Genetic Links Between Inflammasomes and Multiple Sclerosis: Insights from NLR Receptor Variants

The study titled "Genetic analysis of nucleotide-binding leucine-rich repeat (NLR) receptors in multiple sclerosis" explores the genetic underpinnings of multiple sclerosis (MS), with a specific focus on inflammasome-forming NLR receptors. This research delves into the genetic variability within the NLR family and its potential role in MS susceptibility.

Inflammasomes are multiprotein complexes that play a crucial role in innate immunity by recognizing pathogen or danger-associated molecular patterns. Their activation triggers a cascade leading to the secretion of pro-inflammatory cytokines, particularly interleukin-1β (IL-1β) and IL-18, which are central in promoting inflammation. NLR receptors, including NLRP1, NLRP3, and NLRC4, are known to form these inflammasomes and have been implicated in autoimmune diseases such as MS.

The researchers analyzed exome sequencing data from 326 MS patients to identify rare missense or nonsense variants in genes encoding inflammasome-forming NLR receptors, including NLRP1, NLRP3, NLRP6, NLRP7, and NLRC4. They identified 17 rare variants in these genes, which were further genotyped in a larger cohort of 2,503 MS patients and 1,076 healthy controls. Interestingly, none of these variants showed statistically significant differences in frequency between MS patients and controls, suggesting that these variants may not have a major role in MS susceptibility.

However, the study identified some variants of interest that could still be relevant to MS pathophysiology. For instance, two homozygote variants in NLRP1 (p.Ile601Phe and p.Ser1387Ile) were detected in MS patients. NLRP1 is crucial for inflammasome activation, and mutations in this gene have been previously associated with inflammatory syndromes. The researchers suggest that these homozygote variants could contribute to MS risk, although further functional studies are needed to confirm their role.

In addition, the study found a rare missense variant in NLRP3 (p.Leu832Ile) in MS patients, which affects the leucine-rich repeat (LRR) domain of the protein, a critical structure for its function. While this variant did not co-segregate with disease in MS families, its evolutionary conservation and predicted damaging effect on protein function indicate it could be a functional variant contributing to disease severity.

Moreover, the researchers identified truncating mutations in NLRC4 (p.Arg310Ter and p.Glu600Ter) in several MS patients. These loss-of-function mutations might impair the normal inflammasome function, potentially contributing to an exaggerated inflammatory response in MS. Although co-segregation analysis did not strongly support these variants' pathogenicity, their presence in MS patients highlights the need for further investigation into their potential role in the disease.

Overall, the study contributes valuable insights into the complex genetic landscape of MS, specifically concerning inflammasome-forming NLR receptors. While the identified variants did not show a significant association with MS on a population level, some may still play a role in individual cases or families. The findings underscore the importance of continued research into rare genetic variants and their functional consequences in the context of autoimmune diseases like MS.

References:
Popplewell, L.F., Encarnacion, M., Bernales, C.Q. et al. Genetic analysis of nucleotide-binding leucine-rich repeat (NLR) receptors in multiple sclerosis. Immunogenetics 72, 381–385 (2020).