CD40 is a 45-50 kDa type I membrane protein and a member of the tumor necrosis factor (TNF) receptor superfamily. CD40 is also known as pb50 or CDW40. CD40 is expressed primarily by professional antigen-presenting cells and it is also expressed on non-immune cell types. The CD40 expressed by professional antigen-presenting cells plays a critical role in co-stimulation and antigen-presenting cell activation in T cell-dependent immune responses. Signals generated through CD40 in B cells are anti-apoptotic. These signals are also required for T cell-dependent B cell activation and proliferation, isotype switching, up-regulation of costimulatory receptors, germinal center formation and memory generation. CD40 signal transduction is initiated by binding trimeric CD40 ligand (CD40L) which is found on the surface of activated T cells. CD40 engages several signalling pathways in B cells and these include NF-kB, the mitogen-activated protein kinases p38 and c-Jun N-terminal kinase. The 62 amino acid cytoplasmic domain (CD40c) of CD40 contains two linear TNF-receptor associated factor (TRAF) binding domains. The membrane proximal site of CD40c binds TRAF6 and the membrane distal site binds TRAF1, 2 and 3. CD40c is thought to mediate the CD40-dependant signalling pathways by recruitment of TRAF to this multimerized domain. CD40 ligation has also been shown to stimulate iNOS expression, and therefore NO production, by activating NF-kB in IFN-g treated microglial cells. NO derived from microglia has been implicated in the damage of myelin-producing oligodendrocytes in demyelinating disorders like multiple sclerosis (MS) and neuronal death during Alzheimer’s disease and brain trauma. Increased CD40-CD40 ligation has been implicated in the pathogenesis of several autoimmune inflammatory diseases, such as MS, arthritis and insulin-dependant diabetes.
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Regulatory Status |
RUO – Research Use Only |
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