Alternative titles; symbols
HGNC Approved Gene Symbol: CD40
Cytogenetic location: 20q13.12 Genomic coordinates (GRCh38): 20:46,118,314-46,129,858 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.12 | Immunodeficiency with hyper-IgM, type 3 | 606843 | Autosomal recessive | 3 |
CD40 is a cell surface receptor that is expressed on the surface of all mature B cells, most mature B-cell malignancies, and some early B-cell acute lymphocytic leukemias, but is not expressed on plasma cells (Clark, 1990). It is also expressed on monocytes, dendritic cells, endothelial cells, and epithelial cells (van Kooten and Banchereau, 2000).
Stamenkovic et al. (1989) isolated a cDNA encoding the CD40 gene and demonstrated by the predicted sequence of the protein that CD40 is related to human nerve growth factor receptor (162010). It is also closely related to the receptor for TNF-alpha (191160) and to CD27 (186711). These homologies imply that the ligand for CD40 may be a soluble factor and that CD40 is a member of the cytokine receptor family. CD40 is a phosphoprotein and is capable of expression as a homodimer.
Kawabe et al. (1994) and Castigli et al. (1994) confirmed the essential role of CD40 for T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation in mice (see ANIMAL MODEL section). CD40 interacts with the CD40 ligand (CD40LG; 300386), which is found primarily on T cells, playing a role in both humoral and cell-mediated immune responses. Activation of CD40 on B cells by CD40 ligand causes B cell proliferation, differentiation, immunoglobulin isotype switching, germinal center formation, and stimulation of the humoral memory response. CD40 has been found to mediate a broad variety of immune and inflammatory responses (Schonbeck and Libby, 2001). Within the cell, the CD40 molecule acts as a transmembrane signal transducer that leads to activation of intracellular kinases and transcription factors.
Trompouki et al. (2003) identified CYLD (605018) as a deubiquitinating enzyme that negatively regulates activation of the transcription factor NF-kappa-B (164011) by specific tumor necrosis factor receptors (TNFRs). Loss of the deubiquitinating activity of CYLD correlated with tumorigenesis. CYLD inhibits activation of NF-kappa-B by the TNFR family members CD40, XEDAR (300276), and EDAR (604095) in a manner that depends on deubiquitinating activity of CYLD. Downregulation of CYLD by RNA-mediated interference augments both basal and CD40-mediated activation of NF-kappa-B. The inhibition of NF-kappa-B activation by CYLD is mediated, at least in part, by the deubiquitination and inactivation of TNFR-associated factor 2 (TRAF2; 601895) and, to a lesser extent, TRAF6 (602355). Trompouki et al. (2003) concluded that CYLD is a negative regulator of the cytokine-mediated activation of NF-kappa-B that is required for appropriate cellular homeostasis of skin appendages.
Becker et al. (2002) found that mouse macrophages expressing Cd40 specifically bound and internalized human HSP70 (140550) with its bound peptide. Binding of HSP70-peptide complex to the exoplasmic domain of Cd40 was mediated by the N-terminal nucleotide-binding domain of HSP70 in its ADP state. Binding between HSP70 and Cd40 increased in the presence of the peptide substrate, and binding induced signaling via p38 (600289). Becker et al. (2002) concluded that CD40 is a cochaperone-like receptor that mediates the uptake of exogenous HSP70-peptide complexes by macrophages and dendritic cells.
Brodeur et al. (2003) identified a 23-kD protein that bound CD40 as C4BP-alpha (C4BPA; 120830). Flow cytometric analysis demonstrated binding of C4BP to human B-cell lines expressing CD40, but not to cells from CD40-deficient patients. Competitive binding analysis showed that CD40LG and C4BP bound distinct sites on CD40. C4BP induced proliferation, upregulation of CD54 (ICAM1; 147840) and CD86 (601020) surface expression, and, together with IL4 (147780), IgE synthesis in normal B cells, but not in B cells from patients with CD40 or IKBKG (300248) deficiencies. Immunohistochemical analysis showed that C4BP colocalized with CD40 on B cells in tonsillar germinal centers. Brodeur et al. (2003) proposed that C4BP is an activating ligand for CD40 and represents an interface between complement and B-cell activation.
