CD40 (protein)
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RefSeq (mRNA) |
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Location (UCSC) | Chr 20: 46.12 – 46.13 Mb | Chr 2: 164.9 – 164.91 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
In addition it is expressed by various non- hematopoietic cells; activated CD4+ T cells primarily exhibit its ligand CD154, antigen-presenting cells including dendritic cells (DCs), B cells, macrophages, classical and non-classical monocytes, on a variety of non-immune cells including platelets and endothelial cells, and on several types of tumor cells.[5]
Mutations affecting this gene are the cause of autosomal recessive hyper-IgM immunodeficiency.
Discovery
Between the late 1950s and the mid-1980s, several immunology laboratories started to use the new
Function
The protein receptor encoded by this gene is a member of the
Specific effects on cells
In the
The
The expression of CD40 is diverse. CD40 is constitutively expressed by antigen presenting cells, including
Interactions
CD40 (protein) has been shown to interact with TRAF2,[12][13][14] TRAF3,[13][15][16][17] TRAF6,[13][17] TRAF5[13][18] and TTRAP.[19] The remaining member of TRAF4 family, namely TRAF4, positively regulates CD40 signalling, but interacts with CD40 indirectly.[20]
CD40 also interacts with CD40L, due to the role of CD40 in stimulating
CD40 as a drug target in cancer
The CD40 molecule is a potential target for cancer immunotherapy. Anti-CD40 monoclonal antibodies may help prevent the killing of cancer cells by effector cells. Similarly, ligation of CD40 may lead to cell death in some tumor cells, as it is expressed in all lymphoid malignancies and in a number of carcinomas.[6] There are a number of completed and ongoing clinical trials using agonistic anti-CD40 monoclonal antibodies to elicit an anti-tumor T-cell response via dendritic cell activation. Over the past 20 years, numerous human CD40 monoclonal antibodies have been developed and evaluated in clinical trials due to encouraging variability in cancer animal models. Agonistic anti CD -40-Abs are designed to mimic CD40L by cross-linking CD40 and in this way promoting the maturation of DCs and enhancing their antigen presentation ability. This leads to an increase in tumor antigen-specific cytotoxic T cells, which may result in tumor eradication. On the other hand, the preclinical efficacy has not yet been tested in the clinical setting, and none of these monoclonal antibodies have progressed beyond early testing phases. Because of toxicity, the use of CD40 monoclonal antibodies has been limited to suboptimal doses, resulting in inadequate immune activation and antitumor activity.[5] More recently, agonistic CD40 therapy has been shown to decrease T cell cytotoxicity in preclinical glioma models, and in fact affect the efficacy of immune checkpoint blockade. This is likely due to the high mutational burden most of these models display, which causes them to respond better to immune checkpoint blockade than human glioma, but is nonetheless relevant information for research in immunomodulatory therapies.[22]
Hyper Ig-M immunodeficiency and CD40
Hyper-IgM syndrome is a primary immunodeficiency disorder characterized by increased serum levels of immunoglobulin (Ig) M and decreased levels of IgG, IgA, and IgE. CD40 is involved in the development of hyper-IgM syndrome in that it serves as a co-stimulatory molecule in the activation differentiation of B cells, which play a key role in producing immunoglobulins. In hyper-IgM syndrome, mutations in genes involved in CD40 signaling result in impaired B cell activation and differentiation, leading to increased production of IgM and decreased production of other immunoglobulins. As a result, individuals with hyper-IgM syndrome are susceptible to a wide range of infections and have an increased risk of autoimmune diseases and cancer. Currently, treatment for hyper-IgM syndrome involves the replacement of missing immunoglobulins, as well as other therapies to boost the immune system and prevent infections. Research is ongoing to better understand the role of CD40 in hyper-IgM syndrome and to develop new treatments for this disorder.[citation needed][23]
CD40 and drug development
CD40 is a promising target for the development of drugs to treat a variety of diseases, including cancer, autoimmune diseases, and chronic inflammation. By targeting CD40, it is possible to modulate the immune response and enhance the ability of the body to fight against diseases. For example, drugs that block CD40 signaling have shown promise in treating autoimmune diseases, such as rheumatoid arthritis, by suppressing the overactive immune response. On the other hand, drugs that activate CD40 signaling have shown efficacy in treating cancer by boosting the immune response against tumor cells. CD40 also plays a role in the development of chronic inflammation, and targeting CD40 with drugs has the potential to treat diseases such as Crohn's disease and ulcerative colitis. Overall, CD40 represents a promising target for the development of drugs to treat a wide range of diseases.[24][25]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000101017 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000017652 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 35911742.
