We investigate the roles of junctional adhesion molecules (JAMs) in pathology of leukocyte migration, inflammatory diseases and angiogenesis. Simultaneously with other laboratories we discovered the vascular adhesion molecules JAM-B and JAM-C. Expression and production of recombinant JAMs enabled the development of a large panel and monoclonal and polyclonal antibodies, and we produced transgenic mice over-expressing JAM-C in the vasculature and JAM-C and JAM-B deficient mice. Using these reagents and the gene modified animals we showed JAM-C involved in immune responses against microorganisms preventing pneumonia and studied the role of this moleculkes in immunity against Leishmaniasis . Furthermore, antibodies against JAM-C reduced the severity of acute and chronic inflammatory pathologies such as pancreatitis, peritonitis, rheumatoid arthritis. These effects of JAM-C seem to be due to its role in leukocyte transendotheial migration. The molecules form a vascular barrier for tissue leukocytes returning back to the blood i.e. it contributes to the one-way traffic observed during leukocyte homing. In collaboration with Sussan Nourshargh, London we visualized neutrophils and monocytes reverse, polarised transendothelial migration. These events were detected by blocking JAM-C in vitro and in vivo using 3D intravital microscopy of inflammation following ischemia/reperfusion injury. (JAM-C) is expressed by vascular endothelium and also by human but not mouse B lymphocytes. Together with Thomas Matthes, Geneva we recently described that the level of JAM-C expression defines B cell differentiation stages and allows the classification of marginal zone (JAM-C positive) and germinal center (JAM-C negative) B cell lymphomas. Now we found a role for this lymphocyte JAM-C in migration of human B cells, using a xenogeneic NOD/SCID human/mouse model. Treatment with anti-JAM-C antibodies reduced homing of normal and malignant human, JAM-C expressing B cells to bone marrow, lymph nodes and spleen. Blocking spleen homing is remarkable as most other anti-adhesion antibodies reduced homing of B cells only to bone marrow and lymph nodes but not to spleen. Plasmon resonance studies identified JAM-B as the major vascular ligand for JAM-C while homotypic JAM-C interactions remained at background levels. Accordingly, anti-JAM-C antibodies blocked adhesion of JAM-C expressing B cells to blood vessels in human and mouse lymphoid organs. In particular, JAM-B is highly expressed by the spleen vasculature. We will review our work on JAM-C and JAM-B and compare it to the roles of JAM-A, the first molecule discovered and belonging to the JAM family.