From Discrete to Continuous Modeling of Lymphocyte Development and Plasticity in Chronic Diseases

The molecular events leading to differentiation, development, and plasticity of lymphoid cells have been subject of intense research due to their key roles in multiple pathologies, such as lymphoproliferative disorders, tumor growth maintenance and chronic diseases. The emergent roles of lymphoid cells and the use of high-throughput technologies have led to an extensive accumulation of experimental data allowing the reconstruction of gene regulatory networks (GRN) by integrating biochemical signals provided by the microenvironment with transcriptional modules of lineage-specific genes. Computational modeling of GRN has been useful for the identification of molecular switches involved in lymphoid specification, prediction of microenvironment-dependent cell plasticity, and analyses of signaling events occurring downstream the activation of antigen recognition receptors. Among most common modeling strategies to analyze the dynamical behavior of GRN, discrete dynamic models are widely used for their capacity to capture molecular interactions when a limited knowledge of kinetic parameters is present. However, they are less powerful when modeling complex systems sensitive to biochemical gradients. To compensate it, discrete models may be transformed into regulatory networks that includes state variables and parameters varying within a continuous range. This approach is based on a system of differential equations dynamics with regulatory interactions described by fuzzy logic propositions. Here, we discuss the applicability of this method on modeling of development and plasticity processes of adaptive lymphocytes, and its potential implications in the study of pathological landscapes associated to chronic diseases.