We next simulated our model system and the results for Lyn and Syk activation are shown in Figure 7A and 7B. Here, we calculated the value of Lp from the derived relation. We found that the influence of the negative regulator on Lyn and Syk activity produced two different basal states for them before the trigger point, which denotes BCR dependent stimulation. But the interesting prediction from the model was that the sensitivity of either Lyn or Syk response to BCR engagement was sig With initial conditions Lp 0, Sm 0, Sp 0. A is the total amount of Syk molecule present in the cell susceptible to activation. k1 is the membrane asso ciated Lyn at basal level. k2 represents the rate at which activation of Lyn take place after the binding of agonist to the membrane receptor.

k3 is the rate at which Syk is activated by the Lyn. d1 and d2 represents the amount of negative regulator on the active forms of Lyn and Syk respectively at their ground state. nificantly higher when the basal activity of Lyn was lower. This finding would be consistent with the experi mental results obtained in the present study. To further delineate the effect of basal activity on receptor induced signaling, we plotted different peak values with respect to different basal values for Lyn and Syk by varying the parameter for negative regulator. Figure 7C shows the result of the simulation where an inverse relation between basal level of Lyn activity, and the extent of its activation after BCR stimulation is clearly evident. To observe the effect of other parameters especially those acting on the active Syk species we performed a similar analysis on Syk.

A similar qualitative behaviour with dif ferent slope values was again obtained. The results of our modeling analysis thus further sub stantiated our experimental results by highlighting the role played by the negative regulators of signal initiation, such as SHP 1, in determining the cell fate decision. Discussion B lymphocytes represent a good model system to study plasticity in receptor activated signaling processes, and the consequent influence on the cellular phenotypic response. Depending on their state of maturation, anti gen encounter by the B lymphocytes can lead to varied outcomes that range from activation and/or proliferation to anergy, or also to activation induced cell death through apoptotic mechanisms.

In general, mature B lymphocytes undergo activation followed by proliferation upon induction of BCR dependent signal ing by an antigen. In contrast, engagement of the BCR induces AICD preceded by an arrest of the cell cycle in immature and transitional stage immature B cells. This latter process serves to eliminate self reactive B cells during its AV-951 different stages of devel opment. Various cell lines such as WEHI 231, CH31, and B104 among others have been employed as models systems for the study of BCR signaling in imma ture B cells.