Cytokine signaling is thought to require assembly of multicomponent signaling complexes at cytoplasmic segments of membrane-embedded receptors, in which receptor-proximal protein kinases are activated. Matsuzawa et al. (2008) reported that, upon ligation, CD40 formed a complex containing adaptor molecules TRAF2 and TRAF3 (601896), ubiquitin-conjugating enzyme UBC13 (UBE2N; 603679), cellular inhibitor of apoptosis protein-1 (CIAP1, or BIRC2; 601712) and -2 (CIAP2, or BIRC3; 601721), IKK-gamma (IKBKG), and MEKK1 (MAP3K1; 600982). TRAF2, UBC13, and IKK-gamma were required for complex assembly and activation of MEKK1 and MAP kinase cascades. However, the kinases were not activated unless the complex was translocated from the membrane to the cytosol upon CIAP1/CIAP2-induced degradation of TRAF3. Matsuzawa et al. (2008) proposed that this 2-stage signaling mechanism may apply to other innate immune receptors and may account for spatial and temporal separation of MAPK and IKK signaling.
Therapeutic Uses
Using replication defective adenovirus encoding mouse CD154 (Ad-CD154), Kato et al. (1998) modified human chronic lymphocytic leukemia B cells to express a functional ligand for CD40. This not only induced expression of immune accessory molecules on the infected cell, but also allowed it to transactivate noninfected bystander leukemia B cells. In addition, factors that impair the antigen-presenting capacity of leukemia B cells were downmodulated. Kato et al. (1998) suggested that Ad-CD154 can induce a host antileukemia response that may have therapeutic potential.
Interruption of CD40LG-CD40 signaling by administration of an anti-CD40LG antibody was found to limit experimental autoimmune diseases such as collagen-induced arthritis, lupus nephritis, acute or chronic graft-versus-host disease (GVHD; see 614395), multiple sclerosis, and thyroiditis (Mach et al., 1998).
Because CD40 activation can reverse immune suppression and drive antitumor T cell responses, Beatty et al. (2011) tested the combination of an agonist CD40 antibody with gemcitabine chemotherapy in a small cohort of patients with surgically incurable pancreatic ductal adenocarcinoma (PDA; see 260350) and observed tumor regressions in some patients. They reproduced this treatment effect in a genetically engineered mouse model of PDA and found unexpectedly that tumor regression required macrophages but not T cells or gemcitabine. CD40-activated macrophages rapidly infiltrated tumors, became tumoricidal, and facilitated the depletion of tumor stroma. Thus, Beatty et al. (2011) concluded that cancer immune surveillance does not necessarily depend on therapy-induced T cells; rather, their findings demonstrated a CD40-dependent mechanism for targeting tumor stroma in the treatment of cancer.
Li and Ravetch (2011) found that coengagement of the Fc domain of agonistic CD40 monoclonal antibodies with the inhibitory Fc-gamma receptor Fc-gamma-RIIB (604590) is required for immune activation. Direct comparison of monoclonal antibodies to CD40 enhanced for activating Fc-gamma-R binding, hence capable of cytotoxicity, or for inhibitory Fc-gamma-RIIB binding, revealed that enhancing Fc-gamma-RIIB binding conferred immunostimulatory activity and considerably greater antitumor responses. Li and Ravetch (2011) concluded that this unexpected requirement for Fc-gamma-RIIB in enhancing CD40-mediated immune activation has direct implications for the design of agonistic antibodies to TNFR as therapeutics.
Role in Atherosclerosis
Increasing evidence supports the involvement of inflammation and immunity in atherogenesis. Mach et al. (1998) noted that cells in human atherosclerotic lesions express the immune mediator CD40 and its ligand CD40LG. CD40LG-positive T cells accumulate in atheroma, and, by virtue of their early appearance, persistence, and localization at sites of lesion growth and complication, activated T cells may coordinate important aspects of atherogenesis. Ligation of CD40 on atheroma-associated cells in vitro activates functions related to atherogenesis.
