Pathophysiology of multiple sclerosis
The Research Programs Advisory Committee of the National MS Society decided at 1998 to investigate whether looking at lesions of Multiple sclerosis would reveal why people experience the disease so differently.
Team
The Research Programs Advisory Committee of the National MS Society decided to investigate the heterogeneity of the disease curse. In fact, there were already suspicion that MS was a family of diseases. The Advisory Committee function is to recommend research initiatives to the director, and they recomended to investigate the lesions.
Understanding lesion patterns can provide information about differences in disease between individuals and enable doctors to make more accurate treatment decisions.
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.
Early findings
Claudia Luccinetti, neurologist at the Mayo Clinic was appointed director of this project for her previous findings. 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.
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. Nevertheless, at least a group from Australia disputes this.
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 [1]:
- Pattern I: The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, but no signs of complement system activation[2].
- 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 inflamation, 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.
No relationship between these patterns and the clinical subtypes has been stablished by now.
Experimental support
The first experimental support of this theory came in 1999 [3]. 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 [4][5]
Additionally, people with lesions of other patterns were non-responsive, showing that there are at least two different underlying mechanismes 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 [6] in November 2001, while trying to explain the differences in the CSF (Cerebrospinal fluid). Independently, other team in Germany had similar results [PMID 11673319], and other team, again in Oxford, found the same heterogeneity looking for genetical patterns [7].
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.
The lesion project is now part of the Promise 2010 campaign.