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Open Access Research article

A profile of immune response to herpesvirus is associated with radiographic joint damage in rheumatoid arthritis

John M Davis1*, Keith L Knutson2, John A Skinner3, Michael A Strausbauch4, Cynthia S Crowson5, Terry M Therneau5, Peter J Wettstein4, Eric L Matteson16 and Sherine E Gabriel16

Author Affiliations

1 Division of Rheumatology, Department of Medicine, College of Medicine, Mayo Clinic; 200 First Street SW, Rochester, MN 55905, USA

2 Department of Immunology, College of Medicine, Mayo Clinic; 200 First Street SW, Rochester, MN 55905, USA

3 Department of Radiology, College of Medicine, Mayo Clinic; 200 First Street SW, Rochester, MN 55905, USA

4 Department of Surgical Research, College of Medicine, Mayo Clinic; 200 First Street SW, Rochester, MN 55905, USA

5 Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, College of Medicine, Mayo Clinic; 200 First Street SW, Rochester, MN 55905, USA

6 Division of Epidemiology, Department of Health Sciences Research, College of Medicine, Mayo Clinic; 200 First Street SW, Rochester, MN 55905, USA

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Arthritis Research & Therapy 2012, 14:R24  doi:10.1186/ar3706

Published: 31 January 2012

Abstract

Introduction

Progression of joint damage despite appropriate therapy remains a significant problem for patients with rheumatoid arthritis (RA). This study was undertaken to identify profiles of immune response that correlate with radiographic joint damage as a first step toward the discovery of new pathogenic mechanisms of joint destruction in RA.

Methods

The study included 58 patients with RA and 15 healthy controls. The profiles of cytokine release from peripheral blood mononuclear cells (PBMC) in response to stimulation for 48 hours with one of six stimuli, or in media alone, were measured. Immune response profiles identified for each stimulus were correlated with radiographic joint damage as defined by the Sharp-van der Heijde score (SHS), before and after multivariable adjustment. For profiles correlated with the SHS, the distributions of individual cytokines were evaluated in patients according to the severity of joint damage and compared to healthy controls.

Results

The immune response profile for cytomegalovirus (CMV)/Epstein-Barr virus (EBV) stimulation was correlated with both the SHS total and erosion scores (r = 0.31, P = 0.018 and r = 0.33, P = 0.011, respectively). After adjusting for age, sex, disease duration, autoantibody status, CMV/EBV serological status, current disease activity, disability and treatments, the correlation of the CMV/EBV immune response and the SHS erosion score became stronger (r = 0.43, P < 0.003). The CMV/EBV immune response correlated with CMV IgG (r = 0.44, P < 0.001), but not with EBV IgG. The most important cytokines for the CMV/EBV immune response profile were IFN-γ, IL-2, IL-4, IL-5, IL-13 and IL-17A, all of which are associated with T-cell immunity. Both the summary immune response score and the individual responses of IFN-γ and IL-13 to CMV/EBV stimulation were associated with greater joint damage.

Conclusions

A profile of immune response to purified CMV/EBV lysates is associated with radiographic joint damage. The correlation of this immune response to CMV serology implies possible involvement of latent CMV infection. Therefore, the findings suggest that the immune response to latent CMV infection could play a fundamental role in the progression of inflammation and structural joint damage in patients with RA.

Keywords:
rheumatoid arthritis; RA; immune responses; cytokines; T cells; radiographic joint damage; cytomegalovirus, Epstein-Barr virus