Advanced MRI and staging of multiple sclerosis lesions.

Over the past few decades, MRI-based visualization of demyelinated CNS lesions has become pivotal to the diagnosis and monitoring of multiple sclerosis (MS). In this Review, we outline current efforts to correlate imaging findings with the pathology of lesion development in MS, and the pitfalls that are being encountered in this research. Multimodal imaging at high and ultra-high magnetic field strengths is yielding biologically relevant insights into the pathophysiology of blood-brain barrier dynamics and both active and chronic inflammation, as well as mechanisms of lesion healing and remyelination. Here, we parallel the results in humans with advances in imaging of a primate model of MS - experimental autoimmune encephalomyelitis (EAE) in the common marmoset - in which demyelinated lesions resemble their human counterparts far more closely than do EAE lesions in the rodent. This approach holds promise for the identification of innovative biological markers, and for next-generation clinical trials that will focus more on tissue protection and repair.

What's in a name? Experimental encephalomyelitis: 'allergic' or 'autoimmune'.

New linguistic coinage can signify new practices and fresh perceptions in science: descriptors therefore are not trivial. Here, we consider the shifting valence of 'allergic' and 'autoimmune' in conceptions of experimental encephalomyelitis (EE). Ehrlich's dismissal of the relevance to disease of autoimmunity resulted in its 'long struggle for recognition' notwithstanding the convincing attribution in 1904 of the hemolysis of paroxysmal cold hemoglobinuria. Yet allergy did take hold because of its assumption that harmful effects could be ascribed to an extrinsic agent against which immune responses were supposed to be directed, in line with contemporary microbiological research. In 1885 the history of EE began with Pasteur's anti-rabies vaccine, dried virus-infected rabbit spinal cord, with use occasionally inducing a post-vaccinal encephalomyelitis (PVE). From 1933 to 1935, PVE was investigated by Rivers who reported that some monkeys immunized with normal rabbit CNS extracts developed an inflammatory demyelinating EE and anti-brain antibodies: no cause was attributed. In the 1940s Freund developed an adjuvant that greatly potentiated immunization and in 1947 this was applied to animals immunized for EE: induction was accelerated and the disease was called 'E allergic E', initiating the EAE acronym. As recorded, 'the study of autoimmune disease leapt from nothing in 1945 to a vigorous field in the 1950s'. Yet researchers sedulously retained allergic in the EAE acronym until the1980s, long after 'autoimmune' had become available to them. Eventually practitioners for whom autoimmunity had meaning influenced the transition to 'E autoimmune E' as the laboratory analogue of human autoimmune multiple sclerosis.

Genetic analysis of disease subtypes and sexual dimorphisms in mouse experimental allergic encephalomyelitis (EAE): relapsing/remitting and monophasic remitting/nonrelapsing EAE are immunogenetically distinct.

Experimental allergic encephalomyelitis (EAE) is the principal animal model of multiple sclerosis (MS), the major inflammatory disease of the central nervous system. Murine EAE is generally either an acute monophasic or relapsing disease. Because the clinical spectrum of MS is more diverse, the limited range of disease subtypes observed in EAE has raised concern regarding its relevance as a model for MS. During the generation of a large F2 mapping population between the EAE-susceptible SJL/J and EAE-resistant B10.S/DvTe inbred lines, we identified four distinct subtypes of murine EAE resembling clinical subtypes seen in MS. We observed acute progressive, chronic/nonremitting, remitting/relapsing, and monophasic remitting/nonrelapsing EAE. An additional subtype, benign EAE, was identified after histologic examination revealed that some mice had inflammatory infiltrates of the central nervous system, but did not show clinical signs of EAE. Genome exclusion mapping was performed to identify the loci controlling susceptibility to each disease subtype. We report three novel EAE-modifying loci on chromosomes 16, 7, and 13 (eae11-13, respectively). Additionally, unique loci with gender-specific effects govern susceptibility to remitting/relapsing (eae12) and monophasic remitting/nonrelapsing (eae7 and 13) EAE.

Nitric oxide localized to spinal cords of mice with experimental allergic encephalomyelitis: an electron paramagnetic resonance study.

Experimental allergic encephalomyelitis (EAE) is a demyelinating autoimmune disorder that can be induced in susceptible mice by T lymphocytes sensitized to central nervous system (CNS) myelin components and is a prime animal model for the human CNS demyelinating disorder, multiple sclerosis (MS). Although CNS inflammation in which T lymphocytes and activated macrophages are the predominant cell types is observed in mice with EAE and in humans with MS, the exact mechanisms underlying the CNS damage and demyelination are not understood. Nitric oxide (NO), a gaseous free radical, has recently been shown to be a cytolytic product of activated macrophages. Using electron paramagnetic resonance spectroscopy, the nitric oxide free radical complexed with iron-sulfur proteins has been identified in affected spinal cords of mice with EAE, concurrent with the diminution of iron-sulfur proteins. These results indicate NO may play a role in the disease process of EAE, and perhaps MS.

Observer agreement in the assessment of clinical signs in experimental allergic encephalomyelitis.

Rats suffering from experimental allergic encephalomyelitis (EAE) were examined by a number of investigators whose assessments were compared. Considerable consensus of opinion was reached, especially when a standard, easily interpretable, scoring classification was used. More discrepancies occurred when a more expanded scale, differentiating between more clinical grades, was used. It is demonstrated that part of these discrepancies can be overcome by having the examinations done by the same investigator. Possible consequences of these findings for the assessment of clinical signs in EAE are discussed.

Mechanism of demyelination in the guinea pig. Separate sensitization with encephalitogenic myelin basic protein and nonencephalitogenic brain components.

Experimental allergic encephalomyelitis (EAE), accompanied by demyelinating central nervous system (CNS) lesions, can be induced in guinea pigs sensitized with whole guinea pig CNS tissue, but not in animals sensitized with purified myelin basic protein (BP). This type of chronic demyelinating EAE is presumably a result of a combination of a cell-mediated immune response to the encephalitogenic BP and a separate response to other nonencephalitogenic CNS antigens. We report here that demyelinating EAE can be induced when separate sensitizations are used to induce a cell-mediated response to BP and a second immune response to nonencephalitogenic CNS antigens. Animals sensitized in separate sites with guinea pig BP and whole chicken brain develop CNS demyelinating lesions. Animals sensitized only to BP or chicken brain do not develop demyelination.