Antimyeloperoxidase antibodies modulate inflammatory responses and activate profibrotic pathways in human monocytes

Area of Science:

• Immunology
• Cell Biology
• Molecular Medicine

Background:

• Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is characterized by autoantibodies like antimyeloperoxidase (anti-MPO) and antiproteinase 3 (anti-PR3).
• Monocytes play a crucial role in the pathogenesis of AAV, but the specific effects of anti-MPO and anti-PR3 IgG on these cells are not fully understood.

Purpose of the Study:

• To investigate the distinct effects of anti-MPO and anti-PR3 IgG on human monocyte function and gene expression.
• To elucidate the role of Fc receptors, particularly CD32a, in mediating these effects.

Main Methods:

• Human peripheral blood monocytes were cultured with Toll-like receptor (TLR) agonists, anti-MPO IgG, and anti-PR3 IgG.
• Whole transcriptome profiling (RNA sequencing) was performed at 6 and 24 hours.
• Cell-surface marker expression, IL-10 secretion, and monocyte survival were assessed.
• Fc receptor involvement, specifically CD32a, was investigated.

Main Results:

• Anti-MPO IgG, but not anti-PR3 IgG, reduced IL-10 secretion and altered cell-surface marker expression upon TLR stimulation.
• Anti-MPO IgG enhanced monocyte survival independently of TLR stimulation, an effect dependent on CD32a.
• Transcriptional profiling revealed distinct responses to anti-MPO IgG, including enrichment of extracellular matrix genes at 24 hours without TLR stimulation.
• nCounter analysis confirmed key findings and the role of CD32a.

Conclusions:

• Anti-MPO IgG exerts significant, CD32a-dependent effects on human monocytes that differ markedly from anti-PR3 IgG.
• These findings suggest that anti-MPO IgG's activation of a profibrotic transcriptional program may contribute to distinct AAV disease phenotypes.