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

Abstract

SummaryMonocyte subsets with differing functional properties have been defined by their expression of CD14 and CD16. We investigated these subsets in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) and determined their surface expression of ANCA autoantigens. Flow cytometry was performed on blood from 14 patients with active AAV, 46 patients with AAV in remission and 21 controls. There was no change in the proportion of monocytes in each subset in patients with AAV compared with healthy controls. The expression of CD14 on monocytes from patients with active AAV was increased, compared with patients in remission and healthy controls (P < 0Á01).Patients with PR3-ANCA disease in remission also had increased monocyte expression of CD14 compared with controls (P < 0Á01); however, levels in patients with MPO-ANCA disease in remission were lower than active MPO-ANCA patients, and not significantly different from controls. There was a correlation between CD14 and both PR3 and MPO expression on classical monocytes in AAV patients (r 5 0Á79, P < 0Á0001 and r 5 0Á42, P < 0Á005, respectively). In conclusion, there was an increase in monocyte CD14 expression in active AAV and PR3-ANCA disease in remission. The correlation of CD14 expression with ANCA autoantigen expression in AAV may reflect cell activation, and warrants further investigation into the potential for increased CD14 expression to trigger disease induction or relapse.

The role of monocytes in ANCA-associated vasculitides

“…Hattar et al [52] for example, found that pre-incubation of monocytes with anti-PR3 antibodies increased the production of IL-8, TNFα and IL-6 in response to LPS, and of IL-8 upon stimulation with lipoteichoic acid (LTA), constituents of the Gram-negative outer membrane and Gram-positive cell wall respectively. This effect seems to depend on the ANCA-mediated upregulation of the TLR4 co-receptor CD14 [52], an observation recently confirmed in vivo by Tarzi et al [26] who described raised levels of CD14 on circulating monocytes from PR3 patients both during active disease and in remission. Moreover CD14 expression correlated with ANCA antigen expression on monocytes of AAV patients, showing a stronger correlation with PR3 than MPO.…”

“…Monocyte subsets in the context of human disease have been explored, and recent evidence has highlighted the possible role of the intermediate population in autoimmune disorders such as rheumatoid arthritis [25]. Observations from Tarzi et al [26] in our laboratory have also revealed differences in ANCA antigen expression between monocyte subsets in AAV patients and healthy controls, showing that classical and intermediate monocytes display the highest levels of PR3, whereas MPO is more highly expressed on intermediate monocytes. In AAV patients, both PR3 and MPO expression correlate with expression of CD14.…”

“…The results described above suggest that both LPS stimulation during infections, and ANCA challenge in AAV, may use CD14 as a common mechanism of monocyte activation. The persistent up-regulation of CD14 on monocytes in PR3-AAV patients in remission may reflect a long-lasting activation of monocytes in GPA sustained by persistent nasal/upper airway infection, thereby predisposing GPA patients to more frequent relapses than in MPA [26]. Increased monocyte CD14 levels may also have particular relevance to the recently described increased level of the TLR4 ligand, calprotectin, in AAV patients [39].…”

“…Soluble monocyte activation markers, such as MCP1α and VEGF, that reflect systemic chemotactic and inflammatory activity and endothelial activation, show significantly higher levels in patients with acute disease [32]. Monocyte CD11b up-regulation has been shown to persist in quiescent phases of disease [32], and recent studies have demonstrated that monocytes from patients with active AAV, as well as from PR3 positive patients in remission, express increased levels of CD14, suggesting that these cells may be more susceptible to TLR4mediated activation [26]. It could therefore be argued that a certain degree of monocyte activation persists during remission, which may account for the relapsing-remitting character of GPA.…”

“…CD14 and calprotectin are involved in the crosstalk between immune responses to infections and autoimmunity, and may play a pivotal role in the amplification of uncontrolled inflammation in AAV. Both of these molecules remain upregulated in AAV in remission [26,39]. Anti-CD14 monoclonal antibodies (MAb) treatments, alone or coupled with complement inhibition, are being investigated in the intensive care setting as a method of reducing the uncontrolled inflammatory response and its detrimental effects in severe sepsis [58,59,60] and their effect in AAV may be worth investigating.…”