Searching for the Cause

We believe that there are some critical clues in the search for the cause of Multiple Sclerosis. They’re only visible very early on in the process, and as days, weeks, months, and years go by, most of these initial clues become lost.

The clues are: microscopic descriptions of MS lesions at their earliest stage of formation.

That’s because most samples and specimans in MS come from people who have died, either from accidents or natural causes. For these people, there is a low probability that their specimens contain lesions that are only a few days old.

Microscopic Clues

In 1952, Adams and Kubik published a series of cases that described the pathology of many MS lesions, most of which were months-to-years in age.

One individual’s case was of particular interest, however, because among the typical ‘older ‘MS lesions there was one that they estimated to be approximately two days old. Surprisingly, this two-day-old lesion was strikingly different from lesions that were weeks or months in duration.

There was marked oligodendrocyte apoptosis (cell death) but also preservation of myelin sheaths. This suggested that one of the earliest events in MS lesion formation is cell death and that demyelination was a secondary event (see “dying back”).

Changing Definitions

Importantly, Adams and Kubik did not identify the presence of infiltrating or perivascular lymphocytes, or macrophages in this two-day-old lesion. That waited until 2004, when Barnett and Prineas examined 7 cases of newly forming lesions in a more comprehensive analysis.

Based on their findings, the Barnett and Prineas further refined the definition of the newly-forming lesion as having the following characteristics:

• Evidence of blood-brain barrier dysfunction

• Oligodendrocyte apoptosis

• Relative preservation of myelin and axons

• An absence of perivascular or infiltrating lymphocytes

• An absence of macrophages

• … and early activation of microglia.

Then, in 2012, new research by Prineas and Parratt further supported this result. Their findings suggested that the initial targets in MS lesion formation are the blood-brain barrier and oligodendrocytes. Furthermore, the absence of adaptive or innate immune cell infiltrates suggests that immune or autoimmune responses happen after the initial damage.

Possible Causes

In 1986, the Australian physician Timothy Murrell hypothesized that sheep-derived Clostridium perfringens type B or type D may be (one of the) environmental pathogens that cause MS.

Specifically, Murrell reasoned that the epsilon toxin may be responsible for MS lesion formation because:

1. MS occurred in regions where there is a high sheep density, and

2. C. perfringens types B and D produce epsilon toxin, which was known to target the blood-brain-barrier and cause multifocal white matter disease in a pattern that closely resembled Multiple Sclerosis.

While Murrell was under-equipped to formally test his hypothesis, in 2013 Rumah et al showed that people with MS possess antibodies to epsilon toxin… an indication of prior exposure to the toxin.

Further evidence came in 2015 when Linden, Ma, and their colleagues showed that epsilon toxin was a highly specific inducer of oligodendrocyte cell death while leaving neurons, axons, astrocytes and microglia completely unaffected… the tell-tale sign of the newly forming MS lesion.

Today’s Research

Following up on Linden, Ma, and Rumah’s work, ongoing research aims to establish the specific role of epsilon toxin at the blood-brain barrier and to recapitulate the newly forming MS lesion in a model system using epsilon toxin.

The burning question is then what causes disruption of the blood-brain barrier, and what causes cell death in the newly forming lesion?  This question is a central focus of our research efforts.

References

The morbid anatomy of the demyelinative disease.
Adams RD, Kubik CS.
Am J Med. 1952 May;12(5):510-46.

Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion.
Barnett MH, Prineas JW.
Ann Neurol. 2004 Apr;55(4):458-68.

Clostridium perfringens Epsilon Toxin Causes Selective Death of Mature Oligodendrocytes and Central Nervous System Demyelination.
Linden JR, Ma Y, Zhao B, Harris JM, Rumah KR, Schaeren-Wiemers N, Vartanian T.
MBio. 2015 Jun 16;6(3):e02513. doi: 10.1128/mBio.02513-14.

Oligodendrocytes and the early multiple sclerosis lesion.
Prineas JW, Parratt JD.
Ann Neurol. 2012 Jul;72(1):18-31. doi: 10.1002/ana.23634.

Isolation of Clostridium perfringens type B in an individual at first clinical presentation of multiple sclerosis provides clues for environmental triggers of the disease.
Rumah KR, Linden J, Fischetti VA, Vartanian T.
PLoS One. 2013 Oct 16;8(10):e76359. doi: 10.1371/journal.pone.0076359. eCollection 2013.