By flow cytometry and immunoblotting, Inwald et al. (2003) confirmed that platelets constitutively express surface CD40. CD40 mRNA was undetectable, suggesting that the protein is synthesized early in platelet differentiation by megakaryocytes. Ligation of platelet CD40 with recombinant soluble CD40LG trimer caused increased platelet CD62P expression, alpha-granule and dense granule release, and the classic morphologic changes associated with platelet activation. CD40 ligation also caused beta-3 integrin (173470) activation, although this was not accompanied by platelet aggregation. These actions were abrogated by both CD40 and CD40LG blocking antibodies, indicating that activation resulted from CD40LG/CD40 interaction. Blockade of beta-3 integrin had no effect, indicating that outside-in signaling via alpha-IIb (607759)/beta-3 was not contributing to these CD40-mediated effects. CD40 ligation led to enhanced platelet-leukocyte adhesion, which is important in the recruitment of leukocytes to sites of thrombosis or inflammation. The results supported a role for CD40-mediated platelet activation in thrombosis, inflammation, and atherosclerosis.
In a study of 25 cigarette smokers and 25 nonsmokers, Harding et al. (2004) found that smokers had increased concentrations of serum C-reactive protein (CRP; 123260), surface expression of CD40 on monocytes and of CD40LG on platelets, and platelet-monocyte aggregates. The level of plasma cotinine, a nicotine metabolite, correlated with monocyte CD40 expression, platelet CD40LG expression, and platelet-monocyte aggregates. Harding et al. (2004) concluded that cigarette smokers have upregulation of the CD40/CD40LG dyad and platelet-monocyte aggregation that might account for the atherothrombotic consequences of this major cardiovascular risk factor.
Using chromosomal in situ hybridization, Lafage-Pochitaloff et al. (1994) localized the CD40 gene to 20q12-q13.2. This localization correlated well with the mapping of the murine CD40 gene to the distal region of chromosome 2 which shows rather extensive homology of synteny to human 20q11-q13.
By analysis of lymphoblastoid cell lines carrying 20q deletions, Asimakopoulos et al. (1996) placed the CD40 gene within a 19- to 21-cM interval that was almost coincidental with the common deleted region defined by previous analysis of samples from patients with myeloid malignancies.
Ferrari et al. (2001) identified 3 patients with an autosomal recessive form of immunodeficiency with hyper-IgM (HIGM3; 606843) who failed to express CD40 on the cell surface. Sequence analysis of CD40 genomic DNA showed that 1 patient carried a homozygous silent mutation at the fifth basepair position of exon 5 (109535.0001), involving an exonic splicing enhancer and leading to exon skipping and premature termination; the other 2 patients showed a homozygous point mutation in exon 3, resulting in a cysteine-to-arginine substitution (109535.0002). These findings showed that mutations of the CD40 gene cause an autosomal recessive form of hyper-IgM, which is immunologically and clinically indistinguishable from the X-linked form (HIGM1; 308230), which is caused by mutation in the CD40LG gene.
In a female patient with autosomal recessive HIGM3, Kutukculer et al. (2003) identified homozygosity for a splice site mutation (IVS3-2A-T; 109535.0003) in the TNFRSF5 gene.
Peters et al. (2008) identified a missense SNP in the CD40 gene, a C-to-G change in exon 9 (rs11086998), that results in a pro227-to-ala (P227A) change in the cytoplasmic domain of the CD40 protein. Genotyping of the SNP in the Human Genome Diversity Panel showed that P227A had an allele frequency of 29% in persons of Mexican and South American descent, with Mexican Pimas having the highest allele frequency at 46%. In contrast, P227A had an allele frequency of less than 1% in Central Asian, East Asian, and Middle Eastern populations and was absent in the African, Melanesian, and European populations studied. No persons homozygous for P227A were identified. Functional studies in human and murine B cells showed that signaling via the human P227A CD40 variant led to increased IgM production, secretion of IL6 (147620) and TNF, and phosphorylation of the JNK (MAPK8; 601158) target, JUN (165160), compared with wildtype CD40. Binding of the P227A variant and wildtype CD40 to TRAF1 (601711), TRAF2, TRAF3, and TRAF6 was similar. Peters et al. (2008) concluded that the P227A CD40 variant is associated with a gain-of-function immune phenotype. They speculated that the increased inflammatory cytokine and Ig production observed in cells expressing P227A may help protect against infectious diseases prevalent in Latin America, such as Chagas disease.
