Early host defense against virus infections.

Early host defense eliminates many viruses before infections are established while clearing others so they remain subclinical or cause only mild disease. The field of immunology has been shaped by broad concepts, including the pattern recognition theory that currently dominates innate immunology. Focusing on early host responses to virus infections, we analyze the literature to build a working hypothesis for the principles that govern the early line of cellular antiviral defense.

Critically assessing atavism, an evolution-centered and deterministic hypothesis on cancer.

Cancer is most commonly viewed as resulting from somatic mutations enhancing proliferation and invasion. Some hypotheses further propose that these new capacities reveal a breakdown of multicellularity allowing cancer cells to escape proliferation and cooperation control mechanisms that were implemented during evolution of multicellularity. Here we critically review one such hypothesis, named "atavism," which puts forward the idea that cancer results from the re-expression of normally repressed genes forming a program, or toolbox, inherited from unicellular or simple multicellular ancestors.

The conceptual foundations of innate immunity: Taking stock 30 years later.

While largely neglected over decades during which adaptive immunity captured most of the attention, innate immune mechanisms have now become central to our understanding of immunology. Innate immunity provides the first barrier to infection in vertebrates, and it is the sole mechanism of host defense in invertebrates and plants. Innate immunity also plays a critical role in maintaining homeostasis, shaping the microbiota, and in disease contexts such as cancer, neurodegeneration, metabolic syndromes, and aging.

Reuniting philosophy and science to advance cancer research.

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer.

The origin of RNA interference: Adaptive or neutral evolution?

The origin of RNA interference (RNAi) is usually explained by a defense-based hypothesis, in which RNAi evolved as a defense against transposable elements (TEs) and RNA viruses and was already present in the last eukaryotic common ancestor (LECA). However, since RNA antisense regulation and double-stranded RNAs (dsRNAs) are ancient and widespread phenomena, the origin of defensive RNAi should have occurred in parallel with its regulative functions to avoid imbalances in gene regulation. Thus, we propose a neutral evolutionary hypothesis for the origin of RNAi in which qualitative system drift from a prokaryotic antisense RNA gene regulation mechanism leads to the formation of RNAi through constructive neutral evolution (CNE).

Cancer's second genome: Microbial cancer diagnostics and redefining clonal evolution as a multispecies process: Humans and their tumors are not aseptic, and the multispecies nature of cancer modulates clinical care and clonal evolution: Humans and their tumors are not aseptic, and the multispecies nature of cancer modulates clinical care and clonal evolution.

The presence and role of microbes in human cancers has come full circle in the last century. Tumors are no longer considered aseptic, but implications for cancer biology and oncology remain underappreciated. Opportunities to identify and build translational diagnostics, prognostics, and therapeutics that exploit cancer's second genome-the metagenome-are manifold, but require careful consideration of microbial experimental idiosyncrasies that are distinct from host-centric methods.

Interleukin-1β-Activated Microvascular Endothelial Cells Promote DC-SIGN-Positive Alternatively Activated Macrophages as a Mechanism of Skin Fibrosis in Systemic Sclerosis.

Objective: To characterize the role of interleukin-1β (IL-1β) and microvascular endothelial cells (MVECs) in the generation of alternatively activated macrophages in the skin, and to explore their role in the development of skin fibrosis in patients with systemic sclerosis (SSc; scleroderma).

Methods: Conditioned medium prepared with MVECs purified from the skin of healthy donors and the skin of SSc patients was used to generate monocyte-derived macrophages. Flow cytometry, multiplex protein assessment, real-time quantitative polymerase chain reaction, and tissue immunofluorescence were used to characterize MVEC-induced polarization of alternatively activated macrophages.

Redrawing therapeutic boundaries: microbiota and cancer.

The unexpected roles of the microbiota in cancer challenge explanations of carcinogenesis that focus on tumor-intrinsic properties. Most tumors contain bacteria and viruses, and the host's proximal and distal microbiota influence both cancer incidence and therapeutic responsiveness. Continuing the history of cancer-microbe research, these findings raise a key question: to what extent is the microbiota relevant for clinical oncology? We approach this by critically evaluating three issues: how the microbiota provides a predictive biomarker of cancer growth and therapeutic responsiveness, the microbiota's causal role(s) in cancer development, and how therapeutic manipulations of the microbiota improve patient outcomes in cancer.

Immunological exhaustion: How to make a disparate concept operational?

In this essay, we show that 3 distinct approaches to immunological exhaustion coexist and that they only partially overlap, generating potential misunderstandings. Exploring cases ranging from viral infections to cancer, we propose that it is crucial, for experimental and therapeutic purposes, to clarify these approaches and their interconnections so as to make the concept of exhaustion genuinely operational.

TGFβ promotes low IL10-producing ILC2 with profibrotic ability involved in skin fibrosis in systemic sclerosis.

Objective: Innate lymphoid cells-2 (ILC2) were shown to be involved in the development of lung or hepatic fibrosis. We sought to explore the functional and phenotypic heterogeneity of ILC2 in skin fibrosis within systemic sclerosis (SSc).

Methods: Blood samples and skin biopsies from healthy donor or patients with SSc were analysed by immunostaining techniques.

Constitutive immune mechanisms: mediators of host defence and immune regulation.

