Human cytomegalovirus (HCMV) infection in patients with inflammatory bowel diseases (IBD) : role in pathogenesis and autoimmunity

Abstract

Human cytomegalovirus (HCMV) is one of eight members of the herpesvirus family that infects humans. Like other herpes viruses, HCMV establishes a latent infection after the primary infection, and reactivation may occur later in life. HCMV disease of the gastrointestinal (GI) tract is a major cause of morbidity and mortality in immunocompromised patients. The Inflammatory Bowel Diseases (IBD); ulcerative colitis (UC) and Crohn's disease (CD) are believed to have many etiologies and a number of risk factors have been implied in the pathogenesis of IBD. An initial environmental insult most likely leads to damage to the intestinal mucosal barrier and results in an inflammatory response that leads to the development of HID in genetically susceptible individuals. However, the nature of the infectious or environmental agent that may trigger and perpetuate the intestinal inflammation in UC and CD remains unknown. In the last four decades, 33 reports have described HCMV colitis as a complication of IBD. This diagnosis is not frequently considered and, if not made, leads to a high rate of colectomy (67%) and mortality (33%).

Appropriate antiviral therapy appears to eliminate the virus found as a complication of the disease. The current view is that peripheral blood monocytes constitute a major site of viral latency and that differentiation of such cells into tissue macrophages upon stimulation by proinflammatory cytokines can reactivate a latent HCMV infection. In this study, we have detected an active HCMV infection in 85% of patients with UC and in 100% of patients with CD. Cells double stained for HCMV and IL-6 were detected i n intestinal tissue sections in 77% of patients with UC and in 100% of patients with CD. These observations suggest that an active HCMV infection in the intestine is very frequent in patients with IBD, and that the virus may contribute to the inflammatory process through increased production of IL-6. Furthermore, previous studies have also suggested an association between active HCMV infection and production of auto-antibodies against CD13. Here, we found cytotoxic autoantibodies specific for CD13 OBS 3 in 66% and 58% of patients with UC and CD, respectively. These observations suggest that auto-antibodies recognizing CD13 may for example, interfere with cell function, possibly thereby contributing to the chronic inflammation in the bowel of IBD patients.

HCMV may also contribute to the development of different complications in IBD patients. Increased platelet numbers, activation and aggregation are wellrecognized indicators of disease activity in IBD and the virus may interfere with such processes. Here, we observed platelet aggregation and adhesion to HCMV infected endothelial cells in vitro, which could be significantly reduced by blocking of von Willebrand factor (vWF) with monoclonal antibodies. We detected high levels of vWF expression on HCMV infected endothelial cells. The increased thrombogenicity observed was dependent on active virus replication and could be inhibited by foscarnet and ganciclovir, which suggest that a late viral gene may be mediating the phenomenon. We speculate that the increased thrombogenicity by HCMV may contribute to the development of thromboembolic diseases that occur in IBD patients as well as in patients with atherosclerosis. Furthermore, it is well known that active episodes of IBD are histologically characterized by extravasation and infiltration of a large numbers of active neutrophils. We therefore examined whether HCMV could affect neutrophil functions.

Our results suggest that HCMV infected neutrophils become over-reactive and that inhibition of apoptosis may cause the neutrophils to remain in the system for prolonged periods of time. Increased survival of these cells in inflamed tissues and increased release of reactive oxygen species may lead to damaging of the surrounding tissues resulting in further aggravation in diseases such as IBD and possibly also in other chronic inflammatory diseases. In conclusion, we provide evidence that an active HCMV infection is very frequent in IBD patients with severe symptoms, and that the virus may contribute to the inflammatory process and long term complications. Since antiviral drugs against HCMV are available, some IBD patients may in the future benefit from antiviral treatment and may avoid surgical treatment.