Lanzi et al. (2010) demonstrated that mutations in the CD40 gene (see, e.g., 109535.0001, C83R; 109535.0002, and 109535.0004) result in misfolding of the protein, retention in the endoplasmic reticulum (ER), and lack of cell surface CD40 expression. The C83R mutant triggered the unfolded protein response, whereas another mutant triggered the ER-associated degradation (ERAD) pathway, resulting in rapid degradation. The findings indicated that HIGM3 can be regarded as an ER-storage disease.
Associations Pending Confirmation
For discussion of a possible association between variation in the CD40 gene and susceptibility to multiple sclerosis, see 126200.
Kawabe et al. (1994) generated CD40-deficient mice to examine the role of CD40 in the immune response. They found that CD40 is essential for T cell-dependent immunoglobulin class switching and germinal center formation. However, in response to T cell-independent stimulation (with LPS), the mice were able to mount an appropriate antibody response, showing that B cells are capable of differentiating to antibody-forming cells in the absence of CD40. They also observed that basal granulopoiesis was unaffected in mutant mice, but that reactive granulopoiesis seemed to be defective. Castigli et al. (1994) performed similar experiments in mice with the same results.
Mach et al. (1998) studied whether interruption of CD40 signaling influences atherogenesis in vivo in hyperlipidemic mice. Treatment with antibody against mouse CD40LG limited atherosclerosis in mice lacking the receptor for low density lipoprotein that had been fed a high-cholesterol diet for 12 weeks. The antibody reduced the size of aortic atherosclerotic lesions by 59% and their lipid content by 79%. Furthermore, atheroma of mice treated with anti-CD40LG antibody contained significantly fewer macrophages (64%) and T lymphocytes (70%), and exhibited decreased expression of vascular cell adhesion molecule-1. These data supported the involvement of inflammatory pathways in atherosclerosis and indicated a role of CD40 signaling during atherogenesis in hyperlipidemic mice.
Alzheimer disease (104300) has a substantial inflammatory component, and activated microglia may play a central role in neuronal degeneration. Tan et al. (1999) demonstrated that the CD40 expression was increased on cultured microglia treated with freshly solubilized amyloid-beta (104760) and on microglia from a transgenic murine model of Alzheimer disease (Tg APPsw). Increased TNF-alpha production and induction of neuronal injury occurred when amyloid-beta-stimulated microglia were treated with CD40 ligand. Microglia from Tg APPsw mice deficient for CD40 ligand had less activation, suggesting that the CD40-CD40 ligand interaction is necessary for amyloid-beta-induced microglial activation. In addition, abnormal tau (157140) phosphorylation was reduced in Tg APPsw animals deficient for CD40 ligand, suggesting that the CD40-CD40 ligand interaction is an early event in Alzheimer disease pathogenesis.
Agonistic anti-CD40 antibodies can be potent adjuvants of both humoral- and cell-mediated immunity (CMI). Interrupting the interactions of B-cell-expressed CD40 with its T-cell-expressed ligand, CD154, prevents the development of thymus-dependent (TD) humoral responses and some types of CMI. Using flow cytometry and immunohistochemistry, Erickson et al. (2002) showed that mice administered anti-CD40 agonistic antibodies failed to display germinal center/follicular markers when immunized with a TD antigen. Serum IgG levels were enhanced early in the immune response in these mice and then rapidly waned compared to untreated mice. In addition, ELISPOT analysis showed that mice treated with anti-CD40 agonists did not develop long-lived plasma cells in bone marrow or memory B cells. RT-PCR analysis demonstrated that B-cell transcription factor expression was reversed in the treated mice, which had low levels of Bsap (PAX5; 167414), which is normally expressed on differentiating B cells, and high levels of Blimp1 (PRDM1; 603423), which is found on B cells that have terminally differentiated to antibody-secreting cells and plasma cells. Enhanced T-cell help (i.e., T cells expressing higher levels of CD154) mimicked some, but not all, of these responses, suggesting that extrafollicular B-cell differentiation, resulting from increased CD40 signaling, may be a physiologic means to limit the duration and intensity of the humoral immune response.
To evaluate the role of Toll-like receptors (TLRs) in B-cell activation and antibody production, Pasare and Medzhitov (2005) transferred purified B cells from wildtype, Myd88 (602170)-deficient, Tlr4 (603030)-deficient, and Cd40-deficient mice into B cell-deficient mu-MT mice, which have a mutation in the Ighm gene (147020). They found that primary B-cell activation, including induction of IgM, IgG1, and IgG2 responses, but not IgE or, probably, IgA responses, required TLRs in addition to helper T cells. In contrast, Cd40 was required for isotype switching.
