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Abstract Number: 899

Neutrophil Gene Signature and Low Density Granulocyte Subsets Associate with Coronary Plaque Burden and Vascular Inflammation in Systemic Lupus Erythematosus

Philip Carlucci1, Monica Purmalek1, Simantini Sakhardande1, Yenealem Temesgen-Oyelakin1, Amit K. Dey2, Aditya A. Joshi2, Joseph B. Lerman3, Alice Fike1, Michael Davis4, Hong-Wei Sun1, Jonathan H. Chung2, Martin P. Playford2, Pragnesh Mistry1, Gustavo Gutierrez-Cruz1, Stefania Dell'Orso1, Faiza Naz1, Heather Teague2, Zerai G. Manna5, Peter C. Grayson1, Mohammad Naqi1, Marcus Chen2, Sarfaraz A. Hasni1, Nehal N. Mehta2 and Mariana J. Kaplan1, 1NIH/NIAMS, Bethesda, MD, 2NIH/NHLBI, Bethesda, MD, 3NIH/CC, Bethesda, MD, 4NIH/NIAMS, Bethesda, IA, 5NIH/NIAMS, Bethesda, MD, Afghanistan

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: Atherosclerosis, neutrophils and systemic lupus erythematosus (SLE)

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Session Information

Date: Sunday, November 5, 2017

Session Title: 2017 Rheumatology Research Foundation Edmond L. Dubois, MD Memorial Lecture

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Systemic lupus erythematosus (SLE) increases a young woman’s risk of myocardial infarction by up to 50-fold. This marked increase in cardiovascular disease (CVD) risk is not explained by Framingham risk and is not well understood. It has been suggested that innate immune responses associated with aberrant neutrophils, known as low density granulocytes (LDGs), enhance CVD risk by promoting vascular damage due to their proinflammatory properties. LDGs may represent a heterogeneous population of neutrophils and the pathogenicity of various LDG subsets has not been characterized. In this study, we sought to explore the association of these cells with subclinical vascular disease.

Methods: SLE patients fulfilling ACR criteria and healthy controls underwent FDG-PET/CT scans to assess vascular inflammation as target-to-background ratio (TBR) and coronary CT angiogram for coronary plaque characterization. Total and non-calcified plaque burden were quantified using QAngio. Circulating LDGs and cholesterol efflux were measured by previously validated methods. RNA sequencing of whole blood was used to analyze the transcriptional profile of both patients and controls. A neutrophil gene signature was created by calculating a z-score for the most upregulated primary granule neutrophil genes (AZU1, MPO, CTSG, PRTN3, ELANE, DEFA3) found in patients with cardiovascular involvement.

Results: Compared to controls, SLE patients had significantly elevated aortic TBR (1.68±0.16 vs.1.59±0.14, p=0.007) and coronary non-calcified plaque burden (NCB) (0.86±0.33 vs. 0.76±0.19, p=0.022). We identified diverse subsets of LDGs based on maturation. The percentage of an immature subset of LDGs was significantly elevated in peripheral blood mononuclear cells in patients compared to controls (1.6 (3.2-0.47) vs. 0.35 (0.96-0.13), p<0.001). This immature subset associated with the primary granule neutrophil gene signature (β=0.844, p<0.001), TBR (β=0.34 p=0.015), and with NCB (β=0.31, p=0.001) in unadjusted analyses. The neutrophil gene signature also associated with NCB (β = 0.44, p<0.001). In addition, a mature subset of LDGs was present in SLE, which associated with TBR (β=0.23, p=0.02), NCB (β=0.31, p=0.002), and HDL efflux (β=-0.29, p=0.024), supporting previous work that suggests the enhanced neutrophil extracellular trap formation in mature LDGs impairs HDL efflux. These associations persisted after adjusting for traditional risk factors in multivariate analyses.

Conclusion: Patients with SLE have an increase in both aortic vascular inflammation and coronary plaque burden compared to controls. The associations of aberrant neutrophil subsets with this atherosclerotic phenotype support studies suggesting a pathogenic role for these cells in assaulting the vasculature and that targeting responses triggered by these cells may have potential therapeutic benefits.


Disclosure: P. Carlucci, None; M. Purmalek, None; S. Sakhardande, None; Y. Temesgen-Oyelakin, None; A. K. Dey, None; A. A. Joshi, None; J. B. Lerman, None; A. Fike, None; M. Davis, None; H. W. Sun, None; J. H. Chung, None; M. P. Playford, None; P. Mistry, None; G. Gutierrez-Cruz, None; S. Dell'Orso, None; F. Naz, None; H. Teague, None; Z. G. Manna, None; P. C. Grayson, None; M. Naqi, None; M. Chen, None; S. A. Hasni, None; N. N. Mehta, None; M. J. Kaplan, None.

To cite this abstract in AMA style:

Carlucci P, Purmalek M, Sakhardande S, Temesgen-Oyelakin Y, Dey AK, Joshi AA, Lerman JB, Fike A, Davis M, Sun HW, Chung JH, Playford MP, Mistry P, Gutierrez-Cruz G, Dell'Orso S, Naz F, Teague H, Manna ZG, Grayson PC, Naqi M, Chen M, Hasni SA, Mehta NN, Kaplan MJ. Neutrophil Gene Signature and Low Density Granulocyte Subsets Associate with Coronary Plaque Burden and Vascular Inflammation in Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/neutrophil-gene-signature-and-low-density-granulocyte-subsets-associate-with-coronary-plaque-burden-and-vascular-inflammation-in-systemic-lupus-erythematosus/. Accessed May 19, 2022.
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