Enzyme Produced by Gut Bacteria Linked to T-cell Attacks on Myelin in Study

An enzyme produced by bacteria in the gut was seen to activate immune cells linked to the development and progression of multiple sclerosis, a finding that may pave the way for a vaccine that might alter autoimmune mechanisms involved in MS.

The study, “GDP-l-fucose synthase is a CD4⁺ T cell–specific autoantigen in DRB3*02:02 patients with multiple sclerosis,” was published in the journal Science Translational Medicine.

MS, an autoimmune disorder, is characterized by immune cells that become overactive and attack nerve cells and their protective myelin sheath. Several studies and patient tissue analyses suggest that immune T-cells play a critical role in this autoimmune-triggered response. However, it remains unclear what triggers these immune cells to damage and destroy nerve cells in the brain.

“It is crucial to elucidate the target antigens responsible for inducing T and B cell activation to understand MS pathogenesis. In addition, it is a prerequisite for developing antigen-specific tolerization strategies,” the researchers wrote.

An international team of scientists exposed specific T-cells, collected from brain lesions of a patient with secondary progressive MS (SPMS), to different small molecules. Among the tested compounds, they identified the naturally occurring GDP-L-fucose synthase as stimulatory.

Analysis of white and gray matter brain tissue from other MS patients, compared to a samples from people without MS who served as controls, found evidence of 17 GDP-L-fucose synthase small molecules.

GDP-L-fucose synthase is an enzyme naturally produced in human cells, and in bacteria frequently found in the gastrointestinal flora of MS patients.

Further experiments showed that the presence of GDP-L-fucose synthase small molecules could induce both the proliferation and activation of immune T-cells, as determined by the increased production of important immune signaling molecules such as interferon-gamma and interleukin-4.

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Next, researchers evaluated the impact of these small molecules in samples of T-cells taken from the cerebral spinal fluid (CFS) of eight patients with clinically isolated syndrome (CIS) with a demyelinating event — compatible with MS development — and 23 MS patients.

Overall, 19 patients (61.3%) were characterized as non-responders to GDP-L-fucose synthase, as their cells did not react to the compound; six (19.35%) were moderate responders; and another six (19.35%) were high responders. Based on this response pattern, researchers found a positive association between GDP-L-fucose synthase reactivity and attacks on myelin, suggesting a link between the two events.

Because GDP-L-fucose synthase is formed in bacteria in the gut, the team evaluated the sequence of this enzyme in bacterial species reported to be altered in gut flora of MS patients.

They found that the small molecules of GDP-L-fucose synthase identified in the initial screen — and those in bacteria associated with MS — had at least 40% similar sequences. The bacterial-related small molecules could also induce the proliferation and activation of immune T-cells in the CSF.

“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,” Mireia Sospedra, with the University of Zurich’s Clinical Research Priority Program Multiple Sclerosis and the study’s senior author, said in a university news release.

Overall, the researchers believe that GDP-L-fucose synthase molecules derived from gut microbiota act “as an inducer or driver of pathogenic autoimmune responses in multiple sclerosis,” they wrote.

Additional studies are needed to confirm that human and bacterial GDP-L-fucose synthase trigger T-cells to recognize and attack myelin sheaths in neurons, and possibly provide a new insight into the involvement of gut flora on MS development.

Sospedra believes that it may be possible to develop an immunization strategy that differs from those currently available or under development, one that spares healthy, non-autoreactive immune cells and acts only upon reactive T-cells.

“Our clinical approach specifically targets the pathological autoreactive immune cells,” she said.

The team’s clinical approach would rely on blood from MS patients, which is then modified in the lab to attach the immunoactive protein fragments of GDP-L-fucose synthase to the surface of red blood cells. When the blood is reintroduced into a patient’s bloodstream, these protein fragments, the researchers suggest, will help to “re-educate” the immune system to not attack brain tissue.