Genetic Variants in Inflammasome Genes Influence MS Severity, Progression, Study Suggests

Genetic variants that enhance the activity of the NLRP3 inflammasome or the interleukin-1 beta cytokine are linked to higher severity and progression of multiple sclerosis (MS), a study suggests.

The study, “Variants in NLRP3 and NLRC4 inflammasome associate with susceptibility and severity of multiple sclerosis,” was published in the journal Multiple Sclerosis and Related Disorders.

Previous studies with mouse models of MS have shown that a complex of innate immune system receptors and sensors, known as the inflammasome, is likely a player promoting the immune system’s attack on the central nervous system in MS and, consequently, the loss of myelin (the protective coat in neurons).

Follow-up studies showed that people carrying mutations that enhance the function of the NLRP3 inflammasome — one of the three components of the inflammasome complex — had a worse prognosis, once again supporting the role of the inflammasome in MS.

Once activated, the inflammasome triggers an enzyme called caspase-1 that promotes the production of two very powerful proinflammatory cytokines called interleukin (IL)-1 beta and IL-18.

To further evaluate the role of the inflammasome in MS, a team led by researchers at the Universidade de Sao Paulo in Brazil analyzed the genetic sequence of five inflammasome genes — NLRP1, NLRP3, NLRC4, IL-1 beta, and IL-18 — in blood samples retrieved from 264 patients diagnosed with MS or other demyelinating diseases. They also analyzed 233 healthy individuals used as controls.

The team specifically looked at eight variations in certain nucleotides (the building blocks of DNA), called single nucleotide polymorphisms (SNPs). Previous studies reported a link between SNPs in inflammasome-related genes and certain forms of MS.

Results showed that SNPs associated with low serum levels of IL-18 were significantly less frequent in MS patients than in controls. In contrast, variants that enhance the function of NLRP3 and IL-1 beta were associated with severity and progression of MS, as measured by the Expanded Disability Status Scale (EDSS).

These results suggest that the “activation of NLRP3 inflammasome could represent a risk factor for MS clinical presentation,” the researchers wrote.

A particular variant in the NLRC4 gene called NLRC4 rs479333 G > C SNP was less frequent in patients whose disease progressed rapidly compared with those who had a slower disease, an intriguing observation, according to researchers, suggestive of a “protection effect of this variant against a bad prognosis.” Carriers of this variant also responded better to treatment with interferon-beta.

Regarding MS type, the genetic variant that promotes the function of the IL-1 beta gene (IL1B −511 C >T) was significantly more frequent in progressive forms of MS than in relapsing-remitting MS, strengthening once again the negative effects of IL-1 beta in the disease.

An analysis of inflammasome activity in blood monocytes, a group of immune cells, showed that the inflammasome is permanently activated in MS compared with healthy controls.

“This study emphasizes that a constitutive activation of NLRP3 inflammasome, principally through IL-1 beta production, represents a risk factor for both the development of MS and the progression to severe forms of the disease. On the other hand, low IL-18 production and/or NLRC4 activation were beneficial for MS patients,” the team concluded.