Fig 1.
Terminal B cell differentiation.
Precursor Naive B cells can differentiate into three possible cell types depending on proper molecular stimuli. Cytokines secreted by T-helper cells play a central role in the determination of B cell fate. IL-2 and IL-4 are required for the transition of Naive to GC cells. Direct contact of B cells with T cells by means of the CD40L receptor promote the differentiation of Naive or GC cells toward the Mem cell type. Antigen (Ag) activation drives terminal differentiation toward the PC cells, a process that is favored by the presence of IL-21.
Fig 2.
The regulatory network of B cells.
Nodes represent molecules or molecular complexes. Positive and negative regulatory interactions among molecules are represented as green continuous arrows and red blunt arrows respectively.
Table 1.
Attractors of the discrete and continuous models of the B cell regulatory network.
Fig 3.
Attractors and cell types The stationary states of the regulatory network correspond to multiple activation patterns that characterize different cell types.
Table 2.
Fixed point attractors of the continuous system not found in the random search.
Fig 4.
Differentiation from Naive to the PC cell type.
The changes in the activation of all nodes of the network are shown as a heatmap which scales from blue to red as the activation level goes from 0 to 1, respectively. Extracellular signals are simulated as a burst for two or more units of time (arrows). Starting from the Naive (Bach2+, Pax5+) stationary state (t = 0 to t ≈ 25), the system moves to the GC attractor (Bach2+, Bcl6+, Pax5+) due to the presence of a simulated pulse of IL-4 (t ≈ 25) which in turn transit to the Mem attractor (Bach2+, Irf4+, Pax5+) due to the action of CD40L (t ≈ 55) and finally, Mem attractor moves to the PC state (Blimp1+, Irf4+) by the presence of Ag signal (t ≈ 75).
Fig 5.
Nodes represent the fixed point attractors, and the edges correspond to all the possible single-node perturbations able to move the system from one attractor to another. For the continuous model, perturbations are simulated by temporarily change the value of a single node to 0, 1 or 0.5, represented by the symbols “−”, “+” and “int”, respectively. For example, IL-2+ means that a temporal activation of IL-2 is able to cause the system to move from the Naive attractor to the GC attractor. Biologically relevant differentiation routes are represented as blue arrows.
Table 3.
Simulated null mutant attractors.
Table 4.
Simulated constitutive mutant attractors.
Table 5.
Summary of the simulated mutants and external signals.
Table 6.
The set of Boolean rules defining the regulatory network of the terminal differentiation of B cells.
Fig 6.
The activation part of Eq (1) is a sigmoid function of the total input of the node (ωi) Regardless of the value of h, the sigmoid touches the points (0,0), (0.5,0.5) and (1,1).
For values of h ≥ 50 the curve resembles a step function.