved p50 after residues Y60 and N78, while proteinase K cleaved p50 after residues S74 and Q180 [33].

Co-localisations of CD40

  • Immunohistochemical analysis revealed that MCP-1 protein is colocalized with active form of NF-kappaB p50 [34].

Regulatory relationships of CD40

  • Herein we demonstrate that dendritic Langerhans cells (D-Lc) generated by culturing cord blood CD34+ progenitor cells with granulocyte/macrophage colony-stimulating and tumor necrosis factor alpha (TNF-alpha) express functional CD40 at a density higher than that found on B cells [35].
  • Interleukin-10 induces immunoglobulin G isotype switch recombination in human CD40-activated naive B lymphocytes [36].
  • CD40 activation induces a 4-fold (RPMI 8226) and a 6-fold (SV) increase in VEGF transcripts, respectively, under restrictive, but not permissive, temperatures [37].
  • Accordingly, TRAF1 inhibited CD40-dependent but not TNF-R1-dependent NF-kappaB activation [38].
  • Of the six TRAFs identified to date, TRAFs 2, 3, 5, and 6 are reported to associate directly with the cytoplasmic tail of CD40, but previous studies have principally examined transient overexpression of TRAF6 in cells that do not normally express CD40 [39].

Other interactions of CD40

  • CD40 is a member of the tumor necrosis factor (TNF) receptor family of cell surface proteins and was originally described as a B cell restricted antigen [5].
  • Expression of CD40, CD54, and major histocompatibility complex (MHC) class II HLA-DR antigens by lesional keratinocytes was markedly reduced in serial biopsy specimens [40].
  • Combined signaling through the interluekin 4 receptor and CD40 induces an increased expression of Fas with a commensurate increase in the level of TRAF2, but not TRAF3, that is recruited to the receptor complex [21].
  • Expression of TLR2, TLR4, and the activation/maturation marker CD40 was assessed by cell surface labeling [41].
  • Here, we show that via TRAF6, CD40 mediates only the activation of the canonical NF-kappaB pathway [42].

Analytical, diagnostic and therapeutic context of CD40

  • Frozen sections from normal spleen, thyroid, skin, muscle, kidney, lung, or umbilical cord were studied for CD40 expression by immunohistochemistry [20].
  • We propose that a novel mechanism of hepatocyte apoptosis, involving a cooperative interaction between CD40 and Fas, is involved in the hepatocyte loss of chronic liver allograft rejection [43].
  • DSCG had no effect on the induction of epsilon germline transcripts by IL-4 but strongly inhibited CD40 mediated S mu-->S epsilon deletional switch recombination in IL-4-treated B cells as assayed by nested primer PCR [22].
  • Finally, in vivo requirement of gp39/CD40 interaction for specific Ab production was demonstrated by the finding that activated T cells from patients with x-linked hyper IgM syndrome express functionally defective gp39 and respond with depressed Ab titers and fail to switch from IgM to IgG after multiple phage immunizations [44].
  • Messenger RNA levels for CD40 and potential downstream effector molecules were quantified by polymerase chain reaction-based and ribonuclease protection assays, respectively, and nuclear factor (NF) kappaB nuclear translocation was detected by immunofluorescence [45].


