Multiple sclerosis is an autoimmune disease in which the body’s own immune system attacks and damages the protective coating around nerve cells. This coating is made up of myelin – a biological membrane of protein and fatty substances – which is why research efforts to find the disease’s target antigen have so far focused on the myelin membrane’s components. New findings made by the research group from the University of Zurich’s Clinical Research Priority Program Multiple Sclerosis, now suggest that it is worth broadening the research perspective to gain a better understanding of the pathological processes. In the journal Science Translational Medicine, the scientists report that T lymphocytes react to an protein called GDP-L-fucose synthase. This enzyme is formed in human cells as well as in bacteria frequently found in the gastrointestinal flora of patients suffering from multiple sclerosis. Human GDP-l-fucose synthase, also known as FX protein, synthesizes GDP-L-fucose from its substrate GDP-4-keto-6-deoxy-D-mannose. L-fucose is a key component of many important glycoproteins including the blood group antigens and the Lewis(X) ligands.
Much interest has been placed recently on the possible role of the gut microbiome in multiple sclerosis (MS) pathophysiology. Much of the experimental evidence is derived from studies using the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Modifying the gut microbiota with either antibiotic cocktails or probiotics leads to EAE attenuation as well as a multitude of regulatory immune responses. From studies attempting to characterize the composition of the microbiome, it is clear there are some differences in people with MS compared to controls. People with relapsing-remitting MS (RRMS) have an abundance of Anaerostipes, Faecalibacterium, Pseudomonas, Mycoplasma, Haemophilus, Blautia, and Dorea; and a relative decrease of Bacteroides, Prevotella, Parabacteroides and Adlercreutzia. In pediatric MS, patients have higher levels of members of Desulfovibrionaceae and depletion in Lachnospiraceae and Ruminococcaceae. For the genetically defined subgroup of MS patients examined by the researchers, results show that gut microbiota could play a far greater role in the pathogenesis of the disease than previously assumed.
Enzymes analogous to human GDP-L-fucose synthase are coded in many bacterial genomes. Scientists still do not know if this has something to do with the onsety of the disease. It is hypothisizable that a certain similarity exists between the human FX and the bacterial counterparts. In case of gut dysbiosis and consequential immune derangement, bacterial enzymes analogous to GDP-L-fucose synthase could become exposed and challenged by local lymphocytes. This would trigger a possible onset of autoimmunity against the FX protein itself. Scientists though do not know the reason why this autoimmunity would turn against brain cells, as is the case of multipls sclerosis. Be as it may, the team hopes that these findings can soon also be translated into therapy. They plan to test the immunoactive components of GDP-L-fucose synthase using an approach that the researchers have been pursuing for several years already. The team’s clinical approach specifically targets the pathological autoreactive immune cells; it therefore differs radically from other treatments that are currently available, which throttle the whole immune system.
While these treatments often succeed in stopping the progression of the disease, they also weaken the immune system, causing severe side effects. The clinical approach of the research group involves drawing blood from MS patients in a clinical trial,then attaching the immunoactive protein fragments onto the surface of red blood cells in a laboratory. When the blood is reintroduced into the bloodstream of patients, the fragments help to “re-educate” their immune system and make it “tolerate” its own brain tissue. This therapeutic approach aims for effective targeted treatment without severe side effects. Senior author Dr.Mireia Sospedra concludes: “We believe that the immune cells are activated in the intestine and then migrate to the brain, where they cause an inflammatory cascade when they come across the human variant of their target antigen”. Besides, there is another possibly exploring side of the coin. That is, the structure of human FX obtained many years ago, has revealed the key catalytic residues and could be useful for the design of drugs for the treatment of inflammation, auto-immune diseases, and possibly certain types of cancer.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Planas R et al. Sospedra M. Sci Transl Med. 2018 Oct 10;10(462).
Camara-L CR et al. World J Gastroenterol. 2018 Oct 7;24(37):4217.
Jelcic I et al. Sospedra M, Martin R. Cell. 2018 Sep;175(1):85-100.
Sospedra M. Curr Opin Neurology 2018 Jun; 31(3):256-262.