The emergent dynamics of isotype switch

Abstract

The supplanting of the 1° IgM response by the 2° isotype-switched response is one of the best known phenomena of immune system dynamics. Given that the conditions determining which B cells will switch isotype and which ones will not are intrinsic to the entities of the immune system, it should be possible to predict the effects that the small-scale (e.g. molecular) properties have on the large scale dynamics of isotype switch. However, in practice, it is notoriously difficult to predict large scale, emergent effects from small scale conditions. Thus, it is unclear what effects (if any), mutation, IgM avidity and chronic immunization exert on isotype switch. To explore these effects, we have constructed a model of isotype switch. With this model, a modified version of the IMMSIM cellular automaton, we are able to alter small scale parameters at will and thus determine the conditions that lead to the observed large scale dynamics of isotype switch. We show that isotype switch is stabilized by high-IgM avidity, affinity/isotype-dependent cell division, and, surprisingly, mutation. We also demonstrate that chronic immunization leads, in our model, to a severe depletion of the IgM response even while the IgG response remains normal.

Keywords::

• Isotype switch
• IMMSIM cellular automaton
• theoretical models
• population dynamics

Acknowledgements

We are indebted to M. Weigert for his encouragement and many helpful discussions. We thank C. Benedict, F. Celada, K. Harrison, S. Kleinstein, M. Shannon, and M. Weigert for their critical reviews of the manuscript. We also thank J. Wadsack, whose support enabled this publication. Jeff Stewart: Phil Seiden was both brilliant and unfailingly kind. To my friend and mentor, Phil, I thank you.

Declaration of interest: This publication was supported by a grant from the NIH R37 GM-20964. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.