Differential Macrophage/Microglia Activation in Neocortical EAE Lesions in the Marmoset Monkey

Abstract

Recent studies revealed an important involvement of the cerebral cortex in multiple sclerosis (MS) patients. Cortical lesions in MS were reported to be less inflammatory and to show less structural damage than white matter lesions. Animal models reflecting the histopathological hallmarks of cortical demyelinated lesions in MS are sparse. Induction of experimental autoimmune encephalomyelitis (EAE) in the common marmoset has turned out to be an attractive non-human-primate model for MS. In the present study we investigated the presence and detailed cellular composition of cortical inflammatory demyelinating pathology in the common marmoset upon immunization with myelin oligodendrocyte glycoprotein (MOG). Extensive cortical demyelination reflecting the topographically distinct cortical lesion types in MS patients was revealed by immunohistochemistry for myelin basic protein (MBP). We explored the density of T- and B-lymphocytes, MHC-II expressing macrophages/microglia cells and early activated macrophages (MRP14) at perivascular and parenchymal lesions sites in neocortex and subcortical white matter. Despite a similar density of perivascular inflammatory infiltrates in the demyelinated neocortex, a considerable lower fraction of macrophages was found to express MRP14 in the neocortex indicating a different activation pattern in cortical compared with white matter lesions. Furthermore, cortical EAE lesions in marmoset monkeys revealed immunoglobulin leakage and complement component C9 deposition in intracortical but not subpial demyelination. Our findings indicate that the inflammatory response, especially macrophage and microglia activation, may be regulated differently in gray matter areas in primate brain.

A New Targeted Model of Experimental Autoimmune Encephalomyelitis in the Common Marmoset

“…Indeed, cortical lesions have previously been shown to arise after cytokine injections in pre-immunized rats (5,15). However, do lesions of fEAE reflect the histopathological features of human MS plaques?…”

The immunomodulator glatiramer acetate influences spinal motoneuron plasticity during the course of multiple sclerosis in an animal model

“…Synaptic plasticity in the spinal cord may explain, at least in part, the rapid sensorimotor recovery of the animals soon after tetraplegia (3,5). In view of the importance of a better understanding of MS as well as its experimental models, major advances in understanding how cellular and humoral immune responses contribute to the pathogenesis of these diseases have been made in recent years (8)(9)(10)(11)(12). Thus, targeting key elements of the immunological cascade that culminate in neural and glial tissue damage may offer a number of advantages over currently available treatment strategies (13)(14)(15)(16)(17).…”

Experimental Autoimmune Encephalomyelitis in the Common Marmoset, a Bridge Between Rodent EAE and Multiple Sclerosis for Immunotherapy Development

“…Three types of grey matter lesions were found in this EAE model, which were comparable with cortical lesions in MS (Bo et al 2006;Merkler et al 2006a;Pomeroy et al 2005). Leukocortical lesions, which often engaged both the grey and adjacent white matter, were found in all six marmosets brain examined and accounted for 57% of the total number of cortical lesions.…”

“…Furthermore, the cortical thickness was reduced in marmosets with EAE compared to controls, but not differences were observed between demyelinated and myelinated areas (Pomeroy et al 2008). Intracortical lesions, but not subpial lesions, displayed immunoglobulin leakage and complement deposition (Merkler et al 2006a).…”