Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Systemic lupus erythematosus (SLE) patients have an increased risk of developing clinically apparent cardiovascular disease (CVD) and subclinical atherosclerotic plaque, detectable by vascular ultrasound (US). Although dyslipidaemia and immune dysfunction are widely described in SLE, their role in atherosclerosis is unclear. We propose that invariant Natural Killer T (iNKT) cells, which respond to lipid antigens presented by CD1d on antigen presenting cells, play a key role in linking the immune system, lipids and CVD in SLE patients. We observed differential defects in iNKT cell number and function in SLE patients with and without pre-clinical atherosclerosis (SLEP), a condition associated with altered lipid homeostasis. Here we investigate how cellular lipid metabolism influences CD1d-lipid antigen presentation in SLE and how this is altered in SLEP.
Methods: Vascular US on 100 patients with SLE but no history of CVD showed 36 had plaque (SLEP) and 64 had no plaque (SLENP). Blood from 40 SLENP, 34 SLEP and 28 female healthy controls (HCs) (mean age 39) was used to assess monocyte and B cell phenotype. Expression and colocalization of CD1d and lipid rafts (LR, plasma membrane signalling platforms), kinetics of immune synapse formation, and subsequent invariant T cell receptor (iTCR) signalling were assessed by flow cytometry and ImageStream. Expression of genes regulating cellular and membrane lipid content were analyzed using qPCR.
Results: LR expression was increased (p=0.01) and CD1d expression reduced (p=0.01) on B cells from SLE patients compared to HCs. This was associated with increased accumulation of CD1d within LRs in SLE compared to HC B cells (p=0.009). Conversely, no differences in LR and CD1d expression and location were detected in monocytes from HCs or SLE patients. The location of CD1d in relation to LRs can influence the potency of iNKT cell activation. We found that monocytes formed more stable interactions with iNKT cells compared to B cells (p=0.005); these interactions were more rapid between iNKT cells and monocytes from SLEP compared to SLENP patients and HCs and translated to significantly increased iTCR-z phosphorylation in SLEP-monocyte/iNKT cell conjugates (p=0.05). B cell-iNKT cell interactions were reduced in all SLE patients compared to HCs and resulted in altered down-stream iTCR signalling. Since LRs were unaltered in monocytes, we hypothesized that monocyte intracellular and/or CD1d lipid content may be different in SLE patients. mRNA expression of liver X receptor-α and its target genes (a transcriptional program which decreases cellular cholesterol) were decreased in monocytes from SLE patients (p=0.008) favouring accumulation of intracellular lipids. Furthermore monocyte phospholipid content was increased by culture with serum from SLEP compared to SLENP patients.
Conclusion: We propose that monocytes and B cells interact with iNKT cells differently. B cell-iNKT interactions are perturbed in all SLE patients and are associated with altered LR localization. In the setting of pre-clinical atherosclerosis changes in circulating lipids alter monocyte lipid metabolism and the nature of CD1d-lipid antigen they present.
To cite this abstract in AMA style:Waddington K, Smith E, Croca S, Isenberg DA, Rahman A, Pineda Torra I, Jury E. Distinct Metabolic Pathways Regulate Lipid Antigen Presentation By Monocytes and B Cells: Implications for SLE Patients with Pre-Clinical Atherosclerotic Plaque [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/distinct-metabolic-pathways-regulate-lipid-antigen-presentation-by-monocytes-and-b-cells-implications-for-sle-patients-with-pre-clinical-atherosclerotic-plaque/. Accessed August 4, 2021.
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