Low levels of antibodies against common viruses associate with anti-citrullinated protein antibody-positive rheumatoid arthritis; implications for disease aetiology

Abstract

BackgroundInfection by common viruses has long been discussed in the aetiology of a number of autoimmune diseases, including rheumatoid arthritis (RA). However, studies investigating this hypothesis in RA show conflicting results. These studies often lack well-matched control populations, and many do not include data on autoantibodies, genetic risk factors and other environmental factors, which are known to contribute to disease only in subgroups of patients. In the present study, we have therefore examined the role of Epstein-Barr virus (EBV), cytomegalovirus (CMV) and parvovirus B19 (B19) in RA aetiology, by analysing anti-viral antibodies in relation to anti-citrullinated protein antibodies (ACPA), smoking, HLA-DRB1 shared epitope (SE) alleles, and clinical parameters, in both RA patients and matched controls.MethodsAnti-viral antibodies were measured by ELISA in serum samples from 990 RA patients and 700 controls from the Swedish population-based Epidemiological Investigation of RA (EIRA) cohort. Data on ACPA, smoking, SE, inflammation (C-reactive protein) and disease activity score in 28 joints (DAS28) was obtained from the EIRA database. Fisher’s exact test, the chi-squared test, and the Mann-Whitney U test were used to calculate differences in anti-viral antibody frequencies and levels; unconditional logistic regression was used to determine the association of anti-viral antibodies with different RA subsets.ResultsAntibodies against all viruses were highly prevalent in EIRA, with no major differences detected between ACPA-positive RA, ACPA-negative RA and controls. However, both anti-B19 and anti-EBV IgG levels were significantly lower in ACPA-positive RA compared to controls, and there were significant interactions between low levels of anti-B19 and anti-EBV antibodies and SE in the development of ACPA-positive RA.ConclusionWe could not detect an association between RA and elevated anti-viral antibody levels, for any of the three common viruses, EBV, CMV or B19. On the contrary, our study demonstrated association between low anti-EBV/anti-B19 antibody levels and ACPA-positive RA, in particular when HLA-DRB1 SE was present. These data could potentially suggest that high anti-viral antibody levels would be protective against ACPA-positive RA. Further investigations are required to address the mechanisms behind these findings.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1423-9) contains supplementary material, which is available to authorized users.

Prevalence and Incidence of Upper Respiratory Tract Infection Events Are Elevated Prior to the Development of Rheumatoid Arthritis in First-Degree Relatives

“…The immunological hypothesis with a defective immune control of infections at the early stage of RA is further reinforced by the observations that granulocytes are altered in their capacity to induce reactive oxygen species and that B cell evolution to memory B cells is impaired ( 12 , 31 , 32 ). Similarly, the recent report from the Swedish population-based Epidemiological Investigation of early RA (EIRA) supports an insufficient Ab response at the early stage of RA with lower anti-viral IgG levels for EBV, CMV, and parvovirus B19 ( 10 ). If true such a hypothesis would reinforce our observations that differences regarding infectious events concern not only qualitative and immune independent (prevalence) parameters but also immune controlled parameters (infectious events incidence and/or duration).…”

“…Altogether, these arguments support a causative role for infections in RA development. However, these findings regarding the link between Ab against infections and RA risk have not been replicated in large-scale cohorts and meta-analysis ( 8 , 9 ), leading instead to the proposition of an immunological hypothesis as one of the characteristics of RA patients in whom there is an inability of the immune system to properly control viral infections ( 10 ). This is in line with our recent findings, performed at the early stage of RA development in untreated subjects, showing both defects in the innate immune system and an elevated annual rate of infection events ( 11 , 12 ).…”

B Lymphocytes in Rheumatoid Arthritis and the Effects of Anti–TNF-α Agents on B Lymphocytes: A Review of the Literature

“…A link between infectious agents and the development of Rheumatoid arthritis has been proposed and it has been shown that Rheumatoid arthritis patients have increased antibody titers against Epstein-Barr virus 80, 81 or cytomegalovirus 82 , as compared to healthy controls. Although in a few studies viral DNA and proteins have been detected in the synovium and joints of Rheumatoid arthritis patients, 83 these studies have not been confirmed and conclusions cannot be drawn from the current literature.…”

Human MHC-II with Shared Epitope Motifs Are Optimal Epstein-Barr Virus Glycoprotein 42 Ligands—Relation to Rheumatoid Arthritis

“…Nevertheless, other studies claim that no association between EBV infection and onset of RA is evident [ 110 , 125 , 126 ]. For example, findings by Sherina and colleagues, analyzing anti-viral antibodies in relation of ACPAs, smoking HLA-DRB1 alleles and clinical parameters, do not support the hypothesis of EBV involvement in RA onset [ 126 ]. These findings are supported by similar studies analyzing antibody levels to several viral proteins [ 110 ].…”