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

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.

A multiscale model suggests that a moderately weak inhibition of SARS-CoV-2 replication by type I IFN could accelerate the clearance of the virus

“…It was also previously speculated that slow-growing tumours can "sneak through" immune surveillance [26]. An explanation for this is that the immune response tends to overshoot when faced with acute challenges [27]. The extrapolation of this finding to COVID-19 has several implications.…”

Perspectives of (/memorandum for) systems thinking on COVID‐19 pandemic and pathology

“…Data are of course important, but—even in large quantities—without theory or guiding hypotheses, they are of limited use in health care management, 8 , 9 public health issues 10 or theoretical immunology. 11 Often pragmatism—whose methods can be easily applied to generate data—rather than fundamental concepts determine the selection and perspective of a research study. The consecutive plurality of essentially unidimensional research in the various research fields associated with the pandemic could be integrated into a multi‐dimensional, comprehensive, coherent, abstract but understandable, high‐level conceptual framework.…”

Multi-Cellular Immunological Interactions Associated With COVID-19 Infections

“…While multi-cellularity is a well-known concept a structure composed of two or more cell types, the functions performed by groups of cells are less comprehended ( 12 ). It is now acknowledged that immune responses are not only determined by low-level structures (such as a single cell type or subtype) but also by groups of cells ( 13 ).…”