96. Disrupted LFA-1/ICAM-1 axis in intermediate monocytes from patients with active ANCA vasculitis
Creators: name: Herrera1, Carolina A.
name: Dominic Ciavatta1,
name: Free1, Meghan
name: J. Charles Jennette1
name: Falk1, Ronald
Publisher: name: Zenodo
Year: 2022
Subjects: Vasculitis
ANCA
Abstracts
Giant Cell Arthritis
MPA
GPA
EGPA
Takayasu
IgA vasculitis

description: <strong>Background:</strong> Monocytes migrate to tissues via chemotactic gradients and contribute to the development of inflammation and organ damage in ANCA vasculitis. One specific signaling axis involved in monocyte trafficking and adhesion is the LFA-1/ICAM-1 axis. Monocytes expressing lymphocyte function-associated antigen-1 (LFA-1) bind to the intracellular adhesion receptor 1 (ICAM-1), facilitating endothelial adhesion, however monocytes are heterogeneous and the involvement of LFA-1/ICAM-1 in different monocytes subsets (classical CD14<sup>+</sup>CD16<sup>-</sup>, intermediate CD14<sup>+</sup>CD16<sup>+</sup>, non-classical CD14<sup>dim</sup>CD16<sup>+</sup>) remains unexplored in ANCA vasculitis. Since monocyte subsets are phenotypically and functionally different, we aimed to investigate the involvement of the LFA-1/ICAM-1 in different monocyte subsets during ANCA vasculitis relapse and remission. We hypothesize that the LFA-1/ICAM-1 axis is disrupted in intermediate (pro-inflammatory) monocytes during active ANCA vasculitis. <strong>Methods:</strong> Peripheral blood mononuclear cells (PBMCs) were isolated from 53 ANCA vasculitis patients and 31 healthy controls who were enrolled according to IRB guidelines. Patients were diagnosed according to the Chapel Hill Consensus Conference and disease activity was assigned based on the Birmingham Vasculitis Activity Score. Peripheral blood and urinary monocyte subset frequencies and monocyte LFA-1 surface protein expression were quantified by flow cytometry. Serum and urinary soluble ICAM-1 (sICAM-1) levels were measured by ELISA. <strong>Results:</strong> We found that intermediate monocytes are elevated in ANCA vasculitis patients with active disease (p=0.0004) and exhibit decreased surface expression of LFA-1 (p=0.008) compared to healthy controls. Additionally, sICAM-1 levels were significantly increased in the serum of ANCA vasculitis patients with active renal disease compared to patients in remission (p=0.003) and healthy controls (p=&lt;0.0001). In paired serum from longitudinal ANCA vasculitis active and remission pairs, sICAM-1 levels were significantly elevated during active disease compared to remitting disease (p=0.0008). Furthermore, we found a positive correlation between the frequency of intermediate monocytes expressing LFA-1 and levels of circulating sICAM-1 (r=0.77, p=0.004). Lastly, the percentage of urinary monocytes was elevated in ANCA vasculitis patients compared to healthy controls (p=&lt;0.0001), and urinary sICAM-1 levels were elevated in active ANCA vasculitis patients with disease flare compared to healthy controls (p=0.034). <strong>Conclusions:</strong> An increased frequency of intermediate monocytes during active disease and decreased surface expression of LFA-1 on intermediate monocytes in the periphery are consistent with shedding of LFA-1 during disease flare. Elevated sICAM-1 levels in the circulation and in the urine during active disease suggest recruitment of monocytes to sites of inflammation and point to an increased shedding of endothelial membrane-bound ICAM-1 from inflamed tissues. The positive correlation between LFA-1<sup>+</sup> intermediate monocytes and circulating levels of sICAM-1 suggests an expansion of intermediate monocytes and increased recruitment of these cells to tissues during disease flare. These data support the active involvement of intermediate monocytes during disease relapse and propose an important role for the LFA-1/ICAM-1 axis in the recruitment of intermediate monocytes to sites of inflammation. Intermediate monocytes and/or the LFA-1/ICAM-1 axis may serve as potential therapeutic targets to inhibit migration of pro-inflammatory intermediate monocytes, ameliorating tissue inflammation and damage in ANCA vasculitis. <strong>Disclosures</strong>: None <strong>Figure 1.</strong> Serum sICAM-1 ELISA. Correlation of %LFA-1<sup>+</sup> intermediate (CD14<sup>+</sup>CD16<sup>+</sup>) monocytes and serum sICAM-1. ANCA vasculitis patients N=12. Statistics: Linear regression analysis and Pearson correlation.