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Abstract Number: 1449

Altered Splicing in Leukocytes from Patients with Antiphospholipid Syndrome, Systemic Lupus Erythematosus and Antiphospholipid Syndrome with Lupus: Clinical Involvement

Alejandra Maria Patiño-Trives1, Alejandro Ibáñez-Costa2, Carlos Pérez-Sánchez1, Laura Pérez-Sanchez3, Maria Luque-Tevar1, Iván Arias de la Rosa1, María-Carmen Abalos-Aguilera1, Desirée Ruiz-Vilchez4, Pedro Segui5, Mario Espinosa5, Nuria Barbarroja1, Eduardo Collantes4, Justo P. Castaño5, Raul M Luque5, María de los ángeles Aguirre-Zamorano5 and Chary Lopez-Pedrera1, 1Rheumatology Department, Reina Sofia University Hospital/ Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/ University of Cordoba, Cordoba, Spain, Cordoba, Spain, 2IMIBIC/University of Cordoba/Reina Sofia Hospital, Córdoba, 3Hospital Universitario Reina Sofía, Córdoba, Spain, 4Rheumatology Department, Reina Sofia University Hospital/ Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/ University of Cordoba, Cordoba, Spain, Córdoba, Spain, 5IMIBIC/University of Cordoba/Reina Sofia Hospital, Cordoba

Meeting: ACR Convergence 2020

Keywords: autoimmune diseases, Comorbidity, cytokines, Lupus nephritis, lupus-like disease

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Session Information

Date: Sunday, November 8, 2020

Session Title: Antiphospholipid Syndrome (1447–1451)

Session Type: Abstract Session

Session Time: 4:00PM-4:50PM

Background/Purpose: To identify shared and differential changes in the splicing machinery of immune cells from antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE) and antiphospholipid syndrome with lupus (APS plus SLE) patients, and their involvement in the activity and clinical profile of these autoimmune disorders.

Methods: Monocytes, lymphocytes and neutrophils from 70 patients (14 APS, 36 SLE and 20 APS plus SLE) and 23 healthy donors (HD) were purified by immunomagnetic selection. Then, 45 selected elements of the splicing machinery were evaluated using a microfluidic qPCR array (Fluidigm). In parallel, extensive clinical/serological evaluation was performed, comprising renal, obstetric and cardiovascular (CV) involvement, along with autoantibodies and inflammatory molecules. Correlation/association studies and logistic models among those clinical and analytical parameters were developed. Mechanistic in vitro studies were performed by incubation of HD-leukocytes with purified aPL-IgG or anti-dsDNA-IgG. Overexpression of selected components was further performed to evaluate their role in the leukocytes’ activity.

Results: Compared with HD, 35, 31 and 14 splicing machinery components were differentially expressed in monocytes, lymphocytes and neutrophils, respectively, from SLE patients; 25, 17 and 21 on APS patients, and 18, 29 and 23 in APS plus SLE patients.

Although a number of spliceosome components were found commonly deranged in the leukocyte subsets of the three disorders, each disease displayed an specific alteration, further associated with distinctive clinical features. Hence, in APS, altered expression of PRPF8 was linked to heightened CV-risk factors (HTA and dyslipidemia), thrombotic recurrences, and the CV events number. In APS plus SLE patients, RNU4 and SF3B1 were associated to CV-related parameters (HTA, microvascular endothelial dysfunction and apoB/A ratio). Besides, levels of these spliceosome components correlated with those of several plasma inflammatory mediators.

Lastly, in SLE patients, levels of key splicing machinery components (RNU6, PRPF8, RAVER1 and TCERG1) were associated to positivity for anti-dsDNA, activity of the disease (SLEDAI), the inflammatory plasma profile, and enhanced CV-risk factors (carotid-intimae media thickness, endothelial dysfunction and atherogenic index), along with obstetric complications and nephropathy.

Finally, in vitro treatment of HD lymphocytes with aPL-IgG or anti-dsDNA-IgG changed specific spliceosome components found altered in vivo in the three autoimmune diseases. The overexpression of selected spliceosome components in leukocytes further modulated the expression of inflammatory cytokines.

Conclusion: 1) The splicing machinery is profoundly altered in leukocytes from APS, APS plus SLE and SLE patients, and closely related to the activity of these diseases, their autoimmune and inflammatory profiles. 2) The analysis of the splicing machinery allows the segregation of APS, APS plus SLE and SLE, with specific components explaining the CV risk and organ involvement in these highly related autoimmune diseases.

Funded by ISCIII (PI18/0837 and RIER RD16/0012/0015) co-funded with FEDER

Disclosure: A. Patiño-Trives, None; A. Ibáñez-Costa, None; C. Pérez-Sánchez, None; L. Pérez-Sanchez, None; M. Luque-Tevar, None; I. Arias de la Rosa, None; M. Abalos-Aguilera, None; D. Ruiz-Vilchez, None; P. Segui, None; M. Espinosa, None; N. Barbarroja, None; E. Collantes, Abbvie Inc, 5, 8, Amgen, 5, 8, Eli Lilly and Company, 5, 8, Janssen Pharmaceutical, 5, 8, MSD, 5, 8, Novartis, 5, 8, Pfizer Inc, 5, 8, UCB, 5, 8; J. Castaño, None; R. M Luque, None; M. Aguirre-Zamorano, None; C. Lopez-Pedrera, None.

To cite this abstract in AMA style:

Patiño-Trives A, Ibáñez-Costa A, Pérez-Sánchez C, Pérez-Sanchez L, Luque-Tevar M, Arias de la Rosa I, Abalos-Aguilera M, Ruiz-Vilchez D, Segui P, Espinosa M, Barbarroja N, Collantes E, Castaño J, M Luque R, Aguirre-Zamorano M, Lopez-Pedrera C. Altered Splicing in Leukocytes from Patients with Antiphospholipid Syndrome, Systemic Lupus Erythematosus and Antiphospholipid Syndrome with Lupus: Clinical Involvement [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/altered-splicing-in-leukocytes-from-patients-with-antiphospholipid-syndrome-systemic-lupus-erythematosus-and-antiphospholipid-syndrome-with-lupus-clinical-involvement/. Accessed April 11, 2021.
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