Marcus Dühren-von Minden

Responsiveness of B cells is regulated by the hinge region of IgD

Mature B cells express immunoglobulin M (IgM)- and IgD-isotype B cell antigen receptors, but the importance of IgD for B cell function has been unclear. By using a cellular in vitro system and corresponding mouse models, we found that antigens with low valence activated IgM receptors but failed to trigger IgD signaling, whereas polyvalent antigens activated both receptor types. Investigations of the molecular mechanism showed that deletion of the IgD-specific hinge region rendered IgD responsive to monovalent antigen, whereas transferring the hinge to IgM resulted in responsiveness only to polyvalent antigen. Our data suggest that the increased IgD/IgM ratio on conventional B-2 cells is important for preferential immune responses to antigens in immune complexes, and that the increased IgM expression on B-1 cells is essential for B-1 cell homeostasis and function.

PTEN opposes negative selection and enables oncogenic transformation of pre-B cells

Phosphatase and tensin homolog (PTEN) is a negative regulator of the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) signaling pathway and a potent tumor suppressor in many types of cancer. To test a tumor suppressive role for PTEN in pre-B acute lymphoblastic leukemia (ALL), we induced Cre-mediated deletion of Pten in mouse models of pre-B ALL. In contrast to its role as a tumor suppressor in other cancers, loss of one or both alleles of Pten caused rapid cell death of pre-B ALL cells and was sufficient to clear transplant recipient mice of leukemia. Small-molecule inhibition of PTEN in human pre-B ALL cells resulted in hyperactivation of AKT, activation of the p53 tumor suppressor cell cycle checkpoint and cell death. Loss of PTEN function in pre-B ALL cells was functionally equivalent to acute activation of autoreactive pre–B cell receptor signaling, which engaged a deletional checkpoint for the removal of autoreactive B cells. We propose that targeted inhibition of PTEN and hyperactivation of AKT triggers a checkpoint for the elimination of autoreactive B cells and represents a new strategy to overcome drug resistance in human ALL.

Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia

Cell-autonomous B-cell receptor (BcR)-mediated signalling is a hallmark feature of the neoplastic B lymphocytes in chronic lymphocytic leukaemia (CLL). Here we elucidate the structural basis of autonomous activation of CLL B cells, showing that BcR immunoglobulins initiate intracellular signalling through homotypic interactions between epitopes that are specific for each subgroup of patients with homogeneous clinicobiological profiles. The molecular details of the BcR–BcR interactions apparently dictate the clinical course of disease, with stronger affinities and longer half-lives in indolent cases, and weaker, short-lived contacts mediating the aggressive ones. The diversity of homotypic BcR contacts leading to cell-autonomous signalling reconciles the existence of a shared pathogenic mechanism with the biological and clinical heterogeneity of CLL and offers opportunities for innovative treatment strategies.

Selection patterns of B-cell receptors and the natural history of follicular lymphoma

Cutts, B.A., Tran, H.A., Merriman, E., Nandurkar, D., Soo, G., DasGupta, D., Prassannan, N. & Hunt, B.J. (2014) The Utility of the Wells Clinical Prediction Model and Ventilation-Perfusion Scanning for Pulmonary Embolism in Pregnancy. Blood Coagulation and Fibrinolysis, 25, 375–378. DiPEP: Diagnosis of Pulmonary Embolism in Pregnancy ISRCTN21245595. Available at: http:// www.controlled-trials.com/ISRCTN21245595 (Accessed November 28, 2015) Goodacre, S., Nelson-Piercy, C., Hunt, B. & Chan, W.-S. (2015) When should we use diagnostic imaging to investigate for pulmonary embolism in pregnant and postpartum women? Emergency Medical Journal, 32, 78–82. Kline, J.A., Richardson, D.M., Than, M.P., Penaloza, A. & Roy, P.-M. (2014) Systematic Review and Meta-analysis of Pregnant Patients Investigated for Suspected Pulmonary Embolism in the Emergency Department. Academic Emergency Medicine, 21, 949–959. Ramsay, R., Byrd, L., Tower, C., James, J., Prescott, M. & Thachil, J. (2015) The problem of pulmonary embolism diagnosis in pregnancy. Brit J Haematol, 170, 727–736.