Phagocytosis of apoptotic cells by macrophages in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis

Abstract

Summary Anti‐neutrophil cytoplasmic antibody (ANCA)‐associated vasculitis (AAV) is a group of autoimmune diseases, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). It is not known why ANCA develop, but it has been shown that they participate in pathogenesis by activating polymorphonuclear neutrophils (PMNs). In this study we hypothesize that dysregulation of phagocytosis in AAV leads to the accumulation of apoptotic neutrophils seen in association with blood vessels in AAV. These cells progress into secondary necrosis, contributing to tissue damage and autoantibody formation. Peripheral blood cells were counted, and phagocytosis was investigated using monocyte‐derived macrophages (MØ) and PMNs from healthy blood donors (HBD), AAV patients and systemic lupus erythematosus (SLE) patients. Furthermore, the effect of serum was assessed. Phagocytosis was measured using flow cytometry. The results showed no deviation in monocyte subpopulations for AAV patients compared to HBDs, although there was a decrease in lymphocyte and pDC (plasmacytoid dendritic cell) populations (4·2 × 106 cells/l versus 10·4 × 106 cells/l, P < 0·001). The number of neutrophils was increased (6·0 × 109 cells/l versus 3·8 × 109 cells/l, P < 0·001). There were no differences found in the ability of MØs to engulf apoptotic cells, nor when comparing apoptotic PMNs to become engulfed. However, serum from AAV donors tended to decrease the phagocytosis ability of MØs (36%) compared to serum from HBDs (43%). In conclusion, there is no intrinsic dysfunction in the MØs or in the PMNs that have an effect on phagocytic activity, but ANCA may play a role by decreasing phagocytic ability.

CD14 expression is increased on monocytes in patients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis and correlates with the expression of ANCA autoantigens

“…However, there was a statistically significant increase in the overall absolute numbers of monocytes in patients with active AAV compared with patients in remission. In agreement with our results, previous studies examining patients with AAV in remission also found no change in the proportion of monocyte subsets in AAV . As intermediate monocytes express ANCA antigens and activatory Fcγ receptors, and are known to be major secretors of proinflammatory cytokines such as TNF‐α , it is a little surprising that this cell type is not relatively increased in AAV.…”

“…The non‐classical population accounts for approximately 7–10% of circulating monocytes in healthy individuals, and evidence would suggest that these cells patrol the endothelium and respond to viral antigens . Studies have demonstrated a significantly increased proportion of intermediate monocytes in various inflammatory conditions, such as in patients with rheumatoid arthritis or patients at high cardiovascular disease risk , and studies have examined some data on the monocyte populations in AAV patients .…”

A myelopoiesis gene signature during remission in anti-neutrophil cytoplasm antibody-associated vasculitis does not predict relapses but seems to reflect ongoing prednisolone therapy

“…The percentage of LDGs has been reported to be as high as 17% [42]. LDGs have never been described in AAV, and in our previous studies on monocyte subpopulations in AAV we did not detect any contaminations of neutrophils in that range [23,46]. The PBMC fraction of patients and controls in our present study was more than 99% pure according to flow cytofluorometry analysis.…”

High-Dimensional Profiling Reveals Heterogeneity of the Th17 Subset and Its Association With Systemic Immunomodulatory Treatment in Non-infectious Uveitis

“…We confirmed a decrease in the proportion of circulating plasmacytoid (p)DCs in human non-infectious uveitis, but were unable to ascertain a significant increase in CD1c-positive myeloid DCs (mDC1) ( 16 , 46 , 47 ). This is likely to be explained due to a different uveitis population.…”