Altered Antibody Response to Epstein-Barr Virus in Patients With Rheumatoid Arthritis and Healthy Subjects Predisposed to the Disease. A Twin Study.

Anders J Svendsen,Peter Junker,Kirsten O Kyvik,Marie Christine Wulff Westergaard,Marianne A Jakobsen,Gunnar Houen,René Holst,Anette Holck Draborg

doi:10.3389/fimmu.2021.650713

Abstract

Objectives: To study Epstein-Barr virus (EBV) antibody patterns in twin individuals with rheumatoid arthritis (RA) and their healthy co-twins, and to determine the heritability of antibody responses against the EBV encoded EBNA1 protein.Methods: Isotypes of EBNA1 antibodies were measured in 137 RA affected- and 150 healthy twin pairs. We estimated the effect of RA and RA predisposition, anti-citrullinated antibodies (ACPA), IgM rheumatoid factor (RF), the shared epitope (SE) and the PTPN22-T allele (PTPN22) on the level of EBNA1 antibodies. We also determined the heritability of EBNA1 antibody levels.Results: IgA-EBNA1 antibody levels were increased in twins from RA discordant twin pairs irrespective of RA, ACPA or IgM-RF status. The IgG-EBNA1 antibody level was elevated in healthy co-twins from RA discordant twin pairs but not in RA affected twins. The IgM-EBNA1 antibody level was elevated in both RA twins and their healthy co-twins. The effect of RA on the IgA-EBNA1 antibody level was reversed when SE was present and with no effect of PTPN22. The heritability of IgA-, IgG- and IgM-EBNA1 antibody level was 40.6, 65.5, and 54.3%, with no effect of environment shared by the twins.Conclusion: EBNA1 antibody levels are distinctively different between patients with RA and healthy subjects but also between relatives of RA strongly predisposed to RA and healthy subjects. The high level of IgA EBNA1 antibodies associated with RA and a family predisposition to RA is attributable to both genetics incl. the shared epitope and environmental variation.

Highlights

Rheumatoid arthritis is a systemic autoimmune disease which is primarily characterized by peripheral joint synovitis which if left untreated may lead to joint destruction and loss of function
Epstein Barr virus (EBV) has long been suspected to be implicated in the pathogenesis of RA, among others because EBV has been associated with several other autoimmune diseases, e.g., multiple sclerosis and systemic lupus [3]
A total of 283 twin pairs participated in this study, 150 healthy pairs and 133 RA-affected twin pairs (Table 1)

Summary

Introduction

Rheumatoid arthritis is a systemic autoimmune disease which is primarily characterized by peripheral joint synovitis which if left untreated may lead to joint destruction and loss of function. The etiology is unknown, but infections have been proposed as environmental triggers in up to 20% of patients [1]. Polyarthritis resembling RA is common in multiple viral infections including rubella, HTLV-1, parvovirus B19 and hepatitis B and C [2]. Epstein Barr virus (EBV) has long been suspected to be implicated in the pathogenesis of RA, among others because EBV has been associated with several other autoimmune diseases, e.g., multiple sclerosis and systemic lupus [3]. Like RA, EBV infection is chronic with episodic flares. It has a marked tropism for B lymphocytes and exerts a wide range of immune-modulating effects including production of several pro-inflammatory cytokines [5]. In addition EBV is present in synovial lining cells of chronic RA [6] and RA patients have a higher frequency and level of antibodies against specific epitopes on EBV-encoded antigens [7]

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