More MS news articles for Sep 2001

Multiple sclerosis: a two-stage disease

Nature Immunology 2, 762 - 764 (2001) © Nature America, Inc.
Lawrence Steinman

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA. (

The pathogenesis of multiple sclerosis consists of an inflammatory and neurodegnerative phase. Better understanding of these stages has aided the development of specific therapeutic targets.

Multiple sclerosis (MS) usually begins in early adulthood with an autoimmune inflammatory "strike" against components of the myelin sheath. Paralysis, sensory disturbances, lack of coordination and visual impairment are common features. The disease often starts with an "attack" that lasts from a few days to weeks; this is followed by remission that lasts from a few months to years. This relapsing-remitting phase often lasts five to ten years, but approx. 30% of individuals with this form of MS enter a secondary chronic-progressive state. This chronic-progressive state is often characterized by the inability to walk, which leaves the MS patient wheelchair-bound. In the chronic-progressive phase, distinct attacks are rare and the disease progresses insidiously. Occasionally, however, clinical disability begins with this progressive phase, in which case the disease is called "primary-progressive MS". Evidence indicates that the earlier phase of disease, characterized by distinct attacks followed by remission, may be mediated by an autoimmune reaction. The subsequent chronic phase of disease is due to degeneration of both the myelin sheath, which is synthesized by oligodendroglial cells, and the underlying axon, which emanates from the neuronal cell body some distance away. Indeed it is axon loss in the spinal cord and spinal cord atrophy that correlate most strongly with the inability to walk and paralysis (1, 2).

Worldwide, approximately 1,000,000 individuals are afflicted with MS. Women with the disease outnumber men two to one. This bias towards females is seen in other autoimmune diseases, for example, rheumatoid arthritis, systemic lupus erythematosus and thyroiditis. Genome-wide studies have revealed that susceptibility to MS is linked to genes in the major histocompatibility complex (MHC) on chromosome 6 (3-5). Alleles for certain class II genes, HLA-DR and HLA-DQ, confer the strongest risk of contracting MS. Other genes within the HLA complex are involved in the pathogenesis of MS, including expression of tumor necrosis factor-a (TNF-a), various components of the complement cascade and myelin oligodendroglial glycoprotein. More recently, transcriptional profiling with gene microarrays and large-scale sequencing of transcripts from MS lesions have identified a number of genes that are involved in the pathogenesis of acute disease. These include immunoglobulin and interleukin 6 (IL-6) as well as osteopontin, which plays a role in the transition from relapsing-remitting to chronic MS (Fig. 1a).

Figure 1. The two stages of the progression of MS. (a) Autoimmune attack. (b) Neurodegeneration. (ECM, extracellular matrix)

We have recently learned, from sequencing the human genome and the genomes of various microbes, that biological organisms share many genes. Hence various proteins are used, in a modular manner, to build structures whose intrinsic components can resemble each other. If a human and a microbe invading that human share a common gene sequence that encodes one of these conserved structural motifs, the immune system, in recognizing a structure on this foreign microbe, may mistakenly also attack "self". In the context of MS, many microbial protein sequences share homologies with structures found on the myelin sheath; this leads to an attack on myelin via a process called molecular mimicry. Relapses in MS are often triggered by common viral infections. Viruses such as herpesvirus (6), influenza, measles, papilloma virus and Epstein-Barr Virus all have genes encoding sequences that mimic those found in the major structural proteins of myelin. Indeed, antibodies to components of the myelin sheath cross-react and bind sequences from these microbes. T cells also recognize sequences from the myelin sheath that are shared with these microbial sequences6. Once a T cell, B cell or macrophage is activated by a foreign microbe, self-protein or microbial superantigen, it may penetrate the blood-brain barrier.

