The cause of sclerosis multiplex – new discovery?

Illusion of Human MindSclerosis multiplex is the most common inflammatory demyelinating disease of the central nervous system. Scientists have been looking for its reasons for years since it would allow to devise specific medication. Among supposed etiological reasons are genetic burdens, autoimmune reactions and environmental factors.

Scientists from Weill Cornell Medical College focused on the last ones. Their research have shown that Clostridium perfringens may trigger the disease. It is the most common bacteria on Earth and it is present in the soil. There are 5 types of it. Type A colonizes human gastro-intestinal tract and is completely harmless. Types B and D are carriers of ETX gene encoding protoxin – precursor which in environment of animal intestines is enzymatically digested by trypsin and chymotripsin and transformed into active epsilon toxin. It transfers through intestine mucosa and with a bloodstream it enters central nervous system where it causes changes typical for sclerosis multiplex in animals- it damages blood vessels and myelin sheaths of neurons. The scientists claim that the reason of such influence of the toxin is that it binds with until unknown receptor on the surface of blood vessel cells and myelin. It causes emergence of heptametrical pores in cell membrane thus leading to cell osmolysis. Type B was not isolated from human.

The scientists from Weill Cornell Medical College have examined a case of 21-years-old woman who came to a neurologist with symptoms suggesting SM. Diagnosis was confirmed by imaging examination and the analysis of cerebrospinal fluid. Clostridium difficile type B was cultured from stool sample. The material was subjected to PCR analysis which showed production of alpha, beta and epsilon toxins. In order to exclude laboratory mistake the examination was repeated with the use of bacteriophages. The results still showed the presence of Clostridium perfringens type B.

The discovery pushed the scientists into further research. They created test group (30 patients suffering from SM) and control one (31 healthy people). Stool samples were taken from everybody. Isolated bacteria were lysed, DNA was isolated and with the use of PCR the type of produced toxin was specified. It is known that completely harmless A serotype of C. perfringens is present in 50% of population. It was confirmed by the research of scientists from Weill Cornell. Harmless serotype was found in 52% of the control group. In the test group only 23% of patients had gastro-intestinal tract colonized by this strain.

Cerebrospinal fluid and serum of healthy people and those suffering from SM were analysed. Epsilon toxin antibodies were searched in the material. In cerebrospinal fluid they were found in 6/62 SM patients and in 1/40 healthy people. Serum examination has shown their presence in 6/56 SM patients and in none of 60 healthy people who were examined.

The scientists analysed also specificity of toxin’s bindings with blood vessels of the brain and the white matter. In order to do that they incubated frozen fragments of adult mice’s retina with molecules of the toxin marked by fluorescein. This experiment has shown relationship of the toxin with blood vessels of the central nervous system. Then, they added such marked toxin to fragments of mice’s brain and showed specificity of its bindings with myelin.

According to the scientists their discovery needs further analysis and verification on a larger group of patients.

If the results acknowledge, the discovery will create new opportunities in therapy and prevention of sclerosis multiplex. One of options may be a vaccine against C. perfringens type B which is already used in animals. As scientists claim, it would also be valuable to devise a drug preventing the toxin from binding with the receptor. The easiest method seems to be the use of probiotic – a cocktail containing harmless bacteria which by colonizing human gastro-intestinal tract would prevent the development of the harmful one.

Written by: Julia Rudnicka, Anna Kozioł

1. Rumah KR, Linden J, Fischetti VA, Vartanian T. Isolation of Clostridium perfringens type B in an individual at first clinical presentation of multiple sclerosis provides clues for environmental triggers of the disease. PLoS One. 2013 Oct 16;8(10):e76359. doi: 10.1371/journal.pone.0076359. eCollection 2013.
3. Popoff MR (2011) Epsilon toxin: a fascinating pore-forming toxin. The FEBS journal 278: 4602–4615 doi: 10.1111/j.1742-4658.2011.08145.x.
4. Souza AM, Reis JKP, Assis RA, Horta CC, Siqueira FF, et al. (2010) Molecular cloning and expression of epsilon toxin from Clostridium perfringens type D and tests of animal immunization. Genetics and molecular research : GMR 9: 266–276 doi: 10.4238/vol9-1gmr711.
5. Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Annals of neurology 55: 458–468. doi: 10.1002/ana.20016

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