Detection of persistent measles virus infection in Crohn's disease: current status of experimental work.

The aetiology of Crohn’s disease is unknown. Any hypothesis must take into account the continuing increase in incidence in some countries, including the UK. The increase aVects the population from early teens, and specific comprehensive epidemiological studies in children and adolescents show a continuing rise in the rate of age and sex standardised incidence in Scotland. This suggests an environmental trigger, which may interact with underlying genetic susceptibility. A number of such environmental triggers have been proposed, including persistent infections, transient infections in a host with abnormal mucosal immunity, particulate materials, or dietary changes. Persistent infection with the measles virus after wild-type virus infections or immunisation with live attenuated measles vaccine have been proposed as important environmental triggers based on epidemiological observations. 3 Measles is a single stranded RNA virus which can induce immune suppression. Measles infection is generally self limited and results in long term immunity, but rarely, persistent infection may occur after wild-type virus infection. The virus has special aYnity for epithelial cells of the respiratory tract and cells of the immune system, such as lymphocytes and macrophages. A number of chronic diseases have been linked with persistent measles virus infection. These include multiple sclerosis, Paget’s disease, a variety of autoimmune diseases, and autism, although definite evidence is lacking in each. Inflammatory bowel disease (IBD), especially Crohn’s disease, has been linked to persistent measles virus infection. Ekbom et al proposed perinatal exposure to wild-type measles virus may lead to development of Crohn’s disease later in life. 3 Such case control epidemiological studies are of course prone to a variety of confounding factors, especially selection and recall biases. Epidemiologically robust data from a large controlled prospective study showed absence of a link between intrauterine exposure to measles and Crohn’s disease. However, epidemiological studies linking persistent measles virus infection to Crohn’s disease generated a hypothesis for confirmation or rejection by searching for measles virus in Crohn’s aVected tissue. Another line of epidemiological evidence linking Crohn’s disease with measles implicated the vaccine strain, and the safety of measles-mumps-rubella vaccination has been a topic of lively debate both in the medical and lay press. Vaccines against measles, mumps, and rubella (MMR) are produced from live attenuated viruses which have been propagated in a variety of cell substrates, such as embryonated chicken eggs and/or human diploid cells. The genomes of all three viruses consist of a single stranded RNA molecule that has negative polarity for measles and mumps and positive polarity for rubella. MMR vaccines are eVective and safe. Reported side eVects include aseptic meningitis and acute arthritis. Aseptic meningitis was ascribed to the Urabe strain of mumps virus, which was withdrawn in 1992. Arthritis has been related to rubella vaccination but no significant association between chronic arthropathy and rubella vaccination has been found in women. Severe allergic reactions to MMR may be related to egg allergy or allergy to gelatin. In 1995, the safety of measles and MMR vaccination was brought into question by the suggestion that live attenuated measles vaccine may be a risk factor for the development of IBD, especially Crohn’s disease. This link was postulated following epidemiological observations of the temporal link between an increasing incidence of Crohn’s disease and introduction of live attenuated measles vaccine in 1968 in the UK. The MMR vaccine was introduced much later in 1988. However, the increase in the incidence of Crohn’s disease started earlier than 1968 and still continues. A case control study of 140 IBD patients (83 Crohn’s disease) born after 1968 and 280 controls matched for age, sex, and general practitioner area provided no support for the hypothesis that measles vaccination in childhood predisposed to the later development of either IBD overall or Crohn’s disease in particular. In Finland, a countrywide surveillance system to detect serious adverse events was set up in 1982 after introduction of MMR vaccination. By the end of 1996, 1.8 million individuals were immunised and three million vaccine doses were consumed. The rate of serious adverse events with possible or indeterminate causal relationship with MMR vaccination was 5.3 per 100 000 vaccinees or 3.2 per 100 000 vaccine doses. The majority of serious adverse events were neurological or allergic. No association between IBD and MMR vaccination was reported. This is currently the best prospective data on the safety of MMR vaccination. Considerable interest was then generated by the report of the presence of measles virus nucleocapsid protein in intestinal tissues aVected by Crohn’s disease. This article reviews the current state of the evidence from the experimental work regarding the question of persistent measles virus in Crohn’s disease. The epidemiological evidence itself has generated a lively debate but this article deals with the experimental work aiming to confirm or reject the hypothesis formulated from the epidemiological evidence.