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

Abstract

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.\n\nThe 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 to 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]{approx}KD. To remain in this region, B cells respond to changes in [Ag] by proliferation or apoptosis and modulate KD 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.