Distinct Single Cell Gene Expression in Peripheral Blood Monocytes Correlates With Tumor Necrosis Factor Inhibitor...

Area of Science:

• Immunology
• Genomics
• Rheumatology

Background:

• Type I interferon (T1IFN) activity has been previously shown to predict non-response to tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA).
• Monocytes play a crucial role in RA pathogenesis and immune response.
• Understanding the heterogeneity of monocyte responses based on T1IFN activity is essential for personalized treatment strategies.

Purpose of the Study:

• To investigate the biological differences in classical (CL) and non-classical (NC) monocytes from RA patients based on their pre-biologic treatment T1IFN activity.
• To identify specific gene expression patterns associated with T1IFN activity levels.
• To explore potential therapeutic targets for RA patients who do not respond to TNFi.

Main Methods:

• Single-cell gene expression analysis was performed on purified CL (n = 342) and NC (n = 359) monocytes from RA patients.
• Patients were grouped based on pre-biologic T1IFN activity: 'T1IFN undetectable (T1IFN ND) or IFNβ/α >1.3' and 'T1IFN detectable but IFNβ/α ≤ 1.3'.
• Principal component and unsupervised cluster analyses were used to identify differences in gene expression.

Main Results:

• Significant differences in gene expression were observed between monocyte groups defined by T1IFN activity.
• CL monocytes from the T1IFN ND or IFNβ/α >1.3 group showed reduced expression of JAK1 and IFI27.
• NC monocytes from the same group exhibited enriched expression of IFNAR1, IRF1, TNFA, and TLR4, with JAK1 expression being absent in some patients.

Conclusions:

• Differential gene expression in monocytes suggests distinct IFN pathway activation in RA patients with varying responses to TNFi.
• The identified gene expression patterns can help stratify RA patients based on their predicted response to TNFi.
• This research may inform the development of novel therapeutic strategies for TNFi non-responders in RA.