The 2nd International Conference on Drug Discovery & Therapy: Dubai, February 1 - 4, 2010


Session Speaker

Signal Transduction in Chronic Lymphocytic Leukemia B –Lymphocytes
Rasmi AbuHelu, PhD, Santanu Paul, PhD , Patricia Mongini, PhD, Bettie Steinberg, PhD, Kanti R. Rai, MD and Nicholas Chiorazzi, MD.

The B-cell receptor (BCR) is a key signaling molecule that engages antigens and triggers pathways that induce survival, proliferation, differentiation, anergy, or apoptosis. The "choice" of which functional fate the B cell makes is decided upon by a series of receptor and cellular interactions. The potential for ligand-initiated signal transduction through the BCR is assessed in terms of ligand binding affinity for membrane Ig. We have used a series of anti-IgM H chain mAb that differ in their affinities (HB57 - Ka = 5x108 "high", Mu53 - Ka = 2x107 "intermediate", and P24 - Ka = ~2x106 M-1 "low") in both soluble and immobilized forms as models for antigenic stimulation of the BCR, and assessed the response of normal B cells isolated by negative selection from peripheral blood. Proliferative responses were observed upon cross-linking the BCR with antibodies of all affinities at 10 ug/ml of immobilized antibodies for 72 hours, with a modest stimulation at 1ug/ml and no stimulation at either 0.01 or 0.1 ug/ml. Interestingly, the low affinity antibody P24 showed the highest proliferative response (3.3 fold), while stimulation with the moderate affinity antibody was intermediate (2.2 fold) and the response of the high affinity antibody, was negligible. Soluble antibodies did not stimulate proliferation at any concentration tested. When B cells were co-incubated with soluble anti-IgM antibodies plus IL 4,10ug/ml of either high or intermediate affinity induced proliferation with stimulation indices of 2.5 and 1.9, respectively, while the low affinity antibody still had no effect. Co-incubation with IL 4 and immobilized anti-IgM antibodies induced the same pattern of responses as seen with antibody alone, slightly increasing proliferation induced with 1 ug/ml low and intermediate and markedly increasing stimulation by all three antibodies at 10ug/ml. Our results suggest that even in the absence of T cell help, normal B cells can be activated via the BCR upon cross-linking and the efficiency at which this is acc omplished is largely dependent on affinity for the BCR.



[Webmaster]   Copyright © 2010 2nd International Conference on Drug Design & Therapy