IgG Immunocomplexes Sensitize Human Monocytes for Inflammatory Hyperactivity via Transcriptomic and Epigenetic...

Area of Science:

• Immunology
• Rheumatology
• Molecular Biology

Background:

• Circulating immune complexes (ICs) correlate with rheumatoid arthritis (RA) prevalence.
• IgG-ICs are abundant in RA joints, but their pathogenic mechanisms are unclear.

Purpose of the Study:

• To investigate the molecular mechanisms by which IgG-ICs contribute to RA pathogenesis.
• To determine if IgG-ICs can induce a sustained inflammatory state in monocytes and macrophages.

Main Methods:

• Precipitation of IgG-ICs from RA sera and their application to human monocytes.
• In vitro sensitization of monocytes using plate-coated human IgG.
• Transcriptomic and epigenetic analysis of sensitized monocytes.
• Gene expression profiling of macrophages from RA patients' synovium.

Main Results:

• RA serum-derived IgG-ICs sensitized human monocytes to a long-lasting inflammatory state, marked by TNF-α response.
• Plate-coated human IgG mimicked this sensitization, inducing transcriptomic and epigenetic changes.
• Macrophages from RA patients showed gene expression profiles similar to IC-sensitized monocytes, suggesting in vivo priming.

Conclusions:

• IgG-ICs can sustainably reprogram monocytes and macrophages towards inflammation.
• This immune cell sensitization by IgG-ICs may play a critical role in rheumatoid arthritis development.