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 nonimmune cell types. The CD40 expressed by professional antigen-presenting
cells plays a critical role in costimulation and antigen-presenting
cell activation in T cell-dependant immune responses. Signals generated
through CD40 in B cells are antiapoptotic. These signals are also
required for T cell-dependant 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-kappaB, 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 signaling
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-kappaB in IFN-?treated
microglial cells . NO derived from microglia has been implicated
in the damage of myelin-producing oligodendrocytes in demyelating
disorders like multiple sclerosis (MS) and neuronal death during
Alzheimer.s disease and brain trauma. Increased CD40-CD40 ligation
has beenimplicated in the pathogenesis of several autoimmune inflammatory
diseases, such as MS, arthritis and insulin-dependant diabetes.
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