Since long time ago, it was noticed that some forms of MS were special. Some of them were called Multiple sclerosis borderline forms and were studied appart, but even leaving appart these extreme cases, MS was very heterogeneous. The National MS Society decided at 1998 to investigate whether looking at lesions of Multiple sclerosis would reveal the reason of heterogeneity. With this purpose, they launched The lesion project. This is the name given to special cases of Multiple sclerosis [1]. These diseases are now called the MS-borderline, because some authors consider them different diseases and others MS variants. ...

The group has reported promising findings on samples from 83 cases. They found four types of lesions, which differed in immune system activity. Within each person, all lesions were the same, but lesions differed from person to person.

Discovered patterns

The researchers believe that this may be correlated with differences in disease type and prognosis, and perhaps with different responses to treatment. This report suggests that there may be several types of MS with different immune-related causes, and that MS may be a family of several diseases.

The four identified patters are [4]:

• Pattern I: The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, but no signs of complement system activation[5].
• Pattern II: The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, as before, but also signs of complement system activation can be found.
• Pattern III: The scars are difused with inflammation, distal oligodendrogliopathy and microglial activation. There is also lost of myelin associated glicoprotein (MAG). The scars do not surround the blood vessels, and in fact, a rim of preserved myelin appears around the vessels. There is evidence of partial remielinization and oligodendrocyte apoptosis.
• Pattern IV: The scar presents sharp borders and oligodendrocyte degeneration, with a rim of normal appearing white matter. Lack of oligodendrocytes in the center of the scar. There is no complement activation or MAG loss.

The meaning of this fact is controversial. For some investigation teams it means that MS is a heterogeneus disease. Other teams maintain that the shape of the scars can change with time from one type to other and this could be a marker of the disease evolution. Nevertheless, at least a group from Australia disputes this. T cells are a subset of lymphocytes that play a large role in the immune response. ... Macrophages (Greek: big eaters) are cells found in tissues that are responsible for phagocytosis of pathogens, dead cells and cellular debris. ... Oligodendrocytes (from Greek literally meaning few tree cells), or oligodendroglia (Greek, few tree glue)[1], are a variety of neuroglia. ... A complement protein attacking an invader. ... A complement protein attacking an invader. ... Microglia are a type of glial cell that act as the immune cells of the Central nervous system (CNS). ... Oligodendrocytes (from Greek literally meaning few tree cells), or oligodendroglia (Greek, few tree glue)[1], are a variety of neuroglia. ...

Correlation with clinical courses

No definitive relationship between these patterns and the clinical subtypes has been stablished by now, but some relations have been stablished. All the cases with PPMS (primary progressive) had pattern IV (oligodendrocyte degeneration) in the original study ^[1] and nobody with RRMS was found with this pattern. Balo concentric sclerosis lesions have been clasified as pattern III (distal oligodendrogliopathy)^[2]. Neuromyelitis optica was associated with pattern II (complement mediated demielination). Balo concentric sclerosis is one of the borderline foms of multiple sclerosis. ... Devics disease, also known as Devics syndrome, neuromyelitis optica (NMO), or optic-spinal MS, is an autoimmune, inflammatory disorder in which a persons own immune system attacks myelin of the neurons of the optic nerves and spinal cord. ...

Team

Claudia F. Lucchinetti, MD from Mayo Clinic and collaborators from the U.S., Germany and Austria were chosen to conduct this study for their previous contributions in this area. They have amassed a large collection of tissue samples from people with MS through brain biopsies or autopsy. Claudia Luccinetti was appointed director of this project. Main campus in downtown Rochester, Minnesota. ...

The first article about pathophysiological heterogeneity was in 1996 [PMID 8864283] and has been confirmed later by several teams. Four different damage patterns have been identified by her team in the scars of the brain tissue. Understanding lesion patterns can provide information about differences in disease between individuals and enable doctors to make more accurate treatment decisions.

