Article Text

PDF
OP0086 Gene Profiling Reveals Specific Molecular Pathways in the Pathogenesis of Atherosclerosis and Cardiovascular Disease in Primary Antiphospholipid Syndrome, Systemic Lupus Erythematosus and Lupus with Antiphospholipid Syndrome
  1. P. Ruiz-Limon1,
  2. C. Pérez-Sánchez1,
  3. S. Messineo2,
  4. M. Á. Aguirre1,
  5. R. M. Carretero1,
  6. A. Rodriguez-Ariza1,
  7. N. Barbarroja1,
  8. M. Khamashta3,
  9. E. Collantes1,
  10. M. J. Cuadrado3,
  11. C. López-Pedrera1
  1. 1Rheumatology Service, IMIBIC/Reina Sofia Hosp., Cordoba, Spain
  2. 2Dipartimento di Scienze della Salute, Universitá Magna Graecia di Catanzaro, Catanzaro, Italy
  3. 3Lupus Unit, St Thomas Hospital, London, United Kingdom

Abstract

Background Systemic lupus erythematosus (SLE) is characterized by immune-mediated inflammation in multiple organ systems. SLE, primary Antiphospholipid syndrome (APS) and secondary APS (SAPS) share several clinical features, including atherosclerosis (AT) and cardiovascular disease (CVD), but also have some unique distinguishing characteristics.

Objectives To identify shared and differential molecular pathways involved in the pathogenesis of AT and CVD in that autoimmune diseases.

Methods 127 patients (42 APS, 20 SAPS and 56 SLE) and 61 healthy donors were included. Microarray expression profiling was performed in samples of monocytes from these patients and real time RT-PCR of selected genes was used to validate microarray data. Some clinical and inflammatory parameters were also obtained.

Results Comparing to controls, the expression of 555, 1224, and 518 genes were found significantly altered in monocytes from SLE, SAPS, and APS patients, respectively. On the other hand, 1243 genes were differentially regulated in APS vs. SLE, and 605 genes in SAPS vs. SLE. Interestingly, only 220 genes were differentially regulated when comparing APS with SAPS. Approximately 25-30% of the total number of altered genes in the three diseases were related to AT, inflammation and CVD (chemoquines/cytokines and their receptors, molecules related to angiogenesis, oxidative stress, mitochondrial dynamics and metabolism, lipid metabolism and cell to cell signalling). A specific AT/CVD/Inflammation-related gene signature was found for each disease. Thus, compared to LES, APS showed alterations in mitochondria biogenesis and function, oxidative stress and antioxidant defense. Besides the interferon signature found SAPS and SLE patients, a number of genes mediating atherosclerotic/inflammatory signalling were found further altered in SAPS.

Coexistence of APS and presence of aPL are risk factors for subclinical AT and CVD development in SLE. Thus, we further searched for a link between markers of AT, inflammation, and CVD, and the presence of aPL. Multivariate analysis showed that IgG aCL titers independently predicted both atherosclerotic and thrombosis in SAPS. Moreover, a higher percentage of SAPS showed increased carotid intimate media thickness than LES patients. We further found a significant correlation of IgG-aCL titers with circulating levels of inflammatory molecules (tPA, MCP-1, TNFα, and IL-2). Futhermore, in vitro treatment of isolated monocytes with IgG-aCL promoted a significant increase in the expression of the genes most significantly altered in SAPS vs healthy donors, including CCL2, CCL8, ARHGEF5, IFIT1 and PPARG).

Conclusions 1) Gene expression profiling allows the segregation of APS, SAPS and SLE, with specific signatures explaining the pro-atherosclerotic, pro-thrombotic and inflammatory changes in these highly related autoimmune diseases. 2) The identification of key genes regulating specific pathophysiologic pathways will permit the development of targeted therapies for each autoimmune condition.

Acknowledgements Supported by, P08-CVI-04234, and PI12/01511.

Disclosure of Interest None Declared

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.