Background/Purpose: The MHC class I-related chain A (MICA) is a major ligand for the NKG2D receptor of NK and CD8 T cells. MICA expression at the cell surface is triggered by environmental stressors and label malfunctioning cells for their recognition by cytotoxic cells, which is followed by activation of programmed death in the MICA-labeled cells and their subsequent clearance by the immune system. Alterations in this recognition and also abnormal NK functions have been associated to defective apoptosis in SLE. The disruption of the MICA expression pathway is a major immune escape strategy of virus-infected or transformed cells to avoid immune surveillance. MICA can be shed from the cell surface and act as a soluble decoy receptor (sMICA) for cytotoxic cells. Our objective was to study circulating sMICA levels in relationship with innate molecular processes and clinical features in a cohort of patients with lupus.

Methods: 36 patients diagnosed with SLE and 13 healthy controls were recruited for a cross-sectional study. Circulating mononuclear cells were characterized by flow cytometry, and individual populations of monocytes, T and B lymphocytes were purified with magnetic bead sorting (Miltenyi MACS) for gene expression studies. A commercial ELISA (Diaclone) was used for detection of sMICA. Data are shown as median (CI95). The statistical analysis was done with non-parametric tests. An alpha value of 5% was considered significant.

Results: Globally, no differences in sMICA levels were found between patients and controls. However, in the lupus cohort, sMICA correlated with BILAG (ρ 0.428, p 0.023) and with SLEDAI scores (ρ 0.378, p 0.047). Interestingly, the up-regulation of sMICA was inversely associated to circulating NK counts (p 0.07), which were significantly lower in patients than in controls, and further decreased during active disease (p 0.01). Levels of sMICA were particularly high in patients with active nephritis [aLN: 6.0 ng/ml (4.23-7.74), iLN 3.36 ng/ml (2.23-4.67) (p 0.029 vs aLN), healthy controls 3.0 ng/ml (1.66 – 4.39) (p 0.012 vs aLN)]. Furthermore, sMICA correlated with proteinuria (ρ 0,52, p 0.004) and with plasma creatinine (ρ 0.421, p 0.026). On the other hand, no association was observed with dsDNA antibodies or with complement levels. As regards activation of monuclear cell subpopulations, sMICA levels were associated with the up-regulation of TLR2 (p 0.002) and TLR4 (p 0.003) in T lymphocytes, as well as with the transcripts of the interferon sensitive genes IFIT1 (p 0.035) and HERC5 (p 0.018) in these cells. An inverse association between sMICA and MICA gene expression levels in B lymphocytes approached significance (p 0.08).

Conclusion: Our data support an impairment in NK functions in active lupus, and a tight association between kidney flares and the up-regulation of sMICA. This molecule could come either from the innate activation of kidney cells or from PBMCs shedding. Disruption of the MICA pathway could account for a complement-unrelated process of damage in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/circulating-soluble-mica-is-associated-to-lupus-nephritis-and-to-a-tlr-ifn-i-signature-in-t-cells-in-a-cohort-of-adult-sle-patients/