Understanding and Modelling the Complexity of the Immune System Véronique Thomas-Vaslin To cite this version: Véronique Thomas-Vaslin. Understanding and Modelling the Complexity of the Immune System. CS-DC’15 World e-conference, Sep 2015, Tempe, United States. hal-01291113 HAL Id: hal-01291113 https://hal.archives-ouvertes.fr/hal-01291113 Submitted on 20 Mar 2016 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Understanding and Modelling the Complexity of the Immune System Véronique Thomas-Vaslin Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Immunology-Immunopathology- Immunotherapy (I3); Paris, France Corresponding author: Dr. Véronique THOMAS-VASLIN UPMC-INSERM, UMRS959, CNRS, FRE3632 Immunology, Immunopathology, Immunotherapy 83 Boulevard de l'Hôpital, Paris, 75013, France tel: +33142177466 Email: [email protected] Key words: immune system, perception, antigens, environmental complexity, learning, internal representation, repertoire diversity, memory, ecological system, identity, integrity, circular complex system, dynamics, computer modelling 1 Abstract The immune system is a complex biological micro-ecosystem, adaptive, highly diversified, self- organized and cognitive network of cells and molecular entities with degeneracy properties. The adaptive immune system has evolved into a complex system of billions of highly diversified lymphocytes all interacting as a connective dynamic multi-scale organised and distributed system, in order to collectively insure body identity and integrity. This complex system insures species preservation of symbiotic and poly-genomic organisms. The immune system is characterized by complexity at many different levels; network organisation during the development, through fluid cell populations with inter- and intra-cell signalling, an extraordinary lymphocyte somatic receptor diversity, lymphocyte clonotype selection and competition at cell level, migration and interaction inside the immunological tissues and fluid dissemination through the organism, homeostatic regulation, while rapid adaptation to a changing environment. Lymphocytes are the key actors of the immune system of vertebrates, in the middle of a multi-scale biological organization “from molecule to organism”, and at the confluence with other different biological systems and the environment. The perception of antigens induces a network of immuno-receptors that could be viewed as an internal representation of antigens. Fluctuations, variability and diversity are key factor for the immune system to adapt perturbations and aging and to be or not resilient. Theoretical approaches of this complex system and multi-scale dynamic modeling are a challenge in the domain of complex systems. Theoretical, mathematics and computer models developed to improve our understanding of the multi-scale complexity of the immune system should be developed. 2 Introduction The immune system is a complex biological micro-ecosystem, adaptive, highly diversified, self- organized cognitive network of cells and molecular entities with degeneracy properties, allowing in healthy individuals for a robust and resilient system with emergent properties such as anamnestic responses and regulations. The adaptive immune system has evolved into a complex system of billions of highly diversified lymphocytes all interacting as a connective dynamic multi- scale organised and distributed system, in order to collectively insure body identity and integrity, and species preservation of symbiotic organisms exposing polygenomic antigens. The immune system is characterized by complexity at different levels: network organisation through fluid cell populations with inter- and intra-cell signalling, an extraordinary lymphocyte receptor diversity, cell clonotype selection and competition at cell level, migration and interaction inside the immunological tissues and fluid dissemination through the organism, homeostatic regulation while rapid adaptation to a changing environment. Lymphocytes are the key actors of the immune system of vertebrates, in the middle of a multi-scale biological organization “from molecule to organism”, and at the confluence with other different biological systems and the environment. The perception of antigens induces a network of immuno-receptors that could be viewed as an internal representation of antigens. Fluctuations and variability are key factor for the immune system to adapt perturbations and aging. A deeper understanding of T-cell differentiation, diversity, dynamics, repertoires selection and regulation processes is key for fundamental research, medical advancement and drug discovery. Moreover the immune system represents a complex system sharing some transversal properties with other complex systems (organisation as dynamical properties, resilience to perturbations …). 3 Crossing interdisciplinary transversal questions from other complex systems to study the complexity of the immune system Understanding the organization and the regulation of the complex immune system refers to transversal questions already mentioned for other “live” complex systems such as other biological, social or ecological macro systems, with some peculiarities specific to the immune system. Thus, the immune system can be observed and modelled from different point of view with the theoretical and methodological approaches shared by other inter-disciplinary domains using biological, physical, philosophical, mathematical, statistical, and computer approaches. Some examples of the cross-fertilization required to solve open questions concerning specifically the immune system are proposed in Table 1. 4 Transversal questions commons to other complex Questions specific to the immune system systems Study and modeling of adaptive multi-scale system The adaptive immune system Integration of high-throughput multi-scale and Biological generic data from transcriptome, multi-parametric data and metadata and proteome, but also cytome, repertome… sharing Computer or mathematical tools for exploration Supervised and non supervised statistical modeling, and formalization mechanistic reconstruction of immune system and lymphocyte behaviour Theoretical reconstruction Multi-scale analysis, representation of heterogeneous data, organisation of knowledge’s database describing the immune system around the lymphocyte level, from molecule to organism, for data- driven and hypothesis-driven reconstruction Metamodels, multi-formalism for reconstruction Mathematical & computer modelling for and visualization of dynamics, lymphocyte cell population dynamics, differentiation, and behaviour activation, regulation and selection processes; use of oriented object, graphical languages, SMA, ontologies, for modeling the multi-scale entities of the immune system… Fluctuations, stability, variability, regulations at Multi-level/Multi-scale: organism, lymphoid tissues, multi-scale levels lymphocyte populations, cellular and molecular lymphoid repertoires Robustness/resilience and relation to organization Behavior of immune system from development to aging; resilience to perturbations, transition to immunopathologies (infection, autoimmunity, cancer…); immunotherapy/vaccination Model the relationships between biodiversity, Diversity, stability/perturbation of immune functioning and dynamics of the repertoires and lymphocyte populations (eco)systems Self organization, simulation of virtual landscapes Auto-organization of cells in lymphoid organs and development, cell network and immune repertoire Data mining, extraction, visualization of data and Information extraction and visualization of immune semantic and syntactic analysis of scientific literature with concepts specific to immune literature requires artificial intelligence and system automatic learning approaches Table 1: Crossing transversal questions identified for the investigation of the complex systems1 with the questions specific to the immune system. 1 http://roadmap.csregistry.org/tiki-index.php?page=French+Roadmap This live roadmap can be edited with new questions 5 Open question and challenges related to the complexity of the immune system More than transversal questions common to other complex systems, the immune system present some peculiarities that require particular investigations and modelling and this represents new challenges to overcome. Objective identification of immune system cell populations Innate and adaptive immune system subpopulations are currently defined on the basis of the revelation of a combination of cell surface or intracellular/nuclear molecules that the researcher has to define to explore the phenotype and functionality of cells. Thus, the cell populations revealed by cell staining are largely dependant on the mixture and the number of chosen parameters (n) that will drive the number of subpopulations (2n). Techniques like Flow cytometry analysis allow quantification of several parameters from individual cells allowing characterizing cell size, structure, specific phenotype and function of millions of cells