Penetration of the blood-brain barrier by activated lymphocytes is a multistep process (Fig. 1). There are specialized capillary endothelial cells in the central nervous system (CNS) that are nonfenestrated and connected through tight junctions. During the inflammatory response, TNF-a and interferon-b (IFN-b) induce these capillary endothelial cells to express vascular cell adhesion molecule (VCAM) and MHC class II molecules. Activated T cells express integrins, such as very late antigen (VLA-4), and members of the immunoglobulin superfamily, such as CD4, that can bind VCAM and MHC class II molecules, respectively. Once activated, any T cell expressing VLA-4, for example, can bind to adhesion molecules on the surface of inflamed endothelium and "walk-through" the endothelium. In an animal model of MS, acute experimental autoimmune encephalomyelitis (EAE), blockade of VLA-4 reverses clinical paralysis and prevents further relapses in the chronic model of this disease. In acute MS lesions, VLA-4 is found on T cells that collect in the "perivascular lymphocyte cuff", a region around veins and capillaries that is limited by the extracellular matrix. Clinical studies with a human antibody to VLA-4 are now in Phase III following promising Phase II trial results in which the incidence of MS relapses was reduced.

Once the activated lymphocytes have extravasated, they still must pass through a barrier of extracellular matrix, comprised of type IV collagen, before they can enter the CNS. Matrix metalloproteases (MMPs) are a family of structurally and functionally related enzymes that are involved in the degradation of the extracellular matrix as well as the proteolysis of myelin components in MS. MMPs contain Zn2+at their active site, show TNF-a convertase activity and induce the cleavage of TNF-a from a cell-bound to a soluble form. Gelatinase A and B (also called MMP2 and MMP9) play a key role in penetration of the extracellular matrix. These MMPs are detectable in the spinal fluid of MS patients, and gelatinase B immunoreactivity is present in endothelial cells, pericytes, macrophages and astrocytes of MS lesions (7). Myelin-specific T cell clones derived from MS patients also produce gelatinase B upon activation with antigen. The presence of gelatinase B in the perivascular infiltrate is associated with disruption of the type IV collagen-positive basement membrane and is critical in the opening of the blood-brain barrier. Once the blood-brain barrier is breached, inflammatory cells spread into the white matter of the CNS. MMP inhibition by tissue inhibitors of matrix metalloproteases (TIMPs) can block TNF-a and thereby down-regulate the induction of adhesion molecules such as VCAM. TIMP-1 is present in the spinal fluid of MS patients and is inducible by various cytokines, including TNF-a. In terms of MS therapy, IFN-b, a potent inhibitor of gelatinase B activity, has been used relatively successfully in clinical trials. Inhibition of gelatinase is thought to interfere with T cell migration into the CNS as well as T cell secretion of TNF-a. Other MMP inhibitors are currently under intense development for clinical MS trials.

Once immune cells have spread to the white matter of the CNS, the immune response is targeted to the entire supramolecular myelin complex. Antibodies to various myelin proteins and lipids of the myelin sheath, as well as to molecules expressed in the CNS, are secreted by B cells that have migrated to the brain or from serum that has extravasated across the blood-brain barrier (6, 7). Activated complement proteins appear in the spinal fluid along with membrane-attack complexes, which represent the terminal components of this cascade. T cells target certain proteins normally found in the myelin sheath. These include myelin basic protein, myelin oligodendroglial glycoprotein and proteolipid protein, as well as stress proteins such as B crystallin, which is found in the myelin sheath after activation via the inflammatory response. The T cells produce cytokines, notably lymphotoxin-a (LT-a) and TNF-a, which are members of the TNF family. LT- is secreted as a LT-3a homotrimer and, like TNF-a, can bind to the p55 TNF receptor (p55-TNFRI) or the p75 TNFR (p75-TNFRII). These cytokines induce macrophages, microglial cells and astrocytes to produce NO and osteopontin.