The immune system enables organisms to combat infections and to eliminate endogenous challenges. Immune responses can be evoked through diverse inducible pathways. However, various constitutive mechanisms are also required for immunocompetence.

Characterizing causality in cancer.

Philosophers have explored the concept of causality for centuries. Here we argue that ideas about causality from philosophy can help scientists to better understand how cancerous tumors grow and spread in the body. After outlining six characteristics of causality that are relevant to cancer, we emphasize the importance of feedback loops and interactions between tumor-cell-intrinsic and tumor-cell-extrinsic factors for explaining the formation and dissemination of tumors.

Understanding Multicellularity: The Functional Organization of the Intercellular Space.

The aim of this paper is to provide a theoretical framework to understand how multicellular systems realize functionally integrated physiological entities by organizing their intercellular space. From a perspective centered on physiology and integration, biological systems are often characterized as organized in such a way that they realize metabolic self-production and self-maintenance. The existence and activity of their components rely on the network they realize and on the continuous management of the exchange of matter and energy with their environment.

Beyond the tumour microenvironment.

In contrast to the once dominant tumour-centric view of cancer, increasing attention is now being paid to the tumour microenvironment (TME), generally understood as the elements spatially located in the vicinity of the tumour. Thinking in terms of TME has proven extremely useful, in particular because it has helped identify and comprehend the role of nongenetic and noncell-intrinsic factors in cancer development. Yet some current approaches have led to a TME-centric view, which is no less problematic than the former tumour-centric vision of cancer, insofar as it tends to overlook the role of components located beyond the TME, in the 'tumour organismal environment' (TOE).

Immunology and individuality.

Immunology and philosophy have a rich history of dialogue. Immunologists have long been influenced by ideas from philosophy, notably the concept of 'self', and many philosophers have explored the conceptual, theoretical and methodological foundations of immunology. Here, I discuss two aspects of this dialogue: biological individuality and immunogenicity.

The Multiple Layers of the Tumor Environment.

The notion of tumor microenvironment (TME) has been brought to the forefront of recent scientific literature on cancer. However, there is no consensus on how to define and spatially delineate the TME. We propose that the time is ripe to go beyond an all-encompassing list of the components of the TME, and to construct a multilayered view of cancer.

Immunological memory: What's in a name?

Immunological memory is one of the core topics of contemporary immunology. Yet there are many discussions about what this concept precisely means, which components of the immune system display it, and in which phyla it exists. Recent years have seen the multiplication of claims that immunological memory can be found in "innate" immune cells and in many phyla beyond vertebrates (including invertebrates, plants, but also bacteria and archaea), as well as the multiplication of concepts to account for these phenomena, such as "innate immune memory" or "trained immunity".

Re-thinking our understanding of immunity: Robustness in the tissue reconstruction system.

Robustness, understood as the maintenance of specific functionalities of a given system against internal and external perturbations, is pervasive in today's biology. Yet precise applications of this notion to the immune system have been scarce. Here we show that the concept of robustness sheds light on tissue repair, and particularly on the crucial role the immune system plays in this process.

Protective Microbiota: From Localized to Long-Reaching Co-Immunity.

Resident microbiota do not just shape host immunity, they can also contribute to host protection against pathogens and infectious diseases. Previous reviews of the protective roles of the microbiota have focused exclusively on colonization resistance localized within a microenvironment. This review shows that the protection against pathogens also involves the mitigation of pathogenic impact without eliminating the pathogens (i.

Towards a General Theory of Immunity?

Theories are indispensable to organize immunological data into coherent, explanatory, and predictive frameworks. We propose to combine different models to develop a unifying theory of immunity which situates immunology in the wider context of physiology. We believe that the immune system will be increasingly understood as a central component of a network of partner physiological systems that interconnect to maintain homeostasis.

Immune-Mediated Repair: A Matter of Plasticity.

Though the immune system is generally defined as a system of defense, it is increasingly recognized that the immune system also plays a crucial role in tissue repair and its potential dysregulations. In this review, we explore how distinct immune cell types are involved in tissue repair and how they interact in a process that is tightly regulated both spatially and temporally. We insist on the concept of immune cell plasticity which, in recent years, has proved fundamental for the success/understanding of the repair process.

The discontinuity theory of immunity.

Some biological systems detect the rate of change in a stimulus rather than the stimulus itself only. We suggest that the immune system works in this way. According to the discontinuity theory of immunity, the immune system responds to sudden changes in antigenic stimulation and is rendered tolerant by slow or continuous stimulation.

The emerging role of ECM crosslinking in T cell mobility as a hallmark of immunosenescence in humans.

Immunosenescence is thought to result from cellular aging and to reflect exposure to environmental stressors and antigens, including cytomegalovirus (CMV). However, not all of the features of immunosenescence are consistent with this view, and this has led to the emergence of the sister theory of "inflammaging". The recently discovered diffuse tissue distribution of resident memory T cells (T) which don't recirculate, calls these theories into question.

Understanding viruses: Philosophical investigations.

Viruses have been virtually absent from philosophy of biology. In this editorial introduction, we explain why we think viruses are philosophically important. We focus on six issues (the definition of viruses, the individuality and diachronic identity of a virus, the possibility to classify viruses into species, the question of whether viruses are living, the question of whether viruses are organisms, and finally the biological roles of viruses in ecology and evolution), and we show how they relate to classic questions of philosophy of biology and even general philosophy.