Abstract
Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis is characterized by the presence of autoantibodies to myeloperoxidase and proteinase-3, which bind monocytes in addition to neutrophils. While a pathological effect on neutrophils is acknowledged, the impact of ANCA on monocyte function is less well understood. Using IgG from patients we investigated the effect of these autoantibodies on monocytes and found that anti-myeloperoxidase antibodies (MPO-ANCA) reduced both IL-10 and IL-6 secretion in response to LPS. This reduction in IL-10 and IL-6 depended on Fc receptors and enzymatic myeloperoxidase and was accompanied by a significant reduction in TLR-driven signaling pathways. Aligning with changes in TLR signals, oxidized phospholipids, which function as TLR4 antagonists, were increased in monocytes in the presence of MPO-ANCA. We further observed that MPO-ANCA increased monocyte survival and differentiation to macrophages by stimulating CSF-1 production. However, this was independent of myeloperoxidase enzymatic activity and TLR signaling. Macrophages differentiated in the presence of MPO-ANCA secreted more TGF-β and further promoted the development of IL-10– and TGF-β–secreting CD4+ T cells. Thus, MPO-ANCA may promote inflammation by reducing the secretion of antiinflammatory IL-10 from monocytes, and MPO-ANCA can alter the development of macrophages and T cells to potentially promote fibrosis.
Highlights
Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis is a systemic disease with clinical manifestations that include crescentic glomerulonephritis and pulmonary hemorrhage [1]
With LPS, while we did not observe an effect of MPO-ANCA on IL-8 and MIP-1α production by monocytes, and its effects on TNF-α and IL-1β production were variable among donors, both IL-6 and IL-10 were consistently and significantly decreased by MPO-ANCA across all 5 donors, with the most profound effect seen for IL-10
We have discovered some effects of MPO-ANCA on human monocytes with potential implications for pathogenesis in ANCA vasculitis
Summary
Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis is a systemic disease with clinical manifestations that include crescentic glomerulonephritis and pulmonary hemorrhage [1]. The name ANCA vasculitis reflects the fact that it is characterized by autoantibodies against neutrophils [2]. These autoantibodies bind to the proteins myeloperoxidase (MPO) [3] or proteinase-3 (PR3) [4], which are found within granules in neutrophils and in monocytes. In vivo support for the pathogenicity of ANCA is provided by studies in which injection of anti-MPO antibodies causes focal necrotizing crescentic glomerulonephritis in mice in a neutrophildependent manner [7, 8]. The effects of ANCA on MPO- and PR3-expressing monocytes have received far less attention
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