The co-stimulatory CD40L-CD40 dyad is a major driver of atherosclerosis. One of the major cell types expressing CD40 are B cells. CD40 on B cells is crucial for B cell functioning including isotype switching and germinal center formation. In recent years, the role of B cells in atherosclerosis has been studied and B cells have come forward as important players in the pathophysiology of the disease process. As CD40 is an important target in atherosclerosis and essential for B cell functioning, we here investigated the role of conditional ablation of CD40 on B cells (CD19Cre, CD40flfl, Apoe-/- mice) in the development of atherosclerosis. Female mice were fed a 0.15% high cholesterol diet for 14 weeks to induce advanced lesions, while male mice were fed a chow diet to induce initial lesions. As expected, mice lacking CD40 on B cells featured reduced plasma cell as well as germinal center cell numbers in their spleens. Interestingly, both the female mice featuring an advanced plaque phenotype and the males featuring an initial plaque phenotype, showed a strong increase in lesion size (females 1.3 fold increase, males 2 fold increase) in mice lacking CD40 on B cells compared to mice with wild-type B cells. Also, a decrease in multiple IgG subtypes as well as protective IgM subtypes, relevant in the pathophysiology of atherosclerosis, were found in mice lacking B cell CD40. To further delineate which CD40-TRAF signaling pathways (TRAF2, TRAF3/5 or TRAF6) are involved in the production of natural IgM antibodies and IgM/IgG antibodies, we designed small molecule inhibitors (SMI) against CD40-TRAF2 interactions. This was established using virtual ligand screening and high throughput in vitro selection based on CD40 induced NFkB signaling in B cells. For 8 novel CD40-TRAF2 SMIs we found decreases in human and mice B cell proliferation and plasmablast formation in culture, where our already established CD40-TRAF6 inhibitor showed no such effects. These preliminary findings point towards a protective role for B cell CD40, possibly via the secretion of protective antibodies by B1 cells.
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