An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes
Sandrine Levet, … , Jean-Louis Touraine, Hervé Perron
Sandrine Levet, … , Jean-Louis Touraine, Hervé Perron
Published September 7, 2017
Citation Information: JCI Insight. 2017;2(17):e94387. https://doi.org/10.1172/jci.insight.94387.
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Categories: 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 1

HERV-W-Env is expressed in human T1D patients.

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HERV-W-Env is expressed in human T1D patients. (A) Serum from controls (...
(A) Serum from controls (n = 93) and T1D (n = 30) were analyzed by sandwich ELISA using monoclonal antibodies raised against HERV-W-Env. Each sample has been tested in triplicate. Results are presented as mean of the triplicate for each donor and as mean ± SEM for each group. Significance determined by Mann Whitney U test. (B) PBMC RNA was extracted from controls (n = 26) and T1D (n = 23) and analyzed by qRT-PCR assay. HERV-W-env expression was normalized to housekeeping genes B2M and YWHAZ using qbase+ and is expressed as calibrated normalized relative quantities (CNRQ). Each qPCR was done in duplicate, individual CNRQ values are plotted, and mean ± SEM for each group is shown. Significance determined by unpaired t test. (C) HERV-W-Env expression was assessed on pancreas slices from controls (n = 19) and T1D (n = 20) stained using GN_mAb_Env03 and automatically quantified. The HERV-W-Env positive area was reported to the total pancreatic tissue area. Two slides per individuals were quantified — one in the head and one in the tail. Results are presented as mean of the 2 slides for each donor and as mean ± SEM for each group. Significance determined by Mann Whitney U test. Individuals from cohorts presented in A–C were classified into either positive or negative groups for HERV-W-Env based on thresholds set at mean + 2 SD of control group. Cutoffs were set at 0.231 OD450nm for ELISA, at 1.356 CNRQ for qRT-PCR, and at 21.43% for pancreas IHC. Results are presented as contingency plots representing the number of individuals positive (in orange) or negative (in black). Significance determined by χ2 test. (D) Pancreas slices of three nPOD donors stained with GN_mAb_Env03 and adjacent slides coimmunostained with insulin (red) and glucagon (brown) are presented. Pancreatic Langerhans islets are highlighted with red dotted line. nPOD case ID is indicated in the upper right corner, with block number and pancreas zone (PH, pancreas head; PT, pancreas tail). Scale bars: 100 μm. ***P < 0.001, ****P < 0.0001.