Rheumatoid arthritis-associated RBPJ polymorphism alters memory CD4+ T cells

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Notch signaling regulates immune responses in autoimmune diseases.
• RBPJ (recombination signal-binding protein for immunoglobulin kappa J region) is key in Notch pathway activation.
• A rheumatoid arthritis (RA) susceptibility locus (rs874040) implicates the RBPJ gene.

Purpose of the Study:

• Investigate the role of the rs874040 genetic variant in RBPJ expression and T cell function.
• Determine the impact of this variant on Notch signaling and cytokine production in the context of RA.

Main Methods:

• Chromatin state mapping using chromHMM.
• Analysis of RBPJ expression in CD4(+) T cells with different rs874040 alleles.
• Transcriptomic analysis of Notch target genes (IL-9, IL-17, IFNγ).
• In vitro Notch pathway activation using Jagged2-Fc and delta-like 4Fc ligands.

Main Results:

• The rs874040 risk allele (CC) is associated with increased RBPJ expression in memory CD4(+) T cells.
• This allele leads to repressed Notch target genes (IL-9, IL-17, IFNγ) in a basal state.
• Notch pathway activation induces higher levels of IL-9, IL-17A, and IFNγ in rs874040(CC) T cells.
• Elevated RBPJ expression and induced inflammatory cytokines are observed in RA patients' memory T cells.

Conclusions:

• The rs874040(CC) allele promotes a pro-inflammatory T cell phenotype via Notch signaling.
• This genetic predisposition increases susceptibility to rheumatoid arthritis (RA).
• RBPJ and Notch signaling are critical in RA pathogenesis.