Immunological Paradigms, Mechanisms, and Models: Conceptual Understanding Is a Prerequisite to Effective Modeling.

Zvi Grossman

doi:10.3389/fimmu.2019.02522

Abstract

Most mathematical models that describe the individual or collective actions of cells aim at creating faithful representations of limited sets of data in a self-consistent manner. Consistency with relevant physiological rules pertaining to the greater picture is rarely imposed. By themselves, such models have limited predictive or even explanatory value, contrary to standard claims. Here I try to show that a more critical examination of currently held paradigms is necessary and could potentially lead to models that pass the test of time. In considering the evolution of paradigms over the past decades I focus on the “smart surveillance” theory of how T cells can respond differentially, individually and collectively, to both self- and foreign antigens depending on various “contextual” parameters. The overall perspective is that physiological messages to cells are encoded not only in the biochemical connections of signaling molecules to the cellular machinery but also in the magnitude, kinetics, and in the time- and space-contingencies, of sets of stimuli. By rationalizing the feasibility of subthreshold interactions, the “dynamic tuning hypothesis,” a central component of the theory, set the ground for further theoretical and experimental explorations of dynamically regulated immune tolerance, homeostasis and diversity, and of the notion that lymphocytes participate in nonclassical physiological functions. Some of these efforts are reviewed. Another focus of this review is the concomitant regulation of immune activation and homeostasis through the operation of a feedback mechanism controlling the balance between renewal and differentiation of activated cells. Different perspectives on the nature and regulation of chronic immune activation in HIV infection have led to conflicting models of HIV pathogenesis—a major area of research for theoretical immunologists over almost three decades—and can have profound impact on ongoing HIV cure strategies. Altogether, this critical review is intended to constructively influence the outlook of prospective model builders and of interested immunologists on the state of the art and to encourage conceptual work.

Highlights

With some exceptions, the long-term impact of mathematical modeling on basic and clinical immunology has been modest [1,2,3,4], and sometimes counter-productive [5], despite claims to the contrary
“Sensing which assumptions might be critical and which irrelevant to the question at hand is the art of modeling and, for this, there is no substitute for a deep understanding of the biology” [8]
By rationalizing the feasibility of subthreshold interactions, the tuning hypothesis reconciled the physiological requirement of explosive immune responses to acute infections with the plethora of manifestations of intricate context discrimination and adaptive networking associated with homeostasis and functional preparedness, and set the ground for further theoretical and experimental explorations of generalized immunological functions

Summary

Introduction

The long-term impact of mathematical modeling on basic and clinical immunology has been modest [1,2,3,4], and sometimes counter-productive [5], despite claims to the contrary. Several observations suggested to us (a) that additional, “contextual” attributes of infection events were important [1], besides the inherent proinflammatory properties of bacteria and viruses; and (b) that antigen-mediated signals delivered to lymphocytes in the absence of infection were capable of eliciting cellular responses that contributed to the lymphocytes’ own functional integrity and to that of the cells with which they interacted.

Results

Conclusion