A generalized quantitative antibody homeostasis model: regulation of B-cell development by BCR saturation and novel insights into bone marrow function

In a pair of articles, we present a generalized quantitative model for the homeostatic function of clonal humoral immune system. In this first paper, we describe the cycles of B-cell expansion and differentiation driven by B-cell receptor engagement. The fate of a B cell is determined by the signals it receives via its antigen receptor at any point of its lifetime. We express BCR engagement as a function of apparent affinity and free antigen concentration, using the range of 10(−14)–10(−3) M for both factors. We assume that for keeping their BCR responsive, B cells must maintain partial BCR saturation, which is a narrow region defined by [Ag]≈K(D). To remain in this region, B cells respond to changes in [Ag] by proliferation or apoptosis and modulate K(D) by changing BCR structure. We apply this framework to various niches of B-cell development such as the bone marrow, blood, lymphoid follicles and germinal centers. We propose that clustered B cells in the bone marrow and in follicles present antigen to surrounding B cells by exposing antigen captured on complement and Fc receptors. The model suggests that antigen-dependent selection in the bone marrow results in (1) effector BI cells, which develop in blood as a consequence of the inexhaustible nature of soluble antigens, (2) memory cells that survive in antigen rich niches, identified as marginal zone B cells. Finally, the model implies that memory B cells could derive survival signals from abundant non-cognate antigens.