Reveal the mechanisms whereby retinoic acid (RA) potentiates TLR9/RP105-mediated activation of normal human B-cells
We have previously shown that vitamin A in terms of retinoic acid (RA) enhances proliferation and survival of memory B cells via p38 MAPK, and recently we have demonstrated an even stronger effect of RA upon stimulating B cells via Toll-like receptor RP105. The mechanisms have been revealed, and the ability of RA to regulate DNA damage-induced responses is now being explored.
The role of autophagy in RA-mediated responses in human B cells
Autophagy is a cellular process aimed at bulk degradation of long lived proteins and old/damaged organelles. The process in increased by stress such as nutrient deprivation and hypoxia, and it generally promotes survival of the cells. Recently, autophagy has gained new interest in various immunological processes, and se have preliminary results indicating that RA-mediated B cell differentiation into Ig-secreting cells requires autophagy. We are now studying the mechanisms involved, as well as its role in DNA-damage induced death of B cells.
Vitamin A in treatment of immune disorders
Both in common variable immune disorder (CVID) and in multiple sclerosis (MS) is has been shown that TLR9-signaling is compromised. Since RA potentiatesTLR9-signaling in memory B cells, we are now in the process of exploring the possibility of using RA to improve normal function of B cells in these patients. It is known that these patients have an enhanced tendency to develop cancer, presumably due to the radiosensitivity of the cells. We are now elucidating the role of RA in regulating DNA damage responses in normal and CVID-derived B cells, with the aim of improving the chromosome instability in these patients.
Cyclic AMP-signaling in development and treatment of BCP-ALL
Based on our previous results we hypothesize that enhanced cAMP-signaling is implicated in development of B cell precursor Acute lymphoblastic leukemia (BCP-ALL). We have recently shown that whereas DNA damage-responses in malignant BCP are inhibited by cAMP, the normal counterparts in the bone marrow are unaffected. We are now exploring the role of bone-marrow derived stromal cells as a source for providing BCL-ALL cells with cAMP-activating signals, and we are also elucidating the possibility of using inhibitors of cAMP-signaling to improve conventional treatment of BCP-ALL.