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Immune system homeostasis

Immune system homeostasis

The homsostasis role of segmented filamentous bacteria in Diabetes and telemedicine coordinated maturation sustem gut helper T cell responses. Oxford Academic. Dysbiosis can be caused by dysregulated immunity and have life-threatening consequences as we just discussed. Haribhai D.

Immune system homeostasis -

To perform this task, it is organized as a tightly regulated, hierarchically controlled and spatially distributed network with soluble and cellular components. Since mathematics is the universal language for expressing causal and functional relationships between observations, it is natural to use mathematical tools for mechanistically describing immune system dynamics and functioning.

However, as both the immune system's complexity and experimental data sets are huge, it is a substantial challenge to connect these in a mechanistic way. Shifting this simplistic perception of the immune system to a dynamic, multi-level, and spatially resolved system description with molecular and cellular networks is daunting and requires the combination of a solid understanding of the underlying systems biology with the application of appropriate mathematical methodologies.

This may ultimately improve the biological relevance of the generated models and contribute to a better mechanistic understanding of immune system functioning as well as making biologically and clinically relevant predictions for diagnosis and treatment of human diseases.

The aim of this Research Topic was to present current state-of-the-art research on using mathematically driven exploration of the complexity of the immune system. He highlighted that the physiological messages to cells are encoded not only in the biochemical connections of sets of signaling molecules to the cellular machinery but also in their magnitude, kinetics, and time and space contingencies.

Moreover, Grossman used his conceptual postulates to discuss conflicting models of HIV pathogenesis. Castiglione et al. addressed the underlying mechanism of cross-reactive immune responses and antigenic sin that may be beneficial, neutral, or detrimental for the host.

They studied the relationship of clonal dominance with memory cell attrition with an agent-based model. They propose that attrition could serve as a curbing mechanism for the memory-anti-naive phenomenon. Several studies describe novel modeling tools and their applications.

Lanzarotti et al. developed a model for the prediction of cognate T cell receptor TCR targets. It is based on the similarity to a database of TCRs with known targets and may have important implications for the rational design of T cell-based therapies.

With their time-resolved experimental data of splenic transcriptomes from mice infected with the lymphocytic choriomeningitis virus LCMV , Pedragosa et al.

addressed the problem of linking gene expression changes from whole tissue with immune cell dynamics. To this end, they combined weighted gene co-expression network analysis—with digital cell quantifier—providing a novel approach to bridge the genomic with the cellular level during antiviral immune responses.

Meier-Schellersheim et al. discuss how mechanistic rule-based modeling can be used to test immunological hypotheses through quantitative simulations. They considered as an example G-protein-coupled receptor signaling that is utilized by cells to respond to a wide range of extracellular stimuli and explore the cross-talk of multiple cytokine pathways, thereby providing basis for deriving cell population behavior from single-cell models and bridging a current scale gap.

Finally, Enciso et al. demonstrated how discrete dynamic models can be transformed to continuous dynamic models using Fuzzy logic. This approach enables a better description of growth and differentiation of T lymphocytes in various microenvironments.

The consequences of an uneven partitioning of molecular contents on cell fate regulation were studied by Girel et al. They introduced a multi-scale mathematical model of CD8 T cell responses in lymph nodes and showed that the degree of unevenness of molecular partitioning affects the outcome of the immune response and memory cell generation.

Huang et al. considered virus and interferon spread within an infected host as two competing processes and analyzed a well-mixed vs. a spatially segregated scenario.

They defined the conditions under which the interferon response works most effectively and suppresses the infection. A series of six publications considered the architecture and functioning of lymph nodes within an immune response. Novkovic et al. reviewed available computational lymph node models with the focus on the structure and organization of stromal cells.

The authors pointed out that hybrid- and multi-scale models in combination with high-resolution imaging will be important to unravel the complex immune mechanisms that are initiated in lymph nodes.

The study by Moses et al. is focused on the definition of rules specifying the search strategies of T cells for antigen. They discovered striking similarities between the strategies ant colonies use to forage and the immune cells use to find pathogens.

The strategies are based on a variety of search behaviors including directional movement using chemokine gradients, random motion using correlated random walk, and movement along physical networks. Kalogiros et al. developed a mathematical framework to characterize spatio-temporal chemokine gradient formation.

With their Bayesian parameter inference approach, they provided a building block for subsequent multi-scale modeling. Azarov et al. developed an agent-based model to investigate the role of T cell-dendritic cell DC chemoattraction in T cell priming in the lymph node.

They stressed that the balance of naive and activated antigen-specific T cells that are both chemotactically attracted to the neighborhood of DCs determine the overall amplitude of the specific T cell response. Grebennikov et al. developed a physics-based model of T cell motility in lymph nodes.

The cell dynamics is determined by a superposition of autonomous locomotion, intercellular interactions, and viscous dumping. The model was then used to predict the required CD8 T cell frequencies necessary to detect HIV-infected cells before they start releasing virus particles.

McDaniel and Ganusov studied lymphocyte recirculation in sheep. With a series of mathematical models, they estimated the distribution of residence times in ovine lymph nodes. Finally, six publications addressed various aspects of multi-factorial immune-related phenomena and diseases.

Presbitero et al. described the role of alkaline phosphatase AP during cardiac surgery. The exact functions of IELs remain unclear, although they may play crucial roles in epithelial tumor surveillance, reconstruction of gut tissue after injury or in the prevention of pathogenic bacteria penetration.

