80% of patients with autoimmune disease are women. Emerging evidence suggests that aberrant re-activation of immune genes on the second, inactive, X chromosome in female B cells might play a role in the pathogenesis of female-biased autoimmune diseases. However, the extent of epigenetic and transcriptomic landscape perturbation and the mechanisms behind aberrant X chromosome re-activation in female patients with autoimmunity remain completely unknown.
To address this outstanding question, we employed allele-specific single cell full length RNA sequencing (smart-seq2) in combination with flow cytometry to study X chromosome inactivation dynamics during normal lymphopoiesis in bone marrow as well as in rare auto-reactive B cells isolated from peripheral blood of patients with systemic lupus erythematosus (SLE).
Preliminary data analysis revealed that X-linked genes, upregulated in B cells isolated from female patients with SLE, are long non-coding RNA XIST-dependent, suggesting that in SLE there is a dysregulation of XIST-mediated silencing of inactive X chromosome. Additionally, auto-reactive memory B cells that display partial re-activation of the inactive X chromosome, were enriched among CD21-/low memory B cells.
We are now performing smart-seq2 on a larger number of auto-reactive B cells isolated from different patients in order to find common pathways mis-regulated in these cells, which led to aberrant re-activation of the second, inactive X chromosome. This will greatly advance our understanding of gene regulation governing autoimmune disease pathogenesis and shed light on sex-based differences in autoimmunity.