JME appeared spontaneously in JM at the ONPRC 21 years after the colony was established. The initial case of JME occurred in 1986 and since then the disease typically has affected 1–3% of the colony each year, with two exceptions. JME usually occurs in young adult animals, but the disease can present in juvenile or aged animals, and shows no preference for either gender. Clinically, JME causes paralysis, ataxia and ocular motor paresis. While most animals failed to recover sufficiently to be safely returned to the colony, three monkeys recovered, were returned to the colony and then relapsed one or more years later. MRI of eight animals revealed changes similar to acute MS. Pathologically, JME causes multifocal areas of demyelination of varying acuity with loss of oligodendrocytes and variable axonal loss in the white matter of the cerebrum, cerebellum, brainstem and spinal cord associated with macrophages and lymphocytic infiltrates. Chronic inactive demyelinated lesions also occur, suggesting that asymptomatic lesions may occur before clinical JME. JME is the first naturally occurring inflammatory demyelinating disease in an NHP.
JME has clinical, MRI and pathologic similarities to MS. These include similar clinical manifestations, a relapsing course in monkeys that recovered sufficiently to be returned to the colony, MRI abnormalities like those of acute MS lesions and similar neuropathologic abnormalities, including plaque-like demyelinating lesions associated with lymphocytes and macrophages, oligodendrocyte depletion, limited remyelination and variable axonal loss. However, there are some features of JME that differ from MS. These include CSF containing neutrophils as well as lymphocytes in most cases and necrosis and hemorrhage as part of the pathologic continuum. These differences may represent species-specific differences in inflammatory and tissue responses. It is worth noting that EAE in NHP often has neutrophils in the CSF and necrosis and hemorrhage as part of the neuropathology, which differs from EAE in rodents18
. Overall the clinical, MRI and neuropathologic features of JME have more similarities than differences with MS and JME is clearly an inflammatory demyelinating disease. Further investigations are needed to determine the full extent of similarities of JME with MS.
There are several features of JME that makes this an extremely appealing model for MS. First, the disease occurs spontaneously, which makes it distinct from current models of MS that require artificial manipulation to induce disease. Second, it affects a small percentage of animals in the colony, approximately 1–3% each year, suggesting there may be a genetic susceptibility to the disease as there is in MS. The ONPRC began tracing the pedigrees of the JM troop in 2000 utilizing specific microsatellite markers. Interestingly, animals developing JME since 2000 come from distinct matrilines from the original troop, supporting the idea that host genetic factors play a significant part in susceptibility to disease (unpublished data). Determining the genetic factors that coincide with disease and predispose animals to develop JME is currently being explored on archived tissue and new cases. Third, like MS, JME is an inflammatory disease, suggesting either an autoimmune disease or a viral infection. An autoimmune pathogenesis of MS is commonly proposed but definitive evidence of this remains lacking. Auto-reactive T cells and anti-myelin antibodies have been proposed as being critical to the immunopathogenesis of MS19–21
. We are currently assessing new cases of JME for anti-myelin T cell responses and antibodies against myelin antigens.
Finally, based on epidemiologically studies and the histopathology, a viral etiology for MS has long been suspected. Multiple candidate viruses have been proposed but none has been convincingly associated with the disease. Here, we report the isolation of a previously unknown herpesvirus, JMRV, isolated from acute JME lesions. We have been unable to isolate JMRV from normal appearing white matter of JM with and without JME. Complete DNA sequencing reveals this to be a rhadinovirus with significant sequence homologies with RRV and human KSHV. Reagents are being generated against this virus to evaluate the potential role of JMRV in JME. This is of particular interest since human Epstein-Barr virus and human herpesvirus 6 are two herpesviruses that have been implicated as playing a role in the pathogenesis of MS22–30
. Demonstrating that a simian rhadinovirus induces JME will provide a new class of herpesvirus that would warrant investigation in MS.
In summary, JME is a unique spontaneous demyelinating disease in an NHP. Preliminary results suggest that the disease occurs in genetically predisposed monkeys and is associated with a novel simian herpesvirus. Further investigation of the pathogenesis of JME may provide new insights into the pathogenesis of MS.