B Cells Participate in Thymic Negative Selection of Murine Auto-reactive CD4+ T Cells

It is well documented that thymic epithelial cells participate in the process of negative selection in the thymus. In recent years it was reported that also dendritic cells enter the thymus and contribute to this process, thus allowing for the depletion of thymocytes that are specific to peripherally expressed self-antigens. Here we report that also B cells may take part in the elimination of auto-reactive thymocytes. Using a unique mouse model we show that B cells induce negative selection of self-reactive thymocytes in a process that leads to the deletion of these cells whereas regulatory T cells are spared. These findings have direct implication in autoimmunity, as expression of a myelin antigen by B cells in the thymus renders the mice resistant to autoimmune inflammation of the CNS

Evidence of scar tissue: contra-indication to cardiac resynchronization therapy?

Ventricular Dysfunction & Heart Failur

NIM-R7, a novel marker for resting B1 and marginal-zone B lymphocytes, is also expressed on activated T and B cells

In mice, follicular B cells have been studied in detail, while two other B-cell subpopulations – marginal-zone B and B1 cells – are less well understood. In this work we report the expression pattern of p58, a lymphocyte-activation marker, recognized by rat monoclonal antibody, NIM-R7, and present on the latter two cell subpopulations. Staining with NIM-R7 showed that undisturbed marginal-zone B cells, as well as peritoneal cavity and splenic B1a cells, constitutively expressed p58, whereas follicular B cells and resting T lymphocytes did not. Ontogenic analysis of different compartments showed that p58 did not appear at any stage of development, prior to the development of mature T or B2 lymphocytes. Upon polyclonal stimulation, however, p58 appeared on both T and B2 lymphocytes. Finally, ricin A-conjugated NIM-R7 was able to kill the BCL1 lymphoma without effect on mature resting B2 cells. Therefore, p58 may be a potential target for diagnosis or therapy of B1 and marginal-zone B-cell malignancies

Loss of Ikaros DNA-binding function confers integrin-dependent survival on pre-B cells and progression to acute lymphoblastic leukemia

Deletion of the DNA-binding domain of the transcription factor Ikaros generates dominant-negative isoforms that interfere with its activity and correlate with poor prognosis in human precursor B cell acute lymphoblastic leukemia (B-ALL). Here we found that conditional inactivation of the Ikaros DNA-binding domain in early pre-B cells arrested their differentiation at a stage at which integrin-dependent adhesion to niches augmented signaling via mitogen-activated protein kinases, proliferation and self-renewal and attenuated signaling via the pre-B cell signaling complex (pre-BCR) and the differentiation of pre-B cells. Transplantation of polyclonal Ikaros-mutant pre-B cells resulted in long-latency oligoclonal pre-B-ALL, which demonstrates that loss of Ikaros contributes to multistep B cell leukemogenesis. Our results explain how normal pre-B cells transit from a highly proliferative and stroma-dependent phase to a stroma-independent phase during which differentiation is enabled, and suggest potential therapeutic strategies for Ikaros-mutant B-ALL