Kraus et al. (2009) noted that the Epstein-Barr virus-encoded latent membrane protein-1 (LMP1) is a functional oncogenic mimic of CD40 and is expressed as a 6-transmembrane receptor on the cell surface. They created mice expressing a mouse Cd40-LMP1 transgene on a Cd40 -/- background that also either expressed or lacked Traf5 (602356) and observed grossly enlarged spleens and lymph nodes in LMP1-positive Traf5 +/+ mice, but smaller spleens and nodes in LMP1-positive Traf5 -/- mice. The absence of Traf5 in LMP1-positive mice reversed the elevated levels of serum Il6 and anti-double-stranded DNA antibodies, as well as the increased numbers of germinal center B cells, seen in LMP1-positive Traf5 +/+ mice. Similarly, anti-CD40 stimulated LMP1-positive Traf5 +/+ B lymphocytes secreted more Tnfa and Il17 (603149), but not Il10 (124092) or Il12 (161560), than LMP1-positive Traf5 -/- B lymphocytes. These LMP1-induced signaling effects in Traf5 +/+ mice depended on Jnk activation, which was absent in LMP1-positive Traf5 -/- B lymphocytes. Kraus et al. (2009) concluded that TRAF5 has a critical role in LMP1-mediated JNK signaling and that TRAF5 is required for signaling by a specific receptor both in vitro and in vivo.
In an 8-year-old Italian female with immunodeficiency with hyper-IgM (HIGM3; 606843), born of consanguineous parents, Ferrari et al. (2001) found homozygosity for a silent mutation, a 455A-T transversion, at the fifth basepair position of exon 5 of the CD40 gene, involving an exonic splicing enhancer and leading to exon skipping and premature termination. Flow cytometric analysis of patient lymphoblastoid cells showed lack of surface CD40 expression. Glycosylation studies and confocal microscopy showed that the mutant protein was retained in the endoplasmic reticulum.
In a 7-year-old female and her 5-year-old male first cousin in a 'multiply related' Saudi Arabian family, Ferrari et al. (2001) found autosomal recessive immunodeficiency with hyper-IgM (HIGM3; 606843) due to homozygosity for a 294T-C transition in exon 3 of the CD40 gene, resulting in a cys83-to-arg (C83R) substitution.
Lanzi et al. (2010) noted that the C83R mutation affects a cysteine involved in a conserved disulfide bridge in the second cysteine-rich domain, predicted to result in a major conformational change. Flow cytometric analysis of patient lymphoblastoid cells showed lack of surface CD40 expression. Glycosylation studies and confocal microscopy showed that the mutant protein was retained in the endoplasmic reticulum, which activated the unfolded protein response.
In a 12-month-old Turkish girl with immunodeficiency with hyper-IgM (HIGM3; 606843), born of consanguineous parents, Kutukculer et al. (2003) identified homozygosity for an A-to-T substitution at position -2 of the acceptor splice site of intron 3 of the TNFRSF5 gene, in a region coding for the extracellular domain of the protein. Her parents were heterozygous for the mutation.
In a 2-year-old Turkish girl, born of consanguineous parents, with immunodeficiency with hyper-IgM (HIGM3; 606843), Mazzolari et al. (2007) identified a homozygous 3-bp deletion (175delTAA) in exon 2 of the CD40 gene, resulting in the deletion of residue ile33 (I33del) in the extracellular domain. She underwent successful bone marrow transplantation at age 3, resulting in stable multilineage full chimerism and normal immune function.
By in vitro studies, Lanzi et al. (2010) showed that most of the I33del-mutant protein was retained in the endoplasmic reticulum, although a small fraction of the mutant protein reached the cell surface, where it was competent for signaling.
