Showing papers by "Martin Pelletier published in 2020"

The impact and toxicity of glyphosate and glyphosate-based herbicides on health and immunity

Abstract: Glyphosate, or N-phosphomethyl(glycine), is an organophosphorus compound and a competitive inhibitor of the shikimate pathway that allows aromatic amino acid biosynthesis in plants and microorganisms. Its utilization in broad-spectrum herbicides, such as RoundUp®, has continued to increase since 1974; glyphosate, as well as its primary metabolite aminomethylphosphonic acid, is measured in soils, water, plants, animals and food. In humans, glyphosate is detected in blood and urine, especially in exposed workers, and is excreted within a few days. It has long been regarded as harmless in animals, but growing literature has reported health risks associated with glyphosate and glyphosate-based herbicides. In 2017, the International Agency for Research on Cancer (IARC) classified glyphosate as "probably carcinogenic" in humans. However, other national agencies did not tighten their glyphosate restrictions and even prolonged authorizations of its use. There are also discrepancies between countries' authorized levels, demonstrating an absence of a clear consensus on glyphosate to date. This review details the effects of glyphosate and glyphosate-based herbicides on fish and mammal health, focusing on the immune system. Increasing evidence shows that glyphosate and glyphosate-based herbicides exhibit cytotoxic and genotoxic effects, increase oxidative stress, disrupt the estrogen pathway, impair some cerebral functions, and allegedly correlate with some cancers. Glyphosate effects on the immune system appear to alter the complement cascade, phagocytic function, and lymphocyte responses, and increase the production of pro-inflammatory cytokines in fish. In mammals, including humans, glyphosate mainly has cytotoxic and genotoxic effects, causes inflammation, and affects lymphocyte functions and the interactions between microorganisms and the immune system. Importantly, even as many outcomes are still being debated, evidence points to a need for more studies to better decipher the risks from glyphosate and better regulation of its global utilization.

The evaluation of cytokines to help establish diagnosis and guide treatment of autoinflammatory and autoimmune diseases

Abstract: Our knowledge of the role of cytokines in pathologic conditions has increased considerably with the emergence of molecular and genetic studies, particularly in the case of autoinflammatory monogenic diseases. Many rare disorders, considered orphan until recently, are directly related to abnormal gene regulation, and the treatment with biologic agents (biologics) targeting cytokine receptors, intracellular signaling or specific cytokines improve the symptoms of an increasing number of chronic inflammatory diseases. As it is currently impossible to systematically conduct genetic studies for all patients with autoinflammatory and autoimmune diseases, the evaluation of cytokines can be seen as a simple, less time consuming, and less expensive alternative. This approach could be especially useful when the diagnosis of syndromes of diseases of unknown etiology remains problematic. The evaluation of cytokines could also help avoid the current trial-and-error approach, which has the disadvantages of exposing patients to ineffective drugs with possible unnecessary side effects and permanent organ damages. In this review, we discuss the various possibilities, as well as the limitations of evaluating the cytokine profiles of patients suffering from autoinflammatory and autoimmune diseases, with methods such as direct detection of cytokines in the plasma/serum or following ex vivo stimulation of PBMCs leading to the production of their cytokine secretome. The patients' secretome, combined with biomarkers ranging from genetic and epigenetic analyses to immunologic biomarkers, may help not only the diagnosis but also guide the choice of biologics for more efficient and rapid treatments.

Merocytic Dendritic Cells Compose a Conventional Dendritic Cell Subset with Low Metabolic Activity.

Abstract: Conventional dendritic cells (cDCs) are arguably the most potent APCs that induce the activation of naive T cells in response to pathogens. In addition, at steady-state, cDCs help maintain immune tolerance. Two subsets of cDCs have been extensively characterized, namely cDC1 and cDC2, each contributing differently to immune responses. Recently, another dendritic cell (DC) subset, termed merocytic DCs (mcDCs), was defined. In contrast to both cDC1 and cDC2, mcDCs reverse T cell anergy, properties that could be exploited to potentiate cancer treatments. Yet, whether mcDCs represent an unconventional DC or a cDC subset remains to be defined. In this article, we further characterize mcDCs and find that they bear true characteristics of cDC subsets. Indeed, as for cDCs, mcDCs express the cDC-restricted transcription factor Zbtb46 and display very potent APC activity. In addition, mcDC population dynamics parallels that of cDC1 and cDC2 in both reconstitution kinetic studies and parabiotic mice. We next investigated their relatedness to cDC1 and cDC2 and demonstrate that mcDCs are not dependent on cDC1-related Irf8 and Batf3 transcription factors, are dependent on Irf4, a cDC2-specific transcription factor, and express a unique transcriptomic signature. Finally, we find that cDC1, cDC2, and mcDCs all present with different metabolic phenotypes, in which mcDCs exhibit the lowest glucose uptake activity and mcDC survival is the least affected by glycolysis inhibition. Defining the properties of mcDCs in mice may help identify a functionally equivalent subset in humans leading to the development of innovative cancer immunotherapies.