2024 American Academy of Neurology Abstract Website

Objective:

To investigate HLA-DRB1*15:01 haplotype-dependent gene expression patterns in CSF using conventional single-cell RNA sequencing (scRNAseq) data in patients with MS and healthy controls.

Background:

The HLA-DRB1*15:01 haplotype status is a well-known risk factor for the development of multiple sclerosis (MS). However, the transcriptomic patterns of B cells in cerebrospinal fluid (CSF) dependent on the haplotype status at the single-cell level remain to be elucidated.

Design/Methods:

We utilized publicly available raw scRNA-seq data of peripheral blood mononuclear cells (PBMC) and cerebrospinal fluid (CSF) from MS and healthy control subjects to perform gene expression and VDJ analysis. TRUST4 and ArcasHLA were used to obtain data on VDJ sequences of B cell receptors and HLA haplotype status, respectively.

Results:

Among the 1376 B-lineage cells obtained from a total of 25 CSF samples, 29 % of cells were DRB1*15:01 heterozygous, with the remaining being the non-carrier of DRB1*15:01. BCR sequences were obtained from 489 B cells, and of these 102 B cells were clonally expanded. B cells with DRB1*15:01 haplotype had higher expression of SLC26A3 compared to B cells without the allele. Among clonally expanded B cells, DRB1*15:01 haplotype status was associated with higher expression of HSP90AA1 gene.

Conclusions:

We observed altered gene expression patterns depending on DRB1*15:01 status. HSP90 protein is known to promote inflammatory responses, while the expression of SLC26A3 protein (ie. DRA) can be increased by sphingosine-1-phosphate (S1P), a target of S1P modulator. Further transcriptomic studies of B cells in CSF, considering HLA haplotype status, could be valuable in investigating the mechanism of how disease modifying therapy works.