Patients with CD possess defective or inadequate innate immune responses, including cytokine production, pathogen clearance, and recruitment of neutrophils. Dendritic cells and macrophages are critical for initiation of innate immune responses during microbial invasion and inflammation.

In the intestine, the activity of these innate-immune myeloid cells is finely regulated by several mechanisms because the excessive and inadequate initiation of innate immunity leads to the development of IBD.

Currently, intestinal innate-immune myeloid cells are divided into several subsets possessing different abilities to maintain gut immune homeostasis either through enhancing or suppressing T-cell responses 46— Administration of ATP to germ-free mice with few T h 17 cells enhances the accumulation of T h 17 cells in the lamina propria, indicating that ATP derived from commensal bacteria is responsible for initiation of T h cell development.

Regulation of gut immune responses by innate immune cells. C Segmented filamentous bacteria SFB are a potent inducer of T h cell differentiation. In the steady state, T h 17 and T h 1 cells are responsible for protection against pathogens. IL produced by intestinal macrophages limits intestinal inflammation through the persistence of Foxp3 expression in T reg cells 63 and inhibits IL and tumor necrosis factor TNF -α production against commensal bacteria in intestinal myeloid cells via activation of the transcription factor Stat3.

We have recently identified intestinal innate-immune myeloid cells possessing a unique function. Administration of wild-type M reg cells to Stat3-mutant mice ameliorated intestinal inflammation, indicating that a dysfunction of M reg cells is involved in the pathogenesis of IBD. This suggests that intestinal inflammation is not simply a result of defective T reg -cell-mediated suppression but that pathogenic T cells are regulated by multiple regulatory cells in the intestine.

Accordingly, it will be important to determine whether M reg cells are present and fully functional in patients with IBD before we can assess potential clinical application of M reg cells for chronic intestinal inflammation.

Several subsets of intestinal innate-immune myeloid cells thus contribute to the maintenance of gut homeostasis, and dysregulation of activities of these cells leads to development of IBD. The gastrointestinal tract in mammals harbors an estimated 10 14 commensal organisms that exist in a symbiotic relationship with their host.

Recent findings have elucidated that the microflora in the gut influences not only nutrient metabolism but also the development of the immune system 69— In addition, Bacteroides fragilis has been reported to protect animals from experimental colitis induced by pathogens via induction of ILproducing T reg cells 72 Fig.

The beneficial effect of B. Accordingly, mice reared under germ-free conditions fail to induce oral tolerance Meanwhile, segmented filamentous bacteria SFB mediate T h cell initiation in the small intestine Fig. Mice colonized with SFB established resistance to infection of Citrobacter rodentium , indicating that T h cell induction by SFB was responsible for these protective immune responses Mice expressing a human α-defensin gene DEFA5 show loss of SFB and fewer ILproducing T cells Furthermore, SFB colonization induces a high sensitivity to experimental autoimmune encephalomyelitis via induction of T h 17 cells and autoantibody-producing B cells in the central nervous system 78 , T h cell differentiation mediated by SFB colonization is thus connected to the development of autoimmune diseases while contributing to mucosal protection against pathogens.

In addition to immune activation, the microflora is required to inhibit or expel pathogens by competing for nutrients, by producing biosurfactants that prevent adhesion of pathogens on mucosal surfaces, by signaling between bacteria that can lead to down-regulation of toxin production in pathogens, and by up-regulating tight-junction proteins in the intestinal epithelium.

Studies have shown that micronutrients can profoundly affect the generation and maintenance of immune responses For instance, activation of the aryl hydrocarbon receptor AHR by 6-formylindolo[3,2-b]carbazole enhances production of IL and IL by T h 17 cells 81 , In contrast, nuclear translocation of AHR by kynurenine promotes T reg -cell induction.

The activation of RAR—RXR a heterodimer of retinoic acid receptor and retinoid X receptor by retinoic acid, the immunologically active form of vitamin A, can also promote T reg -cell generation.

Furthermore, the interaction of short-chain fatty acids, such as acetate, and GPR43 G-protein-coupled receptor 43 has been shown to promote the resolution of colitis Acetate exerts anti-inflammatory effects on GPRexpressing immune cells such as neutrophils by regulating migration and apoptosis of those cells in the intestine.

In addition, acetate produced by Bifidobacterium longum has been reported to protect mice from lethal infection with Escherichia coli OH7 by enhancing the intestinal epithelial barrier integrity through induction of anti-inflammatory and anti-apoptotic genes Recent advances in our understanding of probiotics, which are live microorganisms that confer a health benefit, strongly suggest that these microorganisms can modulate the maintenance of gut homeostasis.

In the context of intestinal inflammation, administration of probiotics can inhibit the progression of inflammation via IL or TGF-β-bearing T reg cells 85 , Probiotic administration in patients with IBD might therefore become an effective therapeutic approach during clinical remission.

Although recent advances have provided substantial insights into the gut immune homeostasis influenced by microflora, the mechanistic basis of IBD remains poorly understood.

At steady state, the innate immune system plays a key role in gut homeostasis whereas during periods of altered microbiota it can be a direct cause of chronic inflammation In addition, T h 1 and T h 17 cells contribute to the protective responses to pathogens during physiological conditions, whereas excessive activation of these cells is responsible for intestinal inflammation.

We thank C. Hidaka for secretarial assistance and Y. Magota for technical assistance. This work was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, the Ministry of Health, Labour and Welfare and the Osaka Foundation for the Promotion of Clinical Immunology.

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