Appart of this, one of the most remarkable achievements of the Mayo Clinic (though outside from the lesion project) was in neuromyelitis optica (one of the borderline forms), in which the team was able to identify a protein of the neurons, Aquaporin 4 as the target of the immune attack. This has been the first time that the attack mechanisme of a type of MS has been identified ^[3]. Main campus in downtown Rochester, Minnesota. ... Devics disease, also known as optic-spinal MS or neuromyelitis optica (NMO), is an autoimmune disease in which a persons own immune system attacks myelin of the neurons of the optic nerves and spinal cord are affected. ... This is the name given to special cases of Multiple sclerosis [1]. These diseases are now called the MS-borderline, because some authors consider them different diseases and others MS variants. ... Sideview of Aquaporin 1 (AQP1) Channel Aquaporins are a class of integral membrane proteins or more commonly referred to as a class of major intrinsic proteins (MIP) that form pores in the membrane of biological cells. ...

Experimental support

The first experimental support of MS heterogeneity came in 1999 [6]. The researches found that all the people with lesions belonging to the pattern II were responsive to plasmapheresis. This experiment was repeated later in 2005 yielding the same results [7][8] Plasmapheresis is the removal of (components of) blood plasma from the circulation. ...

Additionally, people with lesions of other patterns were non-responsive, showing that there are at least two different underlying mechanisms for causing the lesions. According to one of the researchers involved "Two patterns (I and II) showed close similarities to T-cell-mediated or T-cell plus antibody-mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity."

A third party confirmation was found in Oxford [9] in November 2001, while trying to explain the differences in the Cerebrospinal fluid (CSF). Independently, other team in Germany had similar results [PMID 11673319], and other team, again in Oxford, found the same heterogeneity looking for genetic patterns [10]. Cerebrospinal fluid (CSF), Liquor cerebrospinalis, is a clear bodily fluid that occupies the subarachnoid space in the brain (the space between the skull and the cerebral cortex—more specifically, between the arachnoid and pia layers of the meninges). ...

Other experimental support came on 31 May 2006,from a study that asserts that people non-responsive to interferons is the most responsive to Copaxone [11], and from another study that claims to have identified the autoinmune action in one of the subtypes [PMID 16837931]. Finally, a former variety of MS called Optic-spinal MS has been classified as a variety of Neuromyelitis optica instead, due to the similar behavior of both and the adverse reaction to interferons [12]. This is the first time that a subset of MS is officially classified apart of the others. Devics disease, also known as Devics syndrome, neuromyelitis optica (NMO), or optic-spinal MS, is an autoimmune, inflammatory disorder in which a persons own immune system attacks myelin of the neurons of the optic nerves and spinal cord. ... Devics disease, also known as Devics syndrome, neuromyelitis optica (NMO), or optic-spinal MS, is an autoimmune, inflammatory disorder in which a persons own immune system attacks myelin of the neurons of the optic nerves and spinal cord. ...

The future

The MS Lesion Project has just been renewed with a commitment of $1.2 million for three years.

The investigators are now trying to identify the types of cells involved with tissue destruction, and examining clinical characteristics of the individuals from whom these tissues were taken.

The researchers are attempting this with magnetic resonance images to confirm their initial findings of different patterns of immune pathology and any evidence of possible disease “sub-types” of underlying pathologies. It is possible that such “sub-types” of MS may evolve differently over time and may respond differently to the same therapies. Ultimately investigators could identify which individuals would do best with which treatments.

It seems that this milestone has been achieved with Pulsed magnetization transfer imaging [PMID 16964602] and Diffusion Tensor MRI [PMID 16385020]

The lesion project is now part of the Promise 2010 campaign.

See also

• Multiple sclerosis
• Multiple sclerosis borderline

This is the name given to special cases of Multiple sclerosis [1]. These diseases are now called the MS-borderline, because some authors consider them different diseases and others MS variants. ...

References

External links

• The lesion project page
• Multiple sclerosis news
• MS News at Accelerated Cure Project