The free radical NO is a major mediator in autoimmune diseases. NO is involved in the killing of oligodendroglial cells by microglia. Nitric oxide synthase (iNOS), which catalyzes NO synthesis, has been found in demyelinating lesions in MS. Both IFN-b and TNF-a induce iNOS transcription in astrocytes, microglia and macrophages. The combined effect of antibody, complement, NO and TNF-a damages myelin and induces the macrophage to phagocytose large chunks of the myelin sheath. In addition, macrophages and T cells produce osteopontin. This induces more T helper subset 1 (TH1) cytokines, including IFN-b and IL-12, and down-regulates TH2 cytokines such as IL-10. TH1 cytokines may exacerbate MS, whereas TH2 cytokines may reduce the extent of MS lesions (8). This concerted attack by T cells, B cells, complement and inflammatory mediators such as cytokines, osteopontin and NO produces areas of demyelination, which impairs electrical conduction along the axon and produces the pathophysiological defect.

TNF-a, LT and other members of the TNFR family may also play key roles in the pathogenesis of oligodendroglial damage. TNF expression is elevated in the spinal fluid in MS relapses; TNF has also been found in MS lesions. In addition, myelin basic protein–reactive T cells from HLA-DRB1*15-positive MS patients express increased amounts of TNF-a. Experimental trials with altered peptide analogs of myelin basic protein that down-regulate the expression of TNF and up-regulate TH2 cytokines can decrease the size of new lesions in white matter (8). Similarly the approved drug, Copaxone, induces a shift towards TH2 cytokine production by myelin-reactive T cells. This reduces the frequency of relapses in early MS and decreases the degree of inflammatory activity in white matter.

During chronic MS, when exacerbations and remissions of MS are rare, there is evidence for axon loss and atrophy of the brain and spinal cord (1, 2, 9). In EAE and in MS, AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazoleppropionic acid), which mediates toxicity induced by the excitatory neurotransmitter gluatamate, is present on oligodendroglial cells and neurons. During inflammation in both MS and EAE, lymphocytes, brain microglia and macrophages release excessive amounts of glutamate, which then activate AMPA receptors (Fig. 1). Blockade of these receptors with antagonists can ameliorate EAE, including clinical relapses when treatment is begun after the onset of paralysis (10). The blockade of AMPA receptors does not influence the immune response to myelin antigens but somehow protects oligodendroglial cells and axons from immune-mediated damage. Damage may be due to increased fluxes of calcium, which may cause necrotic damage to oligodendroglial cells and axons. The use of neuroprotective agents that block glutamate receptor subtypes is the key focus in the development of new therapies for stroke and neurodegenerative conditions, and this approach could prove useful for treatment of the chronic degenerative phase of MS as well.

The recognition of an inflammatory and a neurodegenerative phase of MS has facilitated the targeting of therapies that are specific for various stages of MS. Thus, drugs such as IFN-b interfere with lymphocyte migration to brain; altered peptides and Copaxone affect cytokine production by autoimmune T cells; and glutamate receptor antagonists block the insidious atrophy and death of oligodendroglial cells and the underlying axon.


1. Trapp, B. D. et al. New Engl. J. Med. 338, 278-285 (1998). | PubMed | ISI |
2. Loseff, N. A. et al. Brain 119, 701-708 (1996). | PubMed |
3. Haines, J. L. et al. Nature Genet. 13, 469-471 (1996). | PubMed | ISI |
4. Ebers, G. C. et al. Nature Genet. 13, 472-476 (1996). | PubMed | ISI |
5. Sawcer, S. et al. Nature Genet. 13, 464-468 (1996). | PubMed | ISI |
6. Wucherpfennig, K. W. et al. J. Clin. Invest. 100, 1114-1122 (1997). | PubMed | ISI |
7. Conlon, P., Oksenberg, J. R., Zhang, J. & Steinman, L. Neurobiol. Dis. 6, 149-166 (1999). | Article | PubMed | ISI |
8. Kappos, L. et al. Nature Med. 6, 1176-1182 (2000). | Article | PubMed | ISI |
9. Lucchinetti, C. F., Bruck, W., Rodriguez, M. & Lassmann, H. Brain Pathol. 6, 259-274 (1996). | PubMed | ISI |
10. Pitt, D., Werner, P. & Raine, C. Nature Med. 6, 67-70 (2000). | Article | PubMed | ISI |

© 2001 Nature Publishing Group