Asimakopoulos, F. A., White, N. J., Nacheva, E. P., Green, A. R. The human CD40 gene lies within chromosome 20q deletions associated with myeloid malignancies. Brit. J. Haemat. 92: 127-130, 1996. [PubMed: 8562382] [Full Text: https://doi.org/10.1046/j.1365-2141.1996.278812.x]
Beatty, G. L., Chiorean, E. G., Fishman, M. P., Saboury, B., Teitelbaum, U. R., Sun, W., Huhn, R. D., Song, W., Li, D., Sharp, L. L., Torigian, D. A., O'Dwyer, P. J., Vonderheide, R. H. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331: 1612-1616, 2011. [PubMed: 21436454] [Full Text: https://doi.org/10.1126/science.1198443]
Becker, T., Hartl, F.-U., Wieland, F. CD40, an extracellular receptor for binding and uptake of Hsp70-peptide complexes. J. Cell Biol. 158: 1277-1285, 2002. [PubMed: 12356871] [Full Text: https://doi.org/10.1083/jcb.200208083]
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. C4b-binding protein (C4BP) activates B cells through the CD40 receptor. Immunity 18: 837-848, 2003. [PubMed: 12818164] [Full Text: https://doi.org/10.1016/s1074-7613(03)00149-3]
Castigli, E., Alt, F. W., Davidson, L., Bottaro, A., Mizoguchi, E., Bhan, A. K., Geha, R. S. CD40-deficient mice generated by recombination-activating gene-2-deficient blastocyst complementation. Proc. Nat. Acad. Sci. 91: 12135-12139, 1994. [PubMed: 7527552] [Full Text: https://doi.org/10.1073/pnas.91.25.12135]
Clark, E. A. CD40: a cytokine receptor in search of a ligand. Tissue Antigens 36: 33-36, 1990. [PubMed: 1701063] [Full Text: https://doi.org/10.1111/j.1399-0039.1990.tb01795.x]
Erickson, L. D., Durell, B. G., Vogel, L. A., O'Connor, B. P., Cascalho, M., Yasui, T., Kikutani, H., Noelle, R. J. Short-circuiting long-lived humoral immunity by the heightened engagement of CD40. J. Clin. Invest. 109: 613-620, 2002. [PubMed: 11877469] [Full Text: https://doi.org/10.1172/JCI14110]
Ferrari, S., Giliani, S., Insalaco, A., Al-Ghonaium, A., Soresina, A. R., Loubser, M., Avanzini, M. A., Marconi, M., Badolato, R., Ugazio, A. G., Levy, Y., Catalan, N., Durandy, A., Tbakhi, A., Notarangelo, L. D., Plebani, A. Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc. Nat. Acad. Sci. 98: 12614-12619, 2001. [PubMed: 11675497] [Full Text: https://doi.org/10.1073/pnas.221456898]
Harding, S. A., Sarma, J., Josephs, D. H., Cruden, N. L., Din, J. N., Twomey, P. J., Fox, K. A. A., Newby, D. E. Upregulation of the CD40/CD40 ligand dyad and platelet-monocyte aggregation in cigarette smokers. Circulation 109: 1926-1929, 2004. [PubMed: 15078798] [Full Text: https://doi.org/10.1161/01.CIR.0000127128.52679.E4]
Inwald, D. P., McDowall, A., Peters, M. J., Callard, R. E., Klein, N. J. CD40 is constitutively expressed on platelets and provides a novel mechanism for platelet activation. Circ. Res. 92: 1041-1048, 2003. [PubMed: 12676820] [Full Text: https://doi.org/10.1161/01.RES.0000070111.98158.6C]
Kato, K., Cantwell, M. J., Sharma, S., Kipps, T. J. Gene transfer of CD40-ligand induces autologous immune recognition of chronic lymphocytic leukemia B cells. J. Clin. Invest. 101: 1133-1141, 1998. [PubMed: 9486984] [Full Text: https://doi.org/10.1172/JCI1472]
Kawabe, T., Naka, T., Yoshida, K., Tanaka, T., Fujiwara, H., Suematsu, S., Yoshida, N., Kishimoto, T., Kikutani, H. The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1: 167-178, 1994. [PubMed: 7534202] [Full Text: https://doi.org/10.1016/1074-7613(94)90095-7]
Kraus, Z. J., Nakano, H., Bishop, G. A. TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40. Proc. Nat. Acad. Sci. 106: 17140-17145, 2009. [PubMed: 19805155] [Full Text: https://doi.org/10.1073/pnas.0903786106]