- ^ PMID 25324844.
- PMID 9597126.
- ^ "Entrez Gene: CD40 CD40 molecule, TNF receptor superfamily member 5".
- PMID 7534202.
- S2CID 22911861.
- PMID 21330346.
- PMID 10411888.
- ^ PMID 9990007.
- S2CID 4366355.
- PMID 7527023.
- PMID 10984535.
- ^ PMID 9384571.
- PMID 8790348.
- PMID 10764746.
- PMID 33171493.
- PMID 34758832.
- PMID 34226552.
- ^ Yazdani, R., Fekrvand, S., Shahkarami, S., Azizi, G., Moazzami, B., Abolhassani, H., & Aghamohammadi, A. (2019). The hyper IgM syndromes: Epidemiology, pathogenesis, clinical manifestations, diagnosis and management. Clinical immunology (Orlando, Fla.), 198, 19–30. https://doi.org/10.1016/j.clim.2018.11.007
- S2CID 239010744.
- PMID 35911742.
External links
- 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)
Further reading
- Parham P (2004). The Immune System (2nd ed.). Garland Science. pp. 169–173. ISBN 978-0-8153-4093-5.
- Wang JH, Zhang YW, Zhang P, Deng BQ, Ding S, Wang ZK, et al. (September 2013). "CD40 ligand as a potential biomarker for atherosclerotic instability". Neurological Research. 35 (7): 693–700. PMID 23561892.
- PMID 7516669.
- van Kooten C, Banchereau J (January 2000). "CD40-CD40 ligand". Journal of Leukocyte Biology. 67 (1): 2–17. S2CID 35592719.
- Schattner EJ (May 2000). "CD40 ligand in CLL pathogenesis and therapy". Leukemia & Lymphoma. 37 (5–6): 461–472. S2CID 39398949.
- Bhushan A, Covey LR (2002). "CD40:CD40L interactions in X-linked and non-X-linked hyper-IgM syndromes". Immunologic Research. 24 (3): 311–324. S2CID 19537892.
- Cheng G, Schoenberger SP (2002). "CD40 signaling and autoimmunity". Signal Transduction Pathways in Autoimmunity. Current Directions in Autoimmunity. Vol. 5. pp. 51–61. PMID 11826760.
- Dallman C, Johnson PW, Packham G (January 2003). "Differential regulation of cell survival by CD40". Apoptosis. 8 (1): 45–53. S2CID 22461134.
- O'Sullivan B, Thomas R (July 2003). "Recent advances on the role of CD40 and dendritic cells in immunity and tolerance". Current Opinion in Hematology. 10 (4): 272–278. S2CID 43043879.
- Benveniste EN, Nguyen VT, Wesemann DR (January 2004). "Molecular regulation of CD40 gene expression in macrophages and microglia". Brain, Behavior, and Immunity. 18 (1): 7–12. S2CID 8081107.
- Xu Y, Song G (2005). "The role of CD40-CD154 interaction in cell immunoregulation". Journal of Biomedical Science. 11 (4): 426–438. S2CID 202658036.
- Contin C, Couzi L, Moreau JF, Déchanet-Merville J, Merville P (2004). "[Immune dysfuntion of uremic patients: potential role for the soluble form of CD40]". Nephrologie. 25 (4): 119–126. PMID 15291139.