Immunological Paradigms, Mechanisms, and Models: Conceptual Understanding Is a Prerequisite to Effective Modeling
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 mo...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.02522/full |
| _version_ | 1818509825914437632 |
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| author | Zvi Grossman Zvi Grossman |
| author_facet | Zvi Grossman Zvi Grossman |
| author_sort | Zvi Grossman |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T22:50:44Z |
| format | Article |
| id | doaj.art-be956908a8f4423f9f7208d86c049ed8 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-10T22:50:44Z |
| publishDate | 2019-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-be956908a8f4423f9f7208d86c049ed82022-12-22T01:30:26ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-11-011010.3389/fimmu.2019.02522462483Immunological Paradigms, Mechanisms, and Models: Conceptual Understanding Is a Prerequisite to Effective ModelingZvi Grossman0Zvi Grossman1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, United StatesSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelMost 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.https://www.frontiersin.org/article/10.3389/fimmu.2019.02522/fullsmart surveillancechange detectionautoreactivityadaptationtuningfeedback control |
| spellingShingle | Zvi Grossman Zvi Grossman Immunological Paradigms, Mechanisms, and Models: Conceptual Understanding Is a Prerequisite to Effective Modeling Frontiers in Immunology smart surveillance change detection autoreactivity adaptation tuning feedback control |
| title | Immunological Paradigms, Mechanisms, and Models: Conceptual Understanding Is a Prerequisite to Effective Modeling |
| title_full | Immunological Paradigms, Mechanisms, and Models: Conceptual Understanding Is a Prerequisite to Effective Modeling |
| title_fullStr | Immunological Paradigms, Mechanisms, and Models: Conceptual Understanding Is a Prerequisite to Effective Modeling |
| title_full_unstemmed | Immunological Paradigms, Mechanisms, and Models: Conceptual Understanding Is a Prerequisite to Effective Modeling |
| title_short | Immunological Paradigms, Mechanisms, and Models: Conceptual Understanding Is a Prerequisite to Effective Modeling |
| title_sort | immunological paradigms mechanisms and models conceptual understanding is a prerequisite to effective modeling |
| topic | smart surveillance change detection autoreactivity adaptation tuning feedback control |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.02522/full |
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