Kutukculer, N., Moratto, D., Aydinok, Y., Lougaris, V., Aksoylar, S., Plebani, A., Genel, F., Notarangelo, L. D. Disseminated Cryptosporidium infection in an infant with hyper-IgM syndrome caused by CD40 deficiency. J. Pediat. 142: 194-196, 2003. [PubMed: 12584544] [Full Text: https://doi.org/10.1067/mpd.2003.41]
Lafage-Pochitaloff, M., Herman, P., Birg, F., Galizzi, J.-P., Simonetti, J., Mannoni, P., Banchereau, J. Localization of the human CD40 gene to chromosome 20, bands q12-q13.2. Leukemia 8: 1172-1175, 1994. [PubMed: 7518550]
Lanzi, G., Ferrari, S., Vihinen, M., Caraffi, S., Kutukculer, N., Schiaffonati, L., Plebani, A., Notarangelo, L. D., Fra, A. M., Giliani, S. Different molecular behavior of CD40 mutants causing hyper-IgM syndrome. Blood 116: 5867-5874, 2010. [PubMed: 20702779] [Full Text: https://doi.org/10.1182/blood-2010-03-274241]
Li, F., Ravetch, J. V. Inhibitory Fc-gamma receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies. Science 333: 1030-1034, 2011. [PubMed: 21852502] [Full Text: https://doi.org/10.1126/science.1206954]
Mach, F., Schonbeck, U., Sukhova, G. K., Atkinson, E., Libby, P. Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature 394: 200-203, 1998. [PubMed: 9671306] [Full Text: https://doi.org/10.1038/28204]
Matsuzawa, A., Tseng, P.-H., Vallabhapurapu, S., Luo, J.-L., Zhang, W., Wang, H., Vignali, D. A. A., Gallagher, E., Karin, M. Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex. Science 321: 663-668, 2008. Note: Erratum: Science 322: 375 only, 2008. [PubMed: 18635759] [Full Text: https://doi.org/10.1126/science.1157340]
Mazzolari, E., Lanzi, G., Forino, C., Lanfranchi, A., Aksu, G., Ozturk, C., Giliani, S., Notarangelo, L. D., Kutukculer, N. First report of successful stem cell transplantation in a child with CD40 deficiency. Bone Marrow Transplant. 40: 279-281, 2007. [PubMed: 17502893] [Full Text: https://doi.org/10.1038/sj.bmt.1705713]
Pasare, C., Medzhitov, R. Control of B-cell responses by Toll-like receptors. Nature 438: 364-368, 2005. [PubMed: 16292312] [Full Text: https://doi.org/10.1038/nature04267]
Peters, A. L., Plenge, R. M., Graham, R. R., Altshuler, D. M., Moser, K. L., Gaffney, P. M., Bishop, G. A. A novel polymorphism of the human CD40 receptor with enhanced function. Blood 112: 1863-1871, 2008. [PubMed: 18591382] [Full Text: https://doi.org/10.1182/blood-2008-02-138925]
Schonbeck, U., Libby, P. The CD40/CD154 receptor/ligand dyad. Cell Molec. Life Sci. 58: 4-43, 2001. [PubMed: 11229815] [Full Text: https://doi.org/10.1007/pl00000776]
Stamenkovic, I., Clark, E. A., Seed, B. A B-lymphocyte activation molecule related to the nerve growth factor receptor and induced by cytokines in carcinomas. EMBO J. 8: 1403-1410, 1989. [PubMed: 2475341] [Full Text: https://doi.org/10.1002/j.1460-2075.1989.tb03521.x]
Tan, J., Town, T., Paris, D., Mori, T., Suo, Z., Crawford, F., Mattson, M. P., Flavell, R. A., Mullan, M. Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation. Science 286: 2352-2355, 1999. [PubMed: 10600748] [Full Text: https://doi.org/10.1126/science.286.5448.2352]
Trompouki, E., Hatzivassiliou, E., Tsichritzis, T., Farmer, H., Ashworth, A., Mosialos, G. CYLD is a deubiquitinating enzyme that negatively regulates NF-kappa-B activation by TNFR family members. Nature 424: 793-796, 2003. [PubMed: 12917689] [Full Text: https://doi.org/10.1038/nature01803]
van Kooten, C., Banchereau, J. CD40-CD40 ligand. J. Leuko. Biol. 67: 2-17, 2000. [PubMed: 10647992] [Full Text: https://doi.org/10.1002/jlb.67.1.2]