Genetic studies suggest that peripheral immune dysfunctions occurs first in the causal chain of events leading to MS. However, these changes are typically not appreciated when patients present with their first symptom or with an asymptomatic inflammatory lesion; we have only sparsely characterized individuals before they develop disease. Thus, the earliest molecular events leading to damage of the CNS parenchyma remain unknown.
To investigate the correlation between a marker of neuronal integrity (Neurofilament light chain, NfL) and the transcriptional profile of peripheral immune cells during the pre-symptomatic phase in a cohort of first-degree family members of MS patients.
Blood samples were collected from 124 asymptomatic first-degree relatives of MS patients part of the Genes & Environment in MS (GEMS) study, 7 MS patients, and 11 patients with other neuroimmune diseases (ONID), age (20-54). Serum samples were used to assess NfL levels using the SIMOA platform. Cryopreserved peripheral blood mononuclear cells (PBMC) were used to generate RNA-sequencing data. ‘CIBERSORT’ was used to estimate the proportions of major PBMC cell types (CD4 and CD8 T, monocyte, B, and NK) from the gene expression data. ‘WGCNA’ was used to to identify PBMC co-expressed gene modules. Available genotyping data were used to calculate a polygenic MS risk score for each individual.
Serum NfL levels from GEMS individuals increased with age (p=2E-14), and were significantly lower than MS and ONID patients, adjusting for the effects of age and sex. NfL was not elevated in high-risk (high polygenic score) vs. low-risk family member subgroups.
After batch variation and technical variable correction 114 GEMS subjects qualified for PBMC bulk RNA-sequencing analysis. ‘WGCNA’ identified 37 co-expressed gene modules, 4 of which were associated with NfL levels (FDR-adjusted p<0.05), adjusting for effects of age, sex and estimated cell type proportions. One particular module is enriched in myeloid cells, and myeloid-mediated immunity and myeloid activation pathways; an association that persisted after accounting for the proportion of different cell types. The other 3 modules were all enriched for genes upregulated in chronic myelogenous leukemia and downregulated gene targets of KLF1 transcription factor.
The transcriptional programs of some peripheral immune cells strongly correlate with NfL levels; ongoing data replication. These results implicate a cross-talk between the peripheral immune system and the CNS that could provide additional insights into MS pathophysiology; the direction of the association is being explored.