  1. The CD40 antigen and its ligand. Banchereau, J., Bazan, F., Blanchard, D., Brière, F., Galizzi, J.P., van Kooten, C., Liu, Y.J., Rousset, F., Saeland, S. Annu. Rev. Immunol. (1994) [Pubmed]
  2. Correspondence re R. Lapointe et al., CD40-stimulated B lymphocytes pulsed with tumor antigens are effective antigen-presenting cells that can generate specific T cells. Cancer Res 2003;63:2836-43. von Bergwelt-Baildon, M., Schultze, J.L., Maecker, B., Menezes, I., Nadler, L.M. Cancer. Res. (2004) [Pubmed]
  3. The role of CD40 and CD80 accessory cell molecules in dendritic cell-dependent HIV-1 infection. Pinchuk, L.M., Polacino, P.S., Agy, M.B., Klaus, S.J., Clark, E.A. Immunity (1994) [Pubmed]
  4. Human non-germinal center B cell interleukin (IL)-12 production is primarily regulated by T cell signals CD40 ligand, interferon gamma, and IL-10: role of B cells in the maintenance of T cell responses. Schultze, J.L., Michalak, S., Lowne, J., Wong, A., Gilleece, M.H., Gribben, J.G., Nadler, L.M. J. Exp. Med. (1999) [Pubmed]
  5. CD40 expression by human monocytes: regulation by cytokines and activation of monocytes by the ligand for CD40. Alderson, M.R., Armitage, R.J., Tough, T.W., Strockbine, L., Fanslow, W.C., Spriggs, M.K. J. Exp. Med. (1993) [Pubmed]
  6. Suppressor of cytokine signaling 1 inhibits cytokine induction of CD40 expression in macrophages. Wesemann, D.R., Dong, Y., O'Keefe, G.M., Nguyen, V.T., Benveniste, E.N. J. Immunol. (2002) [Pubmed]
  7. Characterization and dynamics of aggresome formation by a cytosolic GFP-chimera. García-Mata, R., Bebök, Z., Sorscher, E.J., Sztul, E.S. J. Cell Biol. (1999) [Pubmed]
  8. Role of nigral NFkappaB p50 and p65 subunit expression in haloperidol-induced neurotoxicity and stereotyped behavior in rats. Saldaña, M., Bonastre, M., Aguilar, E., Marin, C. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. (2006) [Pubmed]
  9. CD40/CD154 interactions at the interface of tolerance and immunity. Quezada, S.A., Jarvinen, L.Z., Lind, E.F., Noelle, R.J. Annu. Rev. Immunol. (2004) [Pubmed]
  10. CD40 and CD154 in cell-mediated immunity. Grewal, I.S., Flavell, R.A. Annu. Rev. Immunol. (1998) [Pubmed]
  11. Functional expression of receptor activator of nuclear factor kappaB in Hodgkin disease cell lines. Fiumara, P., Snell, V., Li, Y., Mukhopadhyay, A., Younes, M., Gillenwater, A.M., Cabanillas, F., Aggarwal, B.B., Younes, A. Blood (2001) [Pubmed]
  12. Germinal center-derived signals act with Bcl-2 to decrease apoptosis and increase clonogenicity of drug-treated human B lymphoma cells. Walker, A., Taylor, S.T., Hickman, J.A., Dive, C. Cancer Res. (1997) [Pubmed]
  13. Viral replication-independent blockade of dendritic cell maturation and interleukin-12 production by human herpesvirus 6. Smith, A.P., Paolucci, C., Di Lullo, G., Burastero, S.E., Santoro, F., Lusso, P. J. Virol. (2005) [Pubmed]
  14. Mechanisms controlling the human immunoglobulin E response: new directions in the therapy of allergic diseases. Leung, D.Y. Pediatr. Res. (1993) [Pubmed]
  15. Suppression of autoreactive T-cell response to glycoprotein IIb/IIIa by blockade of CD40/CD154 interaction: implications for treatment of immune thrombocytopenic purpura. Kuwana, M., Kawakami, Y., Ikeda, Y. Blood (2003) [Pubmed]
