Review
Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy

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Abstract

Multiple sclerosis is a chronic inflammatory disease of the nervous system in which a T-cell-mediated inflammatory process is associated with destruction of myelin sheaths. Although demyelination is the primary event, axons are also destroyed in the lesions, and the loss of axons correlates with permanent functional deficit. Here, we discuss evidence that demyelination and axonal destruction follow different pathogenetic pathways in subgroups of patients. This might, at least in part, explain the heterogeneity in genetic susceptibility, clinical presentation and response to treatment observed between individuals.

Section snippets

Basic features of MS lesions

The pathology of MS is distinguished from that of other inflammatory diseases of the nervous system by the presence of large, multifocal, demyelinated plaques with reactive glial scar formation 1, 2. This demyelinating process is accompanied by an inflammatory reaction with infiltrates composed mainly of T cells and macrophages. Although myelin sheaths are the primary target of tissue destruction, axons, nerve cells and astrocytes are also affected, although to a lesser degree. Active lesions,

Is Th1-mediated autoimmunity against myelin the cause of inflammation in MS?

The pathology of inflammation in MS lesions is consistent with a T-cell-mediated immune reaction, leading to the recruitment of hematogenous macrophages and activation of microglia 4. This is similar to the pathology of experimental autoimmune encephalomyelitis (EAE), a disease induced by immunization of animals with CNS tissue, myelin or myelin proteins. Several features of MS lesions suggest that, as in EAE, the inflammatory process in MS is driven by a Th1-mediated autoimmune response. For

Additional demyelinating amplification factors are required to form demyelinated plaques

In most vertebrates, including rats, guinea pigs and primates, pure T-cell-mediated inflammation of the brain does not lead to demyelination. An exception to this is the mouse, in which extensive activation of macrophages and microglia in EAE, or in certain transgenic models, is associated with primary destruction of myelin. In these mouse models, signaling through TNF receptor 1 is required for the destruction of myelin and oligodendrocytes 13.

Pure inflammatory T-cell-mediated

Heterogenous patterns of demyelination in MS

A major restriction of pathogenetic studies of MS is the limited material available from actively demyelinating lesions, and it has required a large international effort to collect sufficient specimens to perform such a study 19, 20 (Box 1). A detailed immunopathological investigation of this material has revealed a profound heterogeneity in the patterns of demyelination between different patients, although active plaques from the same patient were very similar. All actively demyelinating

Axonal injury and loss: a consequence of inflammatory demyelination

Early descriptions of the pathology of MS, published in the early 1900s, emphasized the functional importance of axonal destruction in the lesions, which led to secondary (Wallerian) tract degeneration and brain atrophy 3. This aspect of MS pathology has received increased attention recently, as serial magnetic resonance imaging (MRI) investigations indicate that axonal loss within the lesions and brain atrophy correlate with permanent, progressive functional deficits. Axonal injury in MS

Is inflammation in MS lesions always deleterious?

As previously discussed, T-cell-mediated inflammation is the apparent driving force behind the pathological process in MS lesions. More recent data, however, indicate that inflammation might also be neuroprotective, or have a role in the repair of damaged tissue within the CNS. For example, autoimmune T cells protect neurons in the optic nerve from secondary degeneration after injury by partial crushing 30. The presence of macrophages stimulates remyelination in organ culture 31, an observation

Clinical identification of subgroups of MS patients

The heterogenous patterns of demyelination in individuals with MS patients are defined by the pathology of active lesions. However, we expect that clinical diagnosis and therapy would be aided by developing clinical and paraclinical markers to identify patient subgroups according to their pathogenetic pathways of lesion formation. As the association between clinical forms of the disease and pathological subtypes is limited, this approach will largely depend upon the development of suitable

Consequences of MS therapy

Demyelination in MS develops by a T-cell-driven inflammatory process. Thus, the primary nature of inflammation is undisputed and will remain central for treatments that modulate the immune system 8. There are, however, several aspects that limit the therapeutic efficacy of strategies directed exclusively against the inflammatory component of the disease. Currently, immune suppression is unable to stop the inflammatory reaction in the CNS and immune modulatory regimes using interferon β or

Outstanding questions

  • What immunological and neurobiological mechanisms underlie the heterogenous patterns of MS pathology?

  • Which are the most suitable clinical and paraclinical markers to define patient subgroups with different pathogenetic pathways in the formation of demyelinated plaques?

  • Do patients with different pathogenetic pathways of demyelination require subtype-specific therapy?

  • Are recent therapies developed against specific mechanisms of demyelination or axonal injury effective in MS patients?

Acknowledgements

These projects were funded by grants of the Bundesministerium für Bildung, Wissenschaft und Kunst (GZ 70.056/2-Pr/4/99), the Gemeinnützige Hertie Stiftung (GHS 2/540/99) and the US Multiple Sclerosis Society (RG 3051-A-1).

Glossary

Primary demyelination
destruction of myelin sheaths with relative sparing of axons.
T helper 1 cells (Th1)
MHC class II-restricted T cells that secrete a spectrum of cytokines including interleukin 2, interferon γ and lymphotoxin α, and elicit a delayed-type hypersensitivity reaction.
T helper 2 cells (Th2)
MHC class II-restricted T cells that secrete mainly interleukins 4, 5, and 6. They stimulate antibody production and are involved in allergic reactions.
Class I-restricted cytotoxic T cells (Tc1)

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