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CD40LG

Official Full Name
CD40 ligand
Organism
Homo sapiens
GeneID
959
Background
The protein encoded by this gene is expressed on the surface of T cells. It regulates B cell function by engaging CD40 on the B cell surface. A defect in this gene results in an inability to undergo immunoglobulin class switch and is associated with hyper-IgM syndrome. [provided by RefSeq, Jul 2008]
Synonyms
IGM; IMD3; TRAP; gp39; CD154; CD40L; HIGM1; T-BAM; TNFSF5; hCD40L;
Bio Chemical Class
Cytokine: tumor necrosis factor
Protein Sequence
MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAVYLHRRLDKIEDERNLHEDFVFMKTIQRCNTGERSLSLLNCEEIKSQFEGFVKDIMLNKEETKKENSFEMQKGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL
Open
Disease
B-cell lymphoma, Diabetes mellitus, Diffuse large B-cell lymphoma, Lupus erythematosus, Lymphoma, Malignant haematopoietic neoplasm, Mature B-cell leukaemia, Mature B-cell lymphoma, Melanoma, Prostate cancer, Rheumatoid arthritis, Sjogren syndrome, Solid tumour/cancer, Thrombocytopenia
Approved Drug
0
Clinical Trial Drug
12 +
Discontinued Drug
3 +

Detailed Information

The CD40LG gene, encoding CD40 ligand (CD40L), plays a critical role in the immune system. Mostly generated on activated CD4+ T cells, it functions as a ligand for the CD40 receptor shown on the surface of B cells and antigen-presenting cells (APCs). Especially in B cell activation, immunoglobulin class flipping, and the development of adaptive immunity, the interplay between CD40L and CD40 determines the modulation of immunological responses.

Gene Structure and Function

A protein-coding gene, CD40LG generates a 39 kDa transmembrane protein. Usually existing in a trimeric form, CD40L is a member of the tumor necrosis factor (TNF) superfamily. It is crucial in humoral and cellular immunological responses. In T cells, CD40L modulates costimulation, therefore improving T-cell proliferation and cytokine synthesis—including IL-4 and IL-10—in concert with TCR/CD3 ligation and CD28 costimulation. Along with activating kinases like MAPK8 and PAK2 in T-cells, this activation triggers the NF-kB signaling cascade.

CD40L binds to CD40 in the presence of IL-4 to provide signals that set off several immunological reactions including IgE synthesis and B-cell growth. This link also underlies immunoglobulin class switching, a technique enabling B cells to produce various types of antibodies fit for combat of various illnesses.

CD40L-CD40 Signaling Pathway

Activation of immune cells depends critically on the CD40L-CD40 interaction. On B cells and APCs, CD40L binding to CD40 attracts TNF receptor-associated factors (TRAFs), therefore activating many intracellular signaling pathways. This controls immune cell development, differentiation, and survival using NF-kB, MAPK, PI3K-AKT, and JAK3-STAT signaling cascade. CD40L-CD40 signaling affects endothelial, smooth muscle, and fibroblast cells, thus influencing cell adhesion, inflammation, and vascular homeostasis.

Clinical Significance of CD40LG

Defects or mutations in the CD40LG gene could lead to Hyper-IgM syndrome, an immunodeficiency disorder defined by the inability to complete immunoglobulin class switching. Because their levels of IgM are high and their other immunoglobulin classes are low, affected individuals are consequently more prone to infections. A decreased adaptive immunological response resulting from CD40L loss follows from reduced T-cell activation and B-cell dysfunction.

Figure 1 describes the targeting of CD40/CD40L pathway: CD40/CD40L checkpoint molecules processing and interaction.Figure 1. The targeting of CD40/CD40L pathway: CD40/CD40L checkpoint molecules processing and interaction. (Tang T, et al., 2021)

Apart from Hyper-IgM syndrome, mutations in CD40LG have also been related to various immunological defects, including CD40L deficiency, which may lead to numerous autoimmune and inflammatory diseases. Active CD40L-CD40 pathway activation has been related, for example, to the pathophysiology of autoimmune diseases like rheumatoid arthritis, Crohn's disease, and systemic lupus erythematosus (SLE).

CD40L as a Therapeutic Target

CD40L and CD40 have become interesting targets for treatments in both cancer immunotherapy and autoimmune illnesses because of their essential importance in immune regulation.

Activation (Agonists)

In cancer therapy, CD40L agonists under research are meant to boost anti-tumor immunity. Turning on CD40 on APCs helps CD40L agonists enhance the presentation of tumor antigens and increase T-cell responses to tumors. Treatments based on CD40L aim to generate a pro-inflammatory immune response that accelerates cancer cell destruction.

Although encouraging, CD40L agonists have to be carefully balanced against negative effects, especially since the CD40-CD40L interaction may cause inflammatory reactions. Though no such medication has been licensed, research points to CD40-targeted cancer immunotherapy as a possible use.

Inhibition (Antagonists)

Under investigation as treatments for autoimmune diseases and conditions needing immune suppression are CD40L antagonists. Overactive CD40L-CD40 signaling has been linked to diseases like psoriasis, rheumatoid arthritis, and SLE. Through its blockage of the CD40-CD40L interaction, CD40L antagonists aim to reduce the overactive immune response linked with certain illnesses.

Early clinical findings suggest their possible usefulness in treating disorders including organ transplantation, systemic lupus erythematosus (SLE), and other autoimmune diseases; monoclonal antibodies targeted against CD40L are under continued investigation.

References:

  1. Elgueta R, Benson MJ, de Vries VC, et al. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev. 2009 May;229(1):152-72.
  2. Laman JD, Claassen E, Noelle RJ. Functions of CD40 and Its Ligand, gp39 (CD40L). Crit Rev Immunol. 2017;37(2-6):371-420.
  3. Zhang T, Pierson RN 3rd, Azimzadeh AM. Update on CD40 and CD154 blockade in transplant models. Immunotherapy. 2015;7(8):899-911.
  4. Tang T, Cheng X, Truong B, et al. Molecular basis and therapeutic implications of CD40/CD40L immune checkpoint. Pharmacol Ther. 2021 Mar;219:107709.
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