Increased Frequency of EBV-Specific Effector Memory CD8+ T Cells Correlates with Higher Viral Load in Rheumatoid Arthritis

Abstract

EBV is a candidate trigger of rheumatoid arthritis (RA). We determined both EBV-specific T cell and B cell responses and cell-associated EBV DNA copies in patients with RA and demographically matched healthy virus carriers. Patients with RA showed increased and broadened IgG responses to lytic and latent EBV-encoded Ags and 7-fold higher levels of EBV copy numbers in circulating blood cells. Additionally, patients with RA exhibited substantial expansions of CD8+ T cells specific for pooled EBV Ags expressed during both B cell transformation and productive viral replication and the frequency of CD8+ T cells specific for these Ags correlated with cellular EBV copy numbers. In contrast, CD4+ T cell responses to EBV and T cell responses to human CMV Ags were unchanged, altogether arguing against a defective control of latent EBV infection in RA. Our data show that the regulation of EBV infection is perturbed in RA and suggest that increased EBV-specific effector T cell and Ab responses are driven by an elevated EBV load in RA.

EBV-specific immune responses in patients with multiple sclerosis responding to IFNβ therapy

“…T-cell responses were determined by CFSE dilution as described previously. 15,16 Overlapping peptides of 12-22 aa length (average of 15 aa length) with 11 aa overlap were designed for the EBNA1 400-641 sequence of the B95-8 EBV strain (A) Serum ELISA for IgG antibody responses to EBV-encoded nuclear antigen 1 (EBNA1). Median EBNA1 antibody concentration before treatment was 9062 U/mL, while after treatment 5804 U/mL.…”

Intrathymic epstein‐barr virus infection is not a prominent feature of myasthenia gravis

“…We additionally determined immune responses to EBV-encoded antigens reported to be deregulated in other autoimmune diseases such as multiple sclerosis. 6 Humoral as well as CD4 þ and CD8 þ T-cell responses to immunodominant viral antigens expressed during B-cell transformation, productive viral replication, and latent infection 8,11,15 proved to be unchanged in EOMG patients. These data are in line with an earlier screen for IgG Ab titers to EBV in patients with MG onset before age 20 years.…”

“…8,11 The peptide mixtures included immunodominant epitopes for CD8 þ T cells from lytic (n ¼ 5) and latent (n ¼ 8) EBV antigens 8 and HCMV phosphoprotein 65 (n ¼ 3), as well as overlapping peptides (n ¼ 51) derived from the most consistently recognized EBV-encoded CD4 þ T-cell antigen, EBNA1. 8,11 Responses comprising at least 10 interferon (IFN)c þ events were considered positive if they were !2Â background (no antigen). Frequencies of antigen-specific T cells were determined by subtracting background frequencies from those of antigen-stimulated positive samples.…”

“…6 Latent EBV infection confers B-cell survival advantages, 7 and according to some hypotheses, could contribute to the formation of ectopic B-cell follicles and the development of antibody (Ab)-mediated tissue damage in autoimmune diseases including EOMG. 8,9 If confirmed, EBV involvement in intrathymic MG pathogenesis might warrant treatment with antiviral drugs that target viral DNA polymerase and inhibit viral replication. The aims of this study were independently to extend the search for EBV-infected B-lineage cells in hyperplastic thymi in treatment-naive EOMG patients, and to determine whether they show altered cellular and humoral EBV-specific immune responses.…”

The Link Of Epstein Barr Virus Infection And Rheumatoid Arthritis Immunopathogenesis

“…There was a correlation between viral load in circulating blood cells and the increase of EBV-specific and IFNã-producing CD8+ T cells, without evidence for defective T cell control of the EBV infection. 66 Although the results on T cell responses thus appear to be discrepant, there is clear evidence from these studies for a higher viral load in RA.…”