Oprea M, Perelson A S
Santa Fe Institute, NM 87501, USA.
J Theor Biol. 1996 Aug 7;181(3):215-36. doi: 10.1006/jtbi.1996.0127.
We have developed a model of the early events that occur during a primary antibody response to a T cell-dependent antigen. Within secondary lymphoid organs, B cell proliferation in response to antigen injection gives rise to two kinds of transient structures: foci that develop in the T cell area, and germinal centers, that develop in the secondary follicles of the B cell area. Foci give rise to plasma cells that are responsible for the majority of early circulating antibody, whereas germinal centers are sites of somatic mutation and memory cell formation. Here we model the cell-cell interactions and cell population kinetics involved in the generation of antibody-forming cell foci, and compare our model with experimental data. We focus on fundamental issues involving the control of B cell proliferation and differentiation, using simple kinetic models that depend on direct cell-cell interactions and on the action of cytokines. We show that with realistic parameter assumptions our model can account for both the rapid cellular expansion and the differentiation of B cells into antibody-secreting cells. By summing the expected antibody production of all the plasmablasts and plasma cells that are generated during the focus response we can account for much of the antibody observed in the serum of mice during a primary response. Lastly, we compare the predictions of our model for two different scenarios for the control of B cell proliferation. In one model, we assume that B cells, once activated, proliferate under the control of cytokines without direct interaction with activated T cells. In the other model, we assume that after dividing B cells return to rest and require a contact-dependent signal from an activated T cell to divide again. The first model gives rise to large foci and antibody levels similar to that observed in experiment, whereas the latter model gives rise to four-fold smaller foci and to circulating antibody levels that are one order of magnitude lower than typical experimental values. This result suggests that B cells may be able to divide without further contact with T cells once a cognate interaction has occurred.
我们构建了一个模型，用于描述对T细胞依赖性抗原产生初次抗体应答期间发生的早期事件。在二级淋巴器官内，B细胞对抗原注射的增殖反应产生了两种瞬时结构：在T细胞区域形成的灶，以及在B细胞区域的二级滤泡中形成的生发中心。灶产生负责大部分早期循环抗体的浆细胞，而生发中心是体细胞突变和记忆细胞形成的场所。在这里，我们对参与抗体形成细胞灶产生的细胞间相互作用和细胞群体动力学进行建模，并将我们的模型与实验数据进行比较。我们使用依赖于直接细胞间相互作用和细胞因子作用的简单动力学模型，关注涉及B细胞增殖和分化控制的基本问题。我们表明，在现实的参数假设下，我们的模型可以解释B细胞的快速细胞扩增以及向抗体分泌细胞的分化。通过汇总在灶反应期间产生的所有浆母细胞和浆细胞的预期抗体产量，我们可以解释在初次反应期间小鼠血清中观察到的大部分抗体。最后，我们比较了我们的模型对B细胞增殖控制的两种不同情况的预测。在一个模型中，我们假设B细胞一旦被激活，就在细胞因子的控制下增殖，而不与激活的T细胞直接相互作用。在另一个模型中，我们假设B细胞分裂后恢复静止状态，并且需要来自激活的T细胞的接触依赖性信号才能再次分裂。第一个模型产生的灶和抗体水平与实验中观察到的相似，而后者模型产生的灶小四倍，循环抗体水平比典型实验值低一个数量级。这一结果表明，一旦发生同源相互作用，B细胞可能能够在不与T细胞进一步接触的情况下进行分裂。
