Modeline Longjohn - January 21, 2019
Understanding the roles and mechanisms of extracellular vesicles in B cell development, activation and malfunction
B cell development in mammals occurs within the bone marrow. Normal B cell development occurs in a set of discrete stages which culminate in the secretion of immune competent antibody secreting Plasma B cells. One of the first surface receptors expressed on developing B cells is CD24, a glycosylated GPI-anchored protein with no transmembrane domain. It is well established that CD24 regulates the transition of B cells from Pro- to Pre-B cell stage via promotion of apoptosis in these cells. Recently, our lab has found an additional role for CD24 whereby engagement of CD24 on immature B cells induces the release of CD24-bearing extracellular vesicles (EVs). These EVs were plasma-membrane derived, which can also be classified as microvesicles (MV), with an average size of approximately 120 nm. Furthermore, using flow cytometry we found that the MV released from CD24-stimulated B cells have different surface protein composition compared to the cells of origin. Preliminary data has also shown that stimulation of CD24 promotes the exchange of lipid and protein (B cell receptor) between B cell lines in culture. However, the role of CD24 induced EVs in B cell development, particularly in the heterogeneous bone marrow microenvironment, is unknown. In addition, it has been discovered that other types of extracellular vesicles are released by abnormally developing B cells such as the immature differentiation arrested B cells (blasts) involved in a type of cancer called B-cell acute lymphoblastic leukemia. Thus, the effects and consequences (molecular and cellular) of general EV release in abnormally developing B-ALL blasts is also unknown. Hence, my research goals are to elucidate the effects of EV secretion, release, and transfer on B cell development in normal systems and in B-ALL. Understanding the mechanisms and functions of EV release in B cell development will offer broader possibilities on maximising immune function such as in vaccination. Concomitantly, elucidating the role of extracellular vesicles in B-ALL could fill in the missing gaps in this pediatric cancer, especially as regards better diagnosis and tracking minimal residual disease (MRD) which cause relapses.