Background/Purpose:

It is widely reported that systemic lupus erythematosus (SLE) patients have an increased risk of atherosclerosis compared to the general population, irrespective of traditional risk factors. We investigated whether this was attributable to differences in the phenotype and function of invariant Natural Killer T cells (iNKT), which promote atherosclerosis by recognising and responding to lipid antigens presented by CD1d, yet have been shown to be deficient in SLE patients.

Methods:

Peripheral blood was obtained from 20 healthy donors and 50 SLE patients assessed for carotid and femoral atherosclerotic plaque by ultrasound scan. Phenotyping of iNKT cells and CD1d⁺antigen presenting cells was performed by flow cytomerty, confocal microscopy and ImageStream cytometry.

Results:

The frequency of iNKT cells in SLE patients with plaque (n=20) was maintained at healthy levels compared to a significant deficiency in non-plaque SLE patients (n=30). Following adjustment for disease activity, iNKT cells from plaque-positive patients had a distinct phenotype compared to healthy and plaque-negative patients, characterised by an increased expression of activation markers CD25 and CD69, chemokine receptor CCR6 and elevated IL-4 and IL-10 production. Furthermore patients with more lipid rich plaque showed enhanced IL-4, IL-8 and IL-10 production compared to those with stable calcified plaque.

The distinct iNKT cell phenotype of plaque-positive patients could be driven by differences in their activation by CD1d⁺ lipid-antigen presenting cells. CD1d expression was significantly reduced on B cells and pro-inflammatory CD14^low monocytes in all SLE patients compared to healthy donors. However, a significant increased association of CD1d to membrane lipid rafts was detected only in B cells and CD14^low monocytes from SLE patients with plaque. The defective iNKT cell phenotype and pattern of CD1d distribution identified in plaque-positive patients was recapitulated in cells from healthy donors by culture with serum isolated from plaque-positive SLE patients but not plaque-negative patients. Finally, we detected that altered activation of healthy iNKT cells could be driven in vitro by lipids isolated from CD1d⁺antigen presenting cells from SLE patients but not from healthy donors.

Conclusion:

These findings support a differential role for iNKT cells in the immunopathogenesis of SLE in patients with and without atherosclerosis that could be maintained by dylipidaemia. iNKT cell phenotype could represent a novel biomarker to predict atherosclerosis in SLE and could lead to improved treatment options for patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/systemic-lupus-erythematosus-patients-with-atherosclerosis-are-characterised-by-a-distinct-invariant-natural-killer-t-cell-phenotype-and-altered-cd1d-mediated-lipid-antigen-presentation/