Rheumatoid arthritis is a systemic disease producing inflammation in diarthroidal joints as well as affecting lungs, heart, nervous system, and skin. It affects about 0.5–1.0% of the adult population and is found worldwide.16
Of the myriad of agents, environmental and genetic, implicated in rheumatoid disease mechanisms and pathology, considerable evidence indicates that viruses may be important environmental triggers. Viruses associated with arthritis‐like symptoms include rubella, hepatitis, alphaviruses, and parvovirus B19.17
Several viruses, including EBV,18
have already been identified within the joint, although no clear link has been established definitively linking these pathogens with rheumatoid arthritis. One such study, by Stahl and colleagues,21
detected the presence of multiple viral DNA in synovial tissue and fluid taken from patients in the early stages of idiopathic arthritis. Up to two thirds of patients tested were positive for at least one virus, with 20% of those patients positive for two or more.
One group of viruses in particular has attracted a large amount of interest over the past two decades with respect to rheumatoid arthritis. These are the retroviruses.10,22
Among the mounting evidence implicating retroviruses in rheumatoid arthritis are the parallels that can be drawn between human and animal retroviral infections. Animal retroviral pathogens such as caprine arthritis encephalitis virus (CAEV) and maedi visna virus (MVV) cause a chronic arthritis in sheep and goats.23
Both diseases show similarities to human rheumatoid arthritis in their pathology. Furthermore, the spontaneous development of rheumatoid arthritis‐like disease in mice transgenic for the HTLV‐1 tax
gene hints at retroviral involvement.24
Also evident is the increased prevalence of rheumatic diseases in areas endemic for retroviruses—for example, HTLV in Japan and southern Central America.25
Seemayer et al26
conducted an elaborate series of experiments involving the co‐culture of rheumatoid patient synovial tissue samples with cell lines known to be permissive for retroviruses. This approach, however, failed to implicate any exogenous retroviral agents in rheumatoid arthritis, although the investigators did not exclude any potential endogenous retroviral activity. Neidhart and colleagues also isolated and identified a retroviral transcript from rheumatoid synovial fluid cells corresponding to ORF2 of the L1‐retrotransposon.27
Additionally human retrovirus‐5 (HRV‐5) has also been implicated as playing a role in rheumatoid arthritis disease pathogenesis,28
although these conclusions were not supported by follow up studies.29
In the present study we showed that levels of HERV‐K10 expression were significantly increased in rheumatoid PBMC samples compared with both disease controls and normal healthy donors (p
0.02). There was no significant difference between osteoarthritis and healthy individuals (p
0.34). These data were supported by previous evidence from Nakagawa et al
, who also showed that HERV‐K10 levels were increased in rheumatoid patients compared with normal healthy donors.30
Furthermore, our data confirm earlier work which showed that normal healthy donors have a baseline level of HERV expression in the peripheral blood.31,32
Consequently it is possible that differential expression of HERVs may be critical in disease states.
It was also shown that HERV‐K10 expression in rheumatoid patients was high at the site of disease (n
17), with levels of expression almost twice as high as those seen in the peripheral blood (data not shown). These findings should be noted as preliminary, and require further verification with additional synovial samples.
In the context of the disease process, the precise role of HERV‐K10 in rheumatoid arthritis remains unclear. It is plausible that the virus could be triggered by the ongoing immune response, or is indeed itself a trigger for rheumatoid arthritis.33
Evidently cells within the microenvironment of the joint (for example, B cells) may harbour HERVs themselves34
and therefore also have the potential to play a role in the disease pathology. It is also possible that external factors may contribute in its activation, leading to changes in HERV expression through a process of bystander activation. Many exogenous viruses such as EBV,35
are known to interact, either directly or indirectly, with endogenous retroviruses. Infection with many of these viruses also leads to an activation of specific host cells (for example, T cells with reference to HTLV‐I) during the course of infection, thus furthering the potential for immune dysregulation. Numerous cytokines are also known to modulate viral expression.38
Thus it is possible that host cells infected and activated by exogenous or endogenous viruses could migrate into the synovium, releasing pro‐inflammatory cytokines such as interleukin 639
and tumour necrosis factor α.40
Such events are likely to activate HERVs within the joint and may explain why levels of HERV activity were increased in the synovial fluid.
We have optimised a novel multiplex RT‐PCR system for the simple detection and semiquantification of HERV‐K10 gag gene against HtRNAS in rheumatoid patients versus controls. Overall there appear to be higher levels of K10 expression in peripheral blood and synovial fluid cells in rheumatoid patients. The possible contribution of HERV‐K10 to rheumatoid arthritis is intriguing and merits further investigation in a larger cohort of patients. Furthermore, the advent of new technologies such as quantitative RT‐PCR and microarrays, applied to this field of research, will undoubtedly help our understanding of the role of these HERVs in rheumatoid arthritis.