Complex Stability and an Irrevertible Transition Reverted by Peptide and Fibroblasts in a Dynamic Model of Innate Immunity

Abstract

We here apply a control analysis and various types of stability analysis to an in silico model of innate immunity that addresses the management of inflammation by a therapeutic peptide. Motivation is the observation, both in silico and in experiments, that this therapy is not robust. Our modeling results demonstrate how (1) the biological phenomena of acute and chronic modes of inflammation may reflect an inherently complex bistability with an irrevertible flip between the two modes, (2) the chronic mode of the model has stable, sometimes unique, steady states, while its acute-mode steady states are stable but not unique, (3) as witnessed by TNF levels, acute inflammation is controlled by multiple processes, whereas its chronic-mode inflammation is only controlled by TNF synthesis and washout, (4) only when the antigen load is close to the acute mode's flipping point, many processes impact very strongly on cells and cytokines, (5) there is no antigen exposure level below which reduction of the antigen load alone initiates a flip back to the acute mode, and (6) adding healthy fibroblasts makes the transition from acute to chronic inflammation revertible, although (7) there is a window of antigen load where such a therapy cannot be effective. This suggests that triple therapies may be essential to overcome chronic inflammation. These may comprise (1) anti-immunoglobulin light chain peptides, (2) a temporarily reduced antigen load, and (3a) fibroblast repopulation or (3b) stem cell strategies.

System-Level Scenarios for the Elucidation of T Cell-Mediated Germinal Center B Cell Differentiation

“…Although, canonically, Tfh cells are presumed to have their lineage traced to Th1 and Th2 branches, recent studies show Tfh cells to have a distinct gene expression profile unlike Th1, Th2, Th17 or Treg cells ( 219 ). As cytokines have been confirmed to promote both T and B cell differentiation, understanding cytokine dynamics is vital, also when examining possible bistabilities of the |GC cycle, as it occurs in other immunology cycles ( 9 ). Although details of the specific mechanisms through which these dynamics occur are beyond the scope of this paper, a few considerations may be the starting point of future research.…”

“…Although great progress has been made in experimentally identifying the signals that steer GCBC fate determination, it remains challenging to study how the dynamic extracellular signals synergize, let alone how changes in signaling strength may affect the system. In view of the positive feedbacks in the GC cycle, and distributed control in cell signaling ( 8 ), it is to be expected that certain minor differences in signaling could make the difference between a proper and improper functioning of cellular immune networks ( 9 ), whereas others may be ineffective due to homeostatic mechanisms.…”