  16. Jak3 is associated with CD40 and is critical for CD40 induction of gene expression in B cells. Hanissian, S.H., Geha, R.S. Immunity (1997) [Pubmed]
  17. C4b-binding protein (C4BP) activates B cells through the CD40 receptor. Brodeur, S.R., Angelini, F., Bacharier, L.B., Blom, A.M., Mizoguchi, E., Fujiwara, H., Plebani, A., Notarangelo, L.D., Dahlback, B., Tsitsikov, E., Geha, R.S. Immunity (2003) [Pubmed]
  18. Induction of human IgE synthesis in B cells by mast cells and basophils. Gauchat, J.F., Henchoz, S., Mazzei, G., Aubry, J.P., Brunner, T., Blasey, H., Life, P., Talabot, D., Flores-Romo, L., Thompson, J. Nature (1993) [Pubmed]
  19. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Henn, V., Slupsky, J.R., Gräfe, M., Anagnostopoulos, I., Förster, R., Müller-Berghaus, G., Kroczek, R.A. Nature (1998) [Pubmed]
  20. Functional interactions of T cells with endothelial cells: the role of CD40L-CD40-mediated signals. Yellin, M.J., Brett, J., Baum, D., Matsushima, A., Szabolcs, M., Stern, D., Chess, L. J. Exp. Med. (1995) [Pubmed]
  21. Assembly and regulation of the CD40 receptor complex in human B cells. Kuhné, M.R., Robbins, M., Hambor, J.E., Mackey, M.F., Kosaka, Y., Nishimura, T., Gigley, J.P., Noelle, R.J., Calderhead, D.M. J. Exp. Med. (1997) [Pubmed]
  22. Disodium cromoglycate inhibits S mu-->S epsilon deletional switch recombination and IgE synthesis in human B cells. Loh, R.K., Jabara, H.H., Geha, R.S. J. Exp. Med. (1994) [Pubmed]
  23. An essential role for Bruton's [corrected] tyrosine kinase in the regulation of B-cell apoptosis. Anderson, J.S., Teutsch, M., Dong, Z., Wortis, H.H. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  24. Inhibitors of XIAP sensitize CD40-activated chronic lymphocytic leukemia cells to CD95-mediated apoptosis. Kater, A.P., Dicker, F., Mangiola, M., Welsh, K., Houghten, R., Ostresh, J., Nefzi, A., Reed, J.C., Pinilla, C., Kipps, T.J. Blood (2005) [Pubmed]
  25. CD40 ligand-mediated activation of the de novo RelB NF-kappaB synthesis pathway in transformed B cells promotes rescue from apoptosis. Mineva, N.D., Rothstein, T.L., Meyers, J.A., Lerner, A., Sonenshein, G.E. J. Biol. Chem. (2007) [Pubmed]
  26. Two differently regulated nuclear factor kappaB activation pathways triggered by the cytoplasmic tail of CD40. Tsukamoto, N., Kobayashi, N., Azuma, S., Yamamoto, T., Inoue, J. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  27. Cutting edge: contrasting roles of TNF receptor-associated factor 2 (TRAF2) and TRAF3 in CD40-activated B lymphocyte differentiation. Hostager, B.S., Bishop, G.A. J. Immunol. (1999) [Pubmed]
  28. A novel member of the TRAF family of putative signal transducing proteins binds to the cytosolic domain of CD40. Sato, T., Irie, S., Reed, J.C. FEBS Lett. (1995) [Pubmed]
  29. Characterization of a CD40-dominant inhibitory receptor mutant. Mehl, A.M., Jones, M., Rowe, M., Brennan, P. J. Immunol. (2001) [Pubmed]
  30. A Salmonella typhi OmpC fusion protein expressing the CD154 Trp140-Ser149 amino acid strand binds CD40 and activates a lymphoma B-cell line. Vega, M.I., Santos-Argumedo, L., Huerta-Yepez, S., Luría-Perez, R., Ortiz-Navarrete, V., Isibasi, A., González-Bonilla, C.R. Immunology (2003) [Pubmed]
  31. Membrane-anchored CD40 is processed by the tumor necrosis factor-alpha-converting enzyme. Implications for CD40 signaling. Contin, C., Pitard, V., Itai, T., Nagata, S., Moreau, J.F., Déchanet-Merville, J. J. Biol. Chem. (2003) [Pubmed]
  32. Molecular cloning of the human B cell CD20 receptor predicts a hydrophobic protein with multiple transmembrane domains. Einfeld, D.A., Brown, J.P., Valentine, M.A., Clark, E.A., Ledbetter, J.A. EMBO J. (1988) [Pubmed]
  33. Conformational changes induced by DNA binding of NF-kappa B. Matthews, J.R., Nicholson, J., Jaffray, E., Kelly, S.M., Price, N.C., Hay, R.T. Nucleic Acids Res. (1995) [Pubmed]
  34. Role of monocyte chemotactic protein-1 and nuclear factor kappa B in the pathogenesis of proliferative diabetic retinopathy. Harada, C., Okumura, A., Namekata, K., Nakamura, K., Mitamura, Y., Ohguro, H., Harada, T. Diabetes Res. Clin. Pract. (2006) [Pubmed]
  35. Activation of human dendritic cells through CD40 cross-linking. Caux, C., Massacrier, C., Vanbervliet, B., Dubois, B., Van Kooten, C., Durand, I., Banchereau, J. J. Exp. Med. (1994) [Pubmed]
  36. Interleukin-10 induces immunoglobulin G isotype switch recombination in human CD40-activated naive B lymphocytes. Malisan, F., Brière, F., Bridon, J.M., Harindranath, N., Mills, F.C., Max, E.E., Banchereau, J., Martinez-Valdez, H. J. Exp. Med. (1996) [Pubmed]
  37. CD40 activation induces p53-dependent vascular endothelial growth factor secretion in human multiple myeloma cells. Tai, Y.T., Podar, K., Gupta, D., Lin, B., Young, G., Akiyama, M., Anderson, K.C. Blood (2002) [Pubmed]
  38. Tumor necrosis factor receptor-associated factor (TRAF) 1 regulates CD40-induced TRAF2-mediated NF-kappaB activation. Fotin-Mleczek, M., Henkler, F., Hausser, A., Glauner, H., Samel, D., Graness, A., Scheurich, P., Mauri, D., Wajant, H. J. Biol. Chem. (2004) [Pubmed]
  39. Characterization of the roles of TNF receptor-associated factor 6 in CD40-mediated B lymphocyte effector functions. Jalukar, S.V., Hostager, B.S., Bishop, G.A. J. Immunol. (2000) [Pubmed]
  40. Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells. Abrams, J.R., Kelley, S.L., Hayes, E., Kikuchi, T., Brown, M.J., Kang, S., Lebwohl, M.G., Guzzo, C.A., Jegasothy, B.V., Linsley, P.S., Krueger, J.G. J. Exp. Med. (2000) [Pubmed]
  41. Characteristics of intestinal dendritic cells in inflammatory bowel diseases. Hart, A.L., Al-Hassi, H.O., Rigby, R.J., Bell, S.J., Emmanuel, A.V., Knight, S.C., Kamm, M.A., Stagg, A.J. Gastroenterology (2005) [Pubmed]
  42. TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-kappaB pathway by TRAF-binding TNFRs. Hauer, J., Püschner, S., Ramakrishnan, P., Simon, U., Bongers, M., Federle, C., Engelmann, H. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  43. CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection. Afford, S.C., Randhawa, S., Eliopoulos, A.G., Hubscher, S.G., Young, L.S., Adams, D.H. J. Exp. Med. (1999) [Pubmed]
  44. B cell activation via CD40 is required for specific antibody production by antigen-stimulated human B cells. Nonoyama, S., Hollenbaugh, D., Aruffo, A., Ledbetter, J.A., Ochs, H.D. J. Exp. Med. (1993) [Pubmed]
  45. The effects of malignant transformation on susceptibility of human urothelial cells to CD40-mediated apoptosis. Bugajska, U., Georgopoulos, N.T., Southgate, J., Johnson, P.W., Graber, P., Gordon, J., Selby, P.J., Trejdosiewicz, L.K. J. Natl. Cancer Inst. (2002) [Pubmed]
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