Megakaryocyte Expansion May Contribute to Pathogenesis of Rheumatoid Arthritis, Systemic Lupus Erythematosus, and Primary Sjögren Syndrome

Megakaryocyte expansion was found in the peripheral blood mononuclear cell (PBMC) composition of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and primary Sjögren syndrome, and may be a shared mechanism in the pathogenesis of these autoimmune diseases, according to study results published in Annals of the Rheumatic Diseases.

Rheumatoid arthritis, SLE, and primary Sjögren syndrome share several clinical, serologic, and immunologic characteristics and are thought to share common causes and disease processes. The PBMCs are immune cells that initiate the autoinflammatory process; however, the specific pathways of gene expression involved in the initiation are unknown.

In the current study, the researchers used RNA sequencing of gene expression signatures, immune cell subsets, and transcription factors to identify common mechanisms in the immunopathogenesis of RA, SLE, and primary Sjögren syndrome.

The researchers collected peripheral blood from 42 patients with RA, 28 patients with SLE, 28 patients with primary Sjögren syndrome, 12 with polyautoimmunity (defined as having RA and primary Sjögren syndrome or SLE and primary Sjögren syndrome), and 21 healthy control participants. Bulk RNA sequencing (RNA-seq) data and flow cytometry were performed to identify enrichment of biological processes, transcription factors, and deconvolution-based immune cell types.

Transcriptional profiles and upregulated genes involved in nucleosome assembly and coagulation were shared across RA, SLE, primary Sjögren syndrome, and polyautoimmunity. Upregulated genes (cell-lineage-specific TFs PBX1, GATA1, TAL1, and GFI1B) showed a strong gene expression signature of megakaryocyte expansion. Immune cell composition using flow cytometry found elevated CD41b⁺CD42b⁺, and CD41b⁺CD61⁺ megakaryocytes, validating the gene expression signatures. Using single-cell RNA-seq data, megakaryocytes were identified by TFs PBX1, GATA1, TAL1, as well as the pre-T-cell antigen receptor gene (PTCRA). Megakaryocytes exhibited heterogeneity and enrichment of genes associated with antigen processing and presentation. Results suggested that elevated megakaryocytes enhance their antigen-presenting function in these autoimmune diseases.

The researchers concluded, “We have presented evidence for peripheral [megakaryocyte] expansion across RA, SLE, and [primary Sjögren syndrome]. Our discovery provides clues that [megakaryocyte] expansion might initially prime autoimmune T cells in the pathogenesis of these [autoimmune diseases].

Reference

Wang Y, Xie X, Zhang C, et al. Rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren’s syndrome shared megakaryocyte expansion in peripheral blood. Ann Rheum Dis. Published online August 30, 2021. doi:10.1136/annrheumdis-2021-220066