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SAT0029 Dectin-1 Mediates Aberrant Innate and Adaptive Immune Response in Patients with Systemic Lupus Erythematosus
  1. M.Y. Mok,
  2. I.K. Lam,
  3. Y. Lo,
  4. D. Luk,
  5. W.C. Lau,
  6. W.K. Chan
  1. Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong

Abstract

Background Dectin-1 is a c-type lectin receptor that signals via syk and is involved in anti-fungal immunity. Dectin-1 was found to trigger experimental inflammatory arthritis, and likely play a role in the pathogenesis of some autoimmune diseases.

Objectives To examine (1) dectin-1 expression on circulating CD14+ monocytes in patients with systemic lupus erythematosus (SLE), (2) the effects of dectin-1 stimulation in ROS production by lupus monocytes and (3) syk signaling and cytokine profile of dectin-1 stimulated lupus monocyte-derived dendritic cells (MDDCs).

Methods SLE patients with active and inactive diseases and healthy subjects were recruited. MDDCs were derived from peripheral monocytes in the presence of IL-4 and GM-CSF. Dectin-1 agonists including curdlan, zymosan and toll-like receptor agonists Pam3CSK4 (TLR2) and LPS (TLR4) were used to stimulate monocytes and/or MDDCs. Dectin-1, ROS and phosphorylated-syk (p-syk) were measured by flow cytometry. Cytokine profile was measured by and multi-bead immunoassay.

Results The percentage of dectin-1 expressing monocytes was significantly lower in active SLE patients (64.5±24.3%) compared to inactive patients (89.6±7.2%) and healthy controls (91.7±9.5%) (both p<0.001). The absolute count of dectin-1 expressing monocytes correlated significantly and inversely with SLEDAI (r=-0.40, p<0.001), anti-dsDNA antibody level (r=-0.29, p=0.004), C3 (r=0.35, p=0.001) and C4 (r=0.24, p=0.02). Despite this, ROS production upon stimulation by dectin-1 agonists was comparable between these 3 groups. Stimulation of dectin-1 led to activation and maturation of MDDCs with upregulation of HLA-DR and CD86 (all p<0.001). SLE MDDCs showed higher p-syk activation compared to normal MDDCs upon dectin-1 stimulation (6.0±2.0 vs 2.8±1.0%, p<0.001). Curdlan-stimulated MDDCs produced higher levels of IL-1β, IL-23 and TNF-α. Adding TLR2 agonist to curdlan, SLE MDDCs produced significantly higher level of IL-1β (327.1±51.5 vs 125.3±88.5, p=0.009) and IL-6 (median 39.8 vs 21.7, p=0.03) compared to normal MDDCs. Combination of TLR4 agonist and curdlan induced IL-12 and TNF-α in normal MDDCs whereas lupus MDDCs produced predominant IL-6 and TNF-α.

Conclusions Active SLE patients had significantly lower circulating dectin-1 expressing CD14+ monocytes which produced comparable level of ROS upon stimulation compared to inactive patients and healthy subjects. Dectin-1 agonists led to activation, maturation and higher p-syk activation in SLE MDDCs. Concomitant dectin-1 and TLR2 stimulation induced production of Th17 promoting cytokines, among which IL-1β and IL-6 were significantly higher in SLE compared to normal MDDCs.

Disclosure of Interest None declared

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