An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes
Sandrine Levet, Julie Medina, Julie Joanou, Amandine Demolder, Nelly Queruel, Kevin Réant, Matthieu Normand, Marine Seffals, Julie Dimier, Raphaële Germi, Thomas Piofczyk, Jacques Portoukalian, Jean-Louis Touraine, Hervé Perron
Sandrine Levet, Julie Medina, Julie Joanou, Amandine Demolder, Nelly Queruel, Kevin Réant, Matthieu Normand, Marine Seffals, Julie Dimier, Raphaële Germi, Thomas Piofczyk, Jacques Portoukalian, Jean-Louis Touraine, Hervé Perron
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Research Article Endocrinology

An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes

Abstract

Human endogenous retroviruses (HERVs), remnants of ancestral viral genomic insertions, are known to represent 8% of the human genome and are associated with several pathologies. In particular, the envelope protein of HERV-W family (HERV-W-Env) has been involved in multiple sclerosis pathogenesis. Investigations to detect HERV-W-Env in a few other autoimmune diseases were negative, except in type-1 diabetes (T1D). In patients suffering from T1D, HERV-W-Env protein was detected in 70% of sera, and its corresponding RNA was detected in 57% of peripheral blood mononuclear cells. While studies on human Langerhans islets evidenced the inhibition of insulin secretion by HERV-W-Env, this endogenous protein was found to be expressed by acinar cells in 75% of human T1D pancreata. An extensive immunohistological analysis further revealed a significant correlation between HERV-W-Env expression and macrophage infiltrates in the exocrine part of human pancreata. Such findings were corroborated by in vivo studies on transgenic mice expressing HERV-W-env gene, which displayed hyperglycemia and decreased levels of insulin, along with immune cell infiltrates in their pancreas. Altogether, these results strongly suggest an involvement of HERV-W-Env in T1D pathogenesis. They also provide potentially novel therapeutic perspectives, since unveiling a pathogenic target in T1D.

Authors

Sandrine Levet, Julie Medina, Julie Joanou, Amandine Demolder, Nelly Queruel, Kevin Réant, Matthieu Normand, Marine Seffals, Julie Dimier, Raphaële Germi, Thomas Piofczyk, Jacques Portoukalian, Jean-Louis Touraine, Hervé Perron

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Figure 5

Direct pathogenic effects of HERV-W-Env toward pancreatic β cells.

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Direct pathogenic effects of HERV-W-Env toward pancreatic β cells. (A) H...
(A) Human Langerhans islets have been exposed for 48 hours to HERV-W-Env (0, 25, 50, 100 ng/ml), and insulin secretion has been measured in response to 20 mM glucose stimulation. Results are presented as individual values and as mean ± SEM. Each condition has been performed in triplicate and in 3 independent experiments. Significance determined by Bonferroni’s test. (B) INS1E cells have been exposed for 72 hours to increasing concentrations of HERV-W-Env (0, 10, 25, 50, 100, 400 ng/ml). Insulin secretion has been measured either in absence of glucose (baseline) or in response to 10 mM glucose stimulation. Results are presented as the difference in concentration between glucose stimulation and baseline. Each condition has been performed in triplicate and in 2 independent experiments, and data are presented as individual values and as mean ± SEM. Significance determined by Bonferroni’s test. (C) Human Langerhans islets have been exposed for 48 hours to HERV-W-Env (0 and 100 ng/ml) and to GNbAC1 (3 μg/ml) or placebo. Insulin secretion has been measured in response to 20 mM glucose stimulation. Results are presented as individual values and as mean ± SEM. Each condition has been performed in triplicate and in 3 independent experiments. Significance determined by unpaired t test. (D) Effect of HERV-W-Env on human Langerhans islet viability has been assessed using human islet microtissues exposed to 0, 100, and 200 ng/ml of HERV-W-Env for 48 hours before being lysed. Lysates were analyzed for ATP content using Promega CellTiter-Glo Luminescent Cell Viability Assay. Results are presented as individual values and as mean ± SEM. Each condition has been performed six times, and 1 experiment has been performed. Significance determined by Dunn’s test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.