Are human endogenous retroviruses triggers of autoimmune diseases? Unveiling associations of three diseases and viral loci.

Bjørn A Nexø,Kathrine L M Schmidt,Bettina Hansen,Magdalena J Laska,Maria Lajer,Peter Rossing,Tove Lorenzen,Lise Tarnow,Hanne M Lindegaard,Sara B Jensen,Kari K Nissen,Shervin Bahrami,Hans-Henrik Parving,Peter Junker,Thor Petersen,Palle Villesen,Kim Hørslev-Petersen

doi:10.1007/s12026-015-8671-z

Abstract

Autoimmune diseases encompass a plethora of conditions in which the immune system attacks its own tissue, identifying them as foreign. Multiple factors are thought to contribute to the development of immune response to self, including differences in genotypes, hormonal milieu, and environmental factors. Viruses including human endogenous retroviruses have long been linked to the occurrence of autoimmunity, but never proven to be causative factors. Endogenous viruses are retroviral sequences embedded in the host germline DNA and transmitted vertically through successive generations in a Mendelian manner. In this study by means of genetic epidemiology, we have searched for the involvement of endogenous retroviruses in three selected autoimmune diseases: multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. We found that at least one human endogenous retroviral locus was associated with each of the three diseases. Although there was a significant overlap, most loci only occurred in one of the studied disease. Remarkably, within each disease, there was a statistical interaction (synergy) between two loci. Additional synergy between retroviral loci and human lymphocyte antigens is reported for multiple sclerosis. We speculate the possibility that recombinants or mixed viral particles are formed and that the resulting viruses stimulate the innate immune system, thereby initiating the autoimmune response.Electronic supplementary materialThe online version of this article (doi:10.1007/s12026-015-8671-z) contains supplementary material, which is available to authorized users.

Highlights

The autoimmune diseases (AID) are a diverse group of conditions characterized by abnormal immune reactivity in association with autoreactive B and T cell responses
We identified one single nucleotide polymorphisms (SNPs) as showing association with type 1 diabetes mellitus (T1DM), rs7650483 near human endogenous retroviruses (HERVs)-K119 encoding gag and env located on chromosome 3 (T allele associated with disease, OR (CI)1.25 (1.08–1.43); PG = 0.0004)
Strong associations between the human lymphocyte antigens (HLA) region and autoimmune disease have been established over the past half century [27]

Summary

Introduction

The autoimmune diseases (AID) are a diverse group of conditions characterized by abnormal immune reactivity in association with autoreactive B and T cell responses. The most common of these diseases include systemic lupus erythematosus, multiple sclerosis (MS), type 1 diabetes mellitus (T1DM), autoimmune thyroid disease, myasthenia gravis, scleroderma, and rheumatoid arthritis (RA) [1]. MS, RA, and T1DM are all characterized by the body’s immune response being directed against its own tissues, causing prolonged inflammation and subsequent tissue destruction. Multiple factors are thought to contribute to the development of immune responses to self, including differences in genotypes, hormonal milieu, and environmental triggers [2, 3]. The significance of environmental effectors is underscored by the generally low concordance rates of major AID in monozygotic twins [3]

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