1. The molecular mechanisms regulating B cell survival in health and disease. In B cells, as in every other tissue, the survival/apoptosis balance is essential for homoeostasis. A vast number of resting cells must be maintained to preserve a diverse B cell repertoire. Long-term B cell persistence in the periphery is dependent on survival signals that are transduced by cell surface receptors. Conversely, resistance to apoptosis, leading to enhanced survival, is associated with initiation and progression of B cell malignancies. Our study focuses on molecules that regulate B cell survival. These molecules have been also associated with tumor progression and metastasis. We are currently analyzing the survival pathways induced in CLL cells derived from patients in various stages. These findings could pave for novel therapeutic strategies aimed at blocking this survival pathway. 2. Regulation of peripheral lymphocytes?? targeting to the LN and sites of inflammation in health and disease. The majority of lymphocytes are capable of tissue selective trafficking (homing), recognizing organ-specific adhesion molecules on specialized endothelial cells. Previous studies focused on the specific recruitment of leukocytes to the lymph nodes (LN) or to sites of inflammation. However, little is known about the molecular mechanisms that negatively control or prevent homing of cells to these sites. Our studies focus on the pathways that restrict homing of specific subsets of immune cells, and thereby fine tune the immune response at specific lymphoid and peripheral tissues. Impaired homing of lymphocytes to peripheral lymph nodes results in attenuated progression of inflammation in various inflammatory models, including asthma, arthritis, inflammatory bowl disease (IBD) and experimental autoimmune encephalomyelitis (EAE). We are currently analyzing the additional pathways